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Progress in the Management of Advanced Thoracic Malignancies in 2017

Open ArchivePublished:January 10, 2018DOI:https://doi.org/10.1016/j.jtho.2018.01.002

      Abstract

      The treatment paradigm of NSCLC underwent a major revolution during the course of 2017. Immune checkpoint inhibitors (ICIs) brought remarkable improvements in response and overall survival both in unselected pretreated patients and in untreated patients with programmed death ligand 1 expression of 50% or more. Furthermore, compelling preliminary results were reported for new combinations of anti–programmed cell death 1/programmed death ligand 1 agents with chemotherapy or anti–cytotoxic T-lymphocyte associated protein 4 inhibitors. The success of the ICIs appeared to extend to patients with SCLC, mesothelioma, or thymic tumors. Furthermore, in SCLC, encouraging activity was reported for an experimental target therapy (rovalpituzumab teserine) and a new chemotherapeutic agent (lurbinectedin). For oncogene-addicted NSCLC, next-generation tyrosine kinase inhibitors (TKIs) (such as osimertinib or alectinib) have demonstrated increased response rates and progression-free survival compared with first-generation TKIs in patients with both EGFR-mutated and ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC. However, because of the lack of mature overall survival data and considering the high efficacy of these drugs in patients with NSCLC previously exposed to first- or second-generation TKIs, definitive conclusions concerning the best treatment sequence cannot yet be drawn. In addition, new oncogenes such as mutant BRAF, tyrosine-protein kinase met gene (MET) and erb-b2 receptor tyrosine kinase 2 gene (HER2), and ret proto-oncogene (RET) rearrangements have joined the list of potential targetable drivers. In conclusion, the field of thoracic oncology is on the verge of a breakthrough that will open up many promising new therapeutic options for physicians and patients. The characterization of biomarkers predictive of sensitivity or resistance to immunotherapy and the identification of the optimal therapeutic combinations (for ICIs) and treatment sequence (for oncogene-addicted NSCLC) represent the toughest upcoming challenges in the domain of thoracic oncology.

      Keywords

      Introduction

      The year 2017 was one of the most active regarding the field of thoracic malignancy therapeutics. Immune checkpoint inhibitors (ICIs), in particular, anti–cytotoxic T-lymphocyte associated protein 4 (CTLA4) and anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) agents (Fig. 1A and B), represent the most important recent developments in the management of thoracic tumors. Their role in patients with previously treated advanced NSCLC was consolidated, and they also emerged as key players in patients with untreated advanced NSCLC as monotherapy or in combination. Additionally, at least five early studies showed promising results for ICIs in patients with previously treated advanced SCLC,
      • Ott P.A.
      • Elez E.
      • Hiret S.
      • et al.
      Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study.
      thymic epithelial tumors,
      • Heery C.R.
      • O’Sullivan-Coyne G.
      • Madan R.A.
      • et al.
      Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.
      • Cho J.
      • Ahn M.J.
      • Yoo K.H.
      • et al.
      A phase II study of pembrolizumab for patients with previously treated advanced thymic epithelial tumor.
      and mesothelioma.
      • Alley E.W.
      • Lopez J.
      • Santoro A.
      • et al.
      Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
      • Zalcman G.
      • Mazieres J.
      • Greillier L.
      • et al.
      Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: updated results of the IFCT-1501 MAPS2 randomized phase II trial.
      In the field of precision medicine, besides EGFR, ALK receptor tyrosine kinase gene (ALK), and BRAF molecular alterations (Fig. 2), recently emerged new potentially actionable targets included ret proto-oncogene (RET) rearrangements and mutations in erb-b2 receptor tyrosine kinase 2 gene (HER2) and EGFR exon 20. Next-generation tyrosine kinase inhibitors (TKIs) proved to be more active than first-generation drugs in patients with EGFR-mutated
      • Soria J.-C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      and ALK-rearranged
      • Hida T.
      • Nokihara H.
      • Kondo M.
      • et al.
      Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.
      • Peters S.
      • Camidge D.R.
      • Shaw A.T.
      • et al.
      Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.
      NSCLC, although definitive conclusions cannot be drawn about the best treatment sequence able not only to improve progression-free survival (PFS) but also to positively affect overall survival (OS). In this review we cover the main advances regarding immunotherapy, targeted therapy, and chemotherapy in patients with NSCLC, for both pretreated and treatment-naive populations, with a particular focus on targeted therapies. Figure 3 presents current standard therapies and sequences in NSCLC treatment and highlights new options. Studies with targeted therapies and chemotherapy in SCLC, mesothelioma, and thymic tumors are also summarized.
      Figure thumbnail gr1
      Figure 1Mechanisms of action of cytotoxic T-lymphocyte associated protein 4 (CTLA4) (A) and programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) (B) inhibitors in different phases of the anticancer immune response. MHC, major histocompatibility complex; Ag, antigen; mAb, monoclonal antibody; TCR, T-cell receptor; PD-L2, programmed death ligand 2.
      Figure thumbnail gr2
      Figure 2Intracellular signalling pathways activated by EGFR mutations, ALK receptor tyrosine kinase gene (ALK) rearrangements, and KRAS/BRAF mutations. EGF, epidermal growth factor; Grb2, growth factor receptor bound protein 2; mut, mutated; STAT, signal transducer and activator of transcription; EML4, echinoderm microtubule associated protein like 4; TKI, tyrosine kinase inhibitor; ALK, anaplastic lymphoma kinase; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin.
      Figure thumbnail gr3
      Figure 3Novel therapeutic options (green for phase III and orange for phase I/II trials) adding to the current standard of care in patients with advanced NSCLC. Immuno, immunotherapy; mut, mutated; ALK, anaplastic lymphoma kinase; MET, tyrosine-protein kinase met; NTRK, neurotrophic receptor tyrosine kinase; CT, chemotherapy; PD-L1, programmed death ligand 1; TC, tumor cell; IC, immune cell; RET, ret proto oncogene; HER2, erb-b2 receptor tyrosine kinase 2; Beva, bevacizumab; Pembro, pembrolizumab.

      Methods for Selection of the Studies

      We reviewed MEDLINE/PubMed for citations from January 2017 up to December 2017; our search terms included lung cancer, pleural mesothelioma, thymic malignancies, immune checkpoint inhibitors, PD-1/PD-L1 inhibitors, CTLA4 inhibitors, targeted therapy, and chemotherapy. We also used the same terms to search abstracts and virtual meeting presentations from the 2017 European Society of Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) conferences, the World Conference on Lung Cancer, and the ESMO Immuno Oncology Congress to identify relevant studies. The search included both clinical trials and cohort studies involving patients with thoracic malignancies, regardless of histologic type, treatment, and therapy line.

      Advances in Advanced NSCLC: Immunotherapy

      Pretreated Patients

      The year 2017 saw the efficacy of PD-1/PD-L1 inhibitors unequivocally established in patients with pretreated advanced NSCLC. Considering that a subset of patients with NSCLC treated with ICIs experience very prolonged OS, follow-up data from ICI studies are now of paramount importance. An update of the phase I CA209-003 trial testing nivolumab in 129 patients with previously treated (1–5 prior lines) NSCLC showed that with 58 months of follow-up, the 5-year OS rate was 16% for patients with squamous cell carcinoma and 15% for patients with nonsquamous cell carcinoma, and the median OS was 9.9 months. No clinical or pathological characteristics correlated with response in the 16 patients who survived more than 5 years.
      • Brahmer J.
      • Horn L.
      • Jackman D.
      • et al.
      Abstract CT077. Five-year follow-up from the CA209–003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): clinical characteristics of long-term survivors.
      Given the long survival in this population, the duration of treatment has become a major topic of debate. In a recent phase III/IV trial (CheckMate 153), continuous nivolumab therapy was compared with observation after 1 year of nivolumab therapy in 220 patients with NSCLC. PFS was better in patients receiving continuous treatment than in those who stopped taking it after 1 year (not reached [NR] versus 10.3 months, hazard ratio [HR] = 0.42, 95% confidence interval [CI]: 0.25–0.71). The OS data are still immature, although a trend favoring continuous treatment was observed, with an HR of 0.63 (95% CI: 0.33–1.20).
      • Spiegel D.R.
      • McLeod M.
      • Hussain M.A.
      • et al.
      Randomized results of fixed-duration (1-yr) vs continuous nivolumab in patients (pts) with advanced non-small cell lung cancer (NSCLC).
      The authors proposed that ICIs be used until progression, but additional data are needed to draw definitive conclusions concerning the optimal duration of treatment with PD-1/PD-L1 inhibitors.
      Several other ICIs were shown to improve outcome in pretreated NSCLC. The phase III OAK trial assessed the efficacy of atezolizumab versus that of docetaxel in patients with NSCLC in second or later lines.
      • Rittmeyer A.
      • Barlesi F.
      • Waterkamp D.
      • et al.
      Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
      The primary efficacy analysis was performed in 850 patients. The coprimary end points were OS rates in the overall population and in patients with PD-L1 expression of 1% or more tested on tumor cells (TCs) or immune cells (ICs) (TC1/2/3 or IC1/2/3 populations, respectively). In the overall population, median OS was significantly improved with atezolizumab (13.8 versus 9.6 months [HR = 0.73, p = 0.0003]), and the 2-year OS rates were 31% and 21% respectively. The OS benefit was observed regardless of histologic type and PD-L1 expression, although concerns were raised about the appropriateness of the antibody (SP142) used to stain TCs and ICs. PD-L1 expression was thus evaluated with the 22C3 immunohistochemistry assay (Agilent Technologies/Dako), the companion diagnostic of pembrolizumab, in 400 tumors from this study.
      • Gadgeel S.
      • Kowanetz M.
      • Zou W.
      • et al.
      Clinical efficacy of atezolizumab (atezo) in PD-L1 subgroups defined by SP142 and 22C3 IHC assays in 2L+ NSCLC: results from the randomized OAK study.
      Atezolizumab was superior to docetaxel in all subgroups, including when tumors had less than 1% PD-L1 expression on TCs. However, these data are still a matter of debate because PD-L1 expression less than 1% was found in 55% of the tumors, whereas the expected rate of negative tumors is around 30%, making it likely that the population with PD-L1 expression less than 1% included patients with false-negative tumors. Other predictive biomarkers were explored in patients treated with atezolizumab. Plasma samples from the phase II POPLAR and phase III OAK studies were retrospectively tested for tumor mutational burden (TMB) by using a 394 gene–based next-generation sequencing assay.
      • Gandara D.
      • Kowanetz M.
      • Mok T.
      • et al.
      Blood-based biomarkers for cancer immunotherapy: tumor mutational burden in blood (bTMB) is associated with improved atezolizumab (atezo) efficacy.
      A total of 13 cutoff points for TMB positivity were analyzed, and OS was significantly longer with atezolizumab than with docetaxel in all TMB subgroups, with a trend for a lower HR when the number of mutations increased.
      Interesting data for avelumab, a human immunoglobulin G1 monoclonal antibody targeting PD-L1 with a shorter half-life than other ICIs (6 days versus 27 days for atezolizumab) were recently presented. Exposure-response and PD-L1 expression in 184 patients with pretreated NSCLC in the JAVELIN phase 1a trial were reported at the 2017 ASCO meeting.
      • Gulley J.R.
      • Spigel D.R.
      • Kelly K.
      • et al.
      Exposure-response and PD-L1 expression analysis of second-line avelumab in patients with advanced NSCLC: data from the JAVELIN Solid Tumor trial.
      In this PD-L1–unselected population, higher exposure to avelumab was associated with improved overall response rates (ORRs) according to the quartiles (Q1–Q4) of trough concentration after the first dose (8.7% for Q1 versus 17.4% for Q4). When 92 patients from the quartiles Q3 and Q4 (>50% of exposure) were analyzed in terms of PD-L1 expression, the ORRs were 25% (≥1%), 26% (≥5%), 33% (≥50%), and 43% (≥80%), respectively. Higher avelumab exposure was associated with a modest increase in immune-related adverse events (irAEs). Of note, the correlation between irAEs and benefit was further explored in a retrospective study that included 134 patients with NSCLC treated with nivolumab in second or later lines. irAEs were reported in 69 patients (51%), 9% of which were grade 3 or 4, and 24 patients (18%) required systemic steroids. The development of irAEs during nivolumab treatment was associated with significant improvements in PFS (HR = 0.525, 95% CI: 0.287–0.937, p = 0.03) and OS (HR = 0.282, 95% CI: 0.101–0.667, p = 0.003).
      • Haratani K.
      • Hayashi H.
      • Chiba Y.
      • et al.
      Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer.
      The efficacy of PD-1/-PD-L1 inhibitors in patients with EGFR-mutated or ALK-rearranged NSCLC remains an unresolved issue. Subgroup analyses of clinical trials testing ICIs in patients with pretreated NSCLC
      • Rittmeyer A.
      • Barlesi F.
      • Waterkamp D.
      • et al.
      Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
      • Herbst R.S.
      • Baas P.
      • Kim D.-W.
      • et al.
      Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
      and recent data from expanded access programs
      • Garassino M.
      • Cortesi E.
      • Grossi F.
      • et al.
      Italian nivolumab expanded access programme in non-squamous non-small cell lung cancer patients: real-world results in never smokers and EGFR positive patients.
      showed an absence of survival benefit and low ORR (∼8%), respectively, in oncogene-addicted tumors. Of 111 patients included in the ATLANTIC phase II trial testing durvalumab in third or later lines, 97 had EGFR-mutated NSCLC, and the ORR was 14.7% in patients with PD-L1 expression of 25% or higher. However, in patients with PD-L1 less than 25%, the ORR was only 5%; furthermore, no objective responses were observed in the 10 evaluable patients with ALK-rearranged NSCLC.
      • Garassino M.
      • Choe B.
      • Gray J.E.
      Durvalumab in ≥ 3rd-line EGFR mutant/ALK+, locally advanced or metastatic NSCLC: results from the phase 2 ATLANTIC study.
      Similarly, in the updated results of the phase II BIRCH study testing atezolizumab in the first-line setting, a promising ORR (31%) and median PFS (7.6 months) were reported for 13 patients with EGFR-mutated PD-L1–positive (TC2/3 or IC2/3) NSCLC,

      Costa E, Felip E, Reck M, et al. OA17.02 Updated efficacy results from the BIRCH study: first-line atezolizumab therapy in PD-L1–selected patients with advanced NSCLC. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      suggesting a potential benefit of ICIs in oncogene-addicted NSCLC if appropriately selected for PD-L1 expression. Finally, intriguing data showed a significant upregulation of PD-L1 expression in patients with T790M-negative EGFR-mutated NSCLC compared with in those with T790M-positive EGFR-mutated NSCLC.
      • Hata A.
      • Katakami N.
      • Nanjo S.
      • et al.
      Programmed death-ligand 1 expression and T790M status in EGFR-mutant non-small cell lung cancer.
      On this basis, CheckMate 772 is currently exploring the use of nivolumab in combination with ipilimumab or chemotherapy in pretreated EGFR-mutated T790M-negative NSCLC.

      ClinicalTrials.gov. A study of nivolumab + chemotherapy or nivolumab + ipilimumab versus chemotherapy in patients with EGFR mutation, T790M negative NSCLC who have failed 1L EGFR TKI therapy. https://clinicaltrials.gov/ct2/show/NCT02864251. Accessed November 6, 2017.

      Finally, during the course of the year, several studies in different tumor types described accelerated tumor growth during ICI treatment.
      • Champiat S.
      • Dercle L.
      • Ammari S.
      • et al.
      Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1.
      • Saâda-Bouzid E.
      • Defaucheux C.
      • Karabajakian A.
      • et al.
      Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.
      This phenomenon, known as hyperprogressive disease (HPD), was recently defined as Response Criteria in Solid Tumors progression at first evaluation during ICI treatment associated with a more than 50% increase in the tumor growth during ICIs compared with growth before initiation of immunotherapy. According to this definition, HPD was retrospectively identified in 14% of patients with advanced NSCLC treated with ICIs and in a lower proportion (5%) of patients treated with single-agent chemotherapy.

      Ferrara R, Caramella C, Texier M, et al. MA10.11 Hyperprogressive disease (HPD) is frequent in non-small cell lung cancer (NSCLC) patients (Pts) treated with anti PD1/PD-L1 agents (IO). Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      In patients treated with ICIs, HPD correlated with the presence of more than two metastatic sites before initiation of an ICI and predicted poor OS compared with Response Criteria in Solid Tumors progression (3.4 versus 5.8 months [HR = 1.55, 95% CI: 1.07–2.25, p = 0.01]).

      Ferrara R, Caramella C, Texier M, et al. MA10.11 Hyperprogressive disease (HPD) is frequent in non-small cell lung cancer (NSCLC) patients (Pts) treated with anti PD1/PD-L1 agents (IO). Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      Frontline Therapy

      Pembrolizumab was approved as frontline therapy in 2017 by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in patients with NSCLC with tumors cells having 50% or higher PD-L1 expression. After a median follow-up of 25.2 months, a comparison of first-line pembrolizumab with platinum-based chemotherapy showed significant improvements in the ORR (45.5% versus 29.8%) and median OS (30 versus 14.2 months [HR = 0.63, 95% CI: 0.47–0.63, p = 0.002]).

      Brahmer J, Abreu Rodriguez D, Robinson. AG OA 17.06. Updated analysis of KEYNOTE-024: pembrolizumab vs platinum-based chemotherapy for advanced NSCLC with PD-L1 TPS ≥50%. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      A total of 82 of 151 patients (62.3%) in the chemotherapy arm crossed over to pembrolizumab in second-line treatment; the ORR was 20.7%, which is surprisingly low for a high–PD-L1–expressing population, suggesting the importance of early introduction of immunotherapy in PD-L1–positive patients. A twin phase III study (Checkmate 026), comparing nivolumab at 3 mg/kg every 2 weeks with platinum-based chemotherapy every 3 weeks for six cycles in patients with advanced or recurrent NSCLC with 1% or higher PD-L1 tumor expression was recently published.
      • Carbone D.P.
      • Reck M.
      • Paz-Ares L.
      • et al.
      First-line nivolumab in stage IV or recurrent non-small-cell lung cancer.
      The primary end point was PFS, as assessed by blinded independent central review in patients with NSCLC with at least 5% PD-L1 expression. Among 423 patients, nivolumab failed to significantly improve PFS (HR = 1.15, 95% CI: 0.91–1.45, p = 0.25). When the threshold of PD-L1 positivity was increased to 50%, the lack of benefit for nivolumab persisted, with an HR for progression or death of 1.07 (95% CI: 0.77–1.49). Median OS was 14.4 months (95% CI: 11.7–17.4) with nivolumab and 13.2 months (95% CI: 10.7–17.1) with chemotherapy (HR = 1.02, 95% CI: 0.80–1.30). An exploratory analysis in 312 patients (58% of randomized patients) assessed the impact of TMB on outcomes. A high TMB was reported in 30% of patients receiving nivolumab versus 39% in the chemotherapy group. The ORR (47% versus 28%) and median PFS (9.7 versus 5.8 [HR = 0.62, 95% CI: 0.38–1) were improved by nivolumab compared with by platinum-based chemotherapy in the high-TMB population. Surprisingly, no difference was seen in OS, potentially because of a 68% crossover rate to second-line immunotherapy in the chemotherapy cohort.
      Efficacy data for atezolizumab in the first-line setting were also recently updated. The phase II BIRCH trial assessed atezolizumab in patients with untreated PD-L1–positive NSCLC.

      Costa E, Felip E, Reck M, et al. OA17.02 Updated efficacy results from the BIRCH study: first-line atezolizumab therapy in PD-L1–selected patients with advanced NSCLC. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      To be eligible, tumors had to express PD-L1 (with SP142) on at least 5% of TCs or ICs (TC2/3 or IC2/3). Among 139 patients, the ORR was 35% for the TC3 or IC3 subgroup (TCs ≥50% or ICs ≥10%). The median OS times were 24.0 months (95% CI: 18.1–30.8) for the overall population and 26.9 months (95% CI: 12.0–NE) for TC3 or IC3 patients. These results were consistent with the efficacy data of pembrolizumab in patients with untreated PD-L1–positive NSCLC.
      In the open-label, multicenter, phase III MYSTIC trial (NCT02453282), 1092 patients with treatment-naive EGFR/ALK wild-type NSCLC with PD-L1 expression of 25% or higher were randomized to receive durvalumab plus tremelimumab, durvalumab, or platinum-based chemotherapy. The coprimary end points were OS and PFS.
      • Peters S.
      • Antonia S.
      • Goldberg S.B.
      • et al.
      191TiP. MYSTIC: a global, phase 3 study of durvalumab (MEDI4736) plus tremelimumab combination therapy or durvalumab monotherapy versus platinum-based chemotherapy (CT) in the first-line treatment of patients (pts) with advanced stage IV NSCLC.
      Results have yet to be published; however, the trial failed to show superiority in PFS of the combination durvalumab plus tremelimumab compared with platinum-based chemotherapy. As the efficacies of nivolumab, pembrolizumab, and durvalumab are similar in patients with pretreated NSCLC, it is more likely that the differences observed in patients with untreated PD-L1–positive NSCLC reflect heterogeneous patient selection.
      In May 2017, the FDA approved pembrolizumab in combination with pemetrexed and carboplatin as first-line treatment of advanced nonsquamous NSCLC regardless of PD-L1 expression; the approval was based on the results of the phase I/II KEYNOTE 021 study, in which 123 patients with advanced nonsquamous NSCLC were randomized 1:1 to receive pembrolizumab combined with carboplatin-pemetrexed versus carboplatin-pemetrexed.
      • Langer C.J.
      • Gadgeel S.M.
      • Borghaei H.
      • et al.
      Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.
      Updated OS data were recently reported (18.7 months median follow-up versus prior follow-up of 10.2 months).

      Borghaei H, Langer CL, Gadgeel S, et al. OA 17.01. Pemetrexed-carboplatin plus pembrolizumab as first-line therapy for advanced nonsquamous NSCLC: KEYNOTE-021 cohort G update. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      Both ORR (56.7% versus 31.7%) and median PFS (19.0 versus 8.9 months) (HR = 0.54, p = 0.0067) were significantly higher with the addition of pembrolizumab. A positive nonsignificant improvement in OS was also reported (NR versus 20.9 months). It is unknown whether the OS benefit of the experimental arm is driven by the patients with high–PD-L1 NSCLC because the subgroup analyses were not updated. The impressive PFS in the control arm may reflect a selected population. It is hoped that the confirmatory phase III trial (KEYNOTE 189

      ClinicalTrials.gov. Study of platinum+pemetrexed chemotherapy with or without pembrolizumab (MK-3475) in participants with first line metastatic non-squamous non-small cell lung cancer (MK-3475-189/KEYNOTE-189). https://clinicaltrials.gov/ct2/show/NCT02578680. Accessed November 6, 2017.

      ) will establish approval for this indication.
      At the 2017 ESMO Immuno Oncology Congress, the results of IMpower150 (NCT02366143), a multicentric open-label phase III trial evaluating the combination of atezolizumab with platinum-based chemotherapy plus bevacizumab, were presented.

      Reck M, Socinski MA, Cappuzzo F, et al. Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMPOWER150). LBA 1_PR. Abstract presented at: ESMO Immuno Oncology Congress; December 7–10, 2017; Geneva, Switzerland.

      In this study, 1202 treatment-naive patients with advanced nonsquamous NSCLC were randomized (1:1:1) to atezolizumab in combination with carboplatin plus paclitaxel (arm A) or in combination with carboplatin plus paclitaxel and bevacizumab (arm B) compared with carboplatin plus paclitaxel and bevacizumab (arm C). After the induction phase, the patients received maintenance treatment with atezolizumab (arm A), atezolizumab plus bevacizumab (arm B), or bevacizumab alone (arm C), until disease progression. The arm B demonstrated improved PFS (coprimary end point) compared with the arm C, both in an intention-to-treat population (8.3 months versus 6.8 months [HR = 0.62, 95% CI: 0.52–0.74, p < 0.0001]) and in a subgroup of patients defined by T-effector gene signature expression (11.3 months versus 6.8 months [HR = 0.51, 95% CI: 0.38–0.68, p < 0.0001]). Benefit was seen irrespective of the PD-L1 expression but with less relevant clone SP142, and more data are needed to define the best scenario for patients with PD-L1–positive (>50% TCs stained and clone other than SP142) NSCLC. The combination of atezolizumab plus carboplatin, paclitaxel, and bevacizumab also showed a promising OS; however, more mature results are expected in the first half of 2018.
      Currently, there are few studies evaluating immunotherapy combinations in NSCLC. The CheckMate 012 phase I, multicohort study evaluated safety and efficacy of nivolumab plus ipilimumab in treatment-naive patients with advanced NSCLC. Patients were randomized (1:1:1) to receive 1 mg/kg of nivolumab every 2 weeks plus 1 mg/kg of ipilimumab every 6 weeks, 3 mg/kg of nivolumab every 2 weeks plus 1 mg/kg of ipilimumab every 12 weeks, or 3 mg/kg of nivolumab every 2 weeks plus 1 mg/kg of ipilimumab every 6 weeks. Of the 77 patients treated, 38 received nivolumab every 2 weeks plus ipilimumab every 12 weeks and 39 patients received nivolumab every 2 weeks plus ipilimumab every 6 weeks. The combination demonstrated a high rate of grade 3 or 4 adverse events (AEs) compared with nivolumab alone, with AE rates of 37% and 33% in the ipilimumab every 12 weeks cohort and ipilimumab every 6 weeks cohort, respectively. However, the combination showed impressive responses, with ORRs of 47% in the ipilimumab every 12 weeks cohort and 38% in the ipilimumab every 6 weeks cohort. Higher response rates were observed in patients with PD-L1 expression of at least 1% (ORR in 57% in both cohorts).
      • Hellmann M.D.
      • Rizvi N.A.
      • Goldman J.W.
      • et al.
      Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study.
      In the CheckMate 012 study, the combination of nivolumab with platinum-based chemotherapy gave an ORR of 46% and 25% 3-year OS in 56 patients with untreated NSCLC. Interestingly, long-term survivors included patients who were never-smokers or who had PD-L1 expression less than 1%.

      Juergens RJ, Hellmann MD, Brahmer J, et al. OA 17.03. First-line nivolumab plus platinum-based doublet chemotherapy for advanced NSCLC: CheckMate 012 3-year update. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      Advances in Advanced NSCLC: Targeted Therapies

      Given the existence of matched targeted therapies and individual strategies, patients with advanced oncogene-addicted NSCLC must be considered separately. The targetable oncogenic drivers identified so far are EGFR mutations (11% in whites
      • Barlesi F.
      • Mazieres J.
      • Merlio J.P.
      • et al.
      Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
      and 47% in Asians
      • Liu L.
      • Liu J.
      • Shao D.
      • et al.
      Comprehensive genomic profiling of lung cancer using a validated panel to explore therapeutic targets in East Asian patients.
      ), ALK rearrangements (5%), BRAF mutations (2%), and ROS1 rearrangements (1%).
      • Barlesi F.
      • Mazieres J.
      • Merlio J.P.
      • et al.
      Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
      Additional actionable genetic aberrations explored over the past year included tyrosine-protein kinase met gene (MET) mutations, HER2 mutation or amplification, and RET and neurotropic tropomyosin receptor kinase gene (NTRK) rearrangements.

      EGFR Mutations

      Treatment of EGFR-mutant adenocarcinoma was widely reshaped during 2017 by the introduction of compelling new drugs in patients with both TKI-naive and pretreated NSCLC. Table 1
      • Soria J.-C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      • Shi Y.K.
      • Wang L.
      • Han B.H.
      • et al.
      First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study.
      • Wu Y.-L.
      • Cheng Y.
      • Zhou X.
      • et al.
      Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.
      • Paz-Ares L.
      • Tan E.-H.
      • O’Byrne K.
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.
      • Mok T.S.
      • Wu Y.-L.
      • Ahn M.-J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      • Nie K.
      • Zhang Z.
      • Zhou X.
      • et al.
      Osimertinib compared to docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated non-small cell lung cancer.
      • Mok T.S.K.
      • Kim S.-W.
      • Wu Y.-L.
      • et al.
      Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive non-small-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analyses.
      • Rosell R.
      • Dafni U.
      • Felip E.
      • et al.
      Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial.

      Elamin YY, Robichaux J, Lam VK, et al. OA 12.01. The preclinical and clinical activity of poziotinib, a potent, selective inhibitor of EGFR exon 20 mutant NSCLC. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      summarizes efficacy results of the major clinical trials in patients with EGFR-mutated NSCLC published or presented during 2017. Figure 4 represents possible sequential treatment strategies and corresponding cumulative PFS with first- and next-generation EGFR TKIs in EGFR-mutated NSCLC.
      Table 1Clinical Trials in EGFR-Mutated NSCLC Performed or Published in 2017
      ReferenceTrialPhaseTreatmentLinePatients, nORRPFS, moOS, mo
      Shi et al.
      • Shi Y.K.
      • Wang L.
      • Han B.H.
      • et al.
      First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study.
      CONVINCEIIIIcotinib vs. cisplatin + pemetrexedFirst148 vs. 137NA11.2 vs. 7.9 (p = 0.006)30.5 vs. 32.1 (p = 0.8)
      Wu et al.
      • Wu Y.-L.
      • Cheng Y.
      • Zhou X.
      • et al.
      Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.
      ARCHER 1050IIIDacomitinib vs. gefitinibFirst227 vs. 22575% vs. 72%14.7 vs. 9.2 (p < 0.0001)Not mature
      Paz-Ares et al.
      • Paz-Ares L.
      • Tan E.-H.
      • O’Byrne K.
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.
      LUX-LUNG 7IIBAfatinib vs. gefitinibFirst160 vs. 15970% vs. 56%11 vs. 10.9 (p = 0.01)27.9 vs. 24.5 (p = 0.2)
      Mok et al.
      • Mok T.S.
      • Wu Y.-L.
      • Ahn M.-J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      AURA 3IIIOsimertinib vs. platinum + pemetrexedSecond279 vs. 14071% vs. 31%10.1 vs. 4.4 (p < 0.001)Not mature
      Nie et al.
      • Nie K.
      • Zhang Z.
      • Zhou X.
      • et al.
      Osimertinib compared to docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated non-small cell lung cancer.
      IIIOsimertinib vs. docetaxel + bevacizumabThird74 vs. 7361% vs. 8%10.2 vs. 3 (p < 0.0001)NR vs. NR
      Mok et al.
      • Mok T.S.K.
      • Kim S.-W.
      • Wu Y.-L.
      • et al.
      Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive non-small-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analyses.
      IMPRESSIIIGefitinib + cisplatin + pemetrexed vs. cisplatin + pemetrexedSecond133 vs. 13232% vs. 34%5.4 vs. 5.4 (p = 0.2)13.4 vs. 19.5 (p = 0.01)
      Soria et al.
      • Soria J.-C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      FLAURAIIIOsimertinib vs. gefitinib/erlotinibFirst279 vs. 27780% vs. 76%18.9 vs. 10.2 (p < 0.001)NR vs. NR
      Rosell et al.
      • Rosell R.
      • Dafni U.
      • Felip E.
      • et al.
      Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial.
      BELIEFIIErlotinib + bevacizumabFirst10977%13.2/16
      In T790M-positive patients.
      28.2
      Elamin et al.

      Elamin YY, Robichaux J, Lam VK, et al. OA 12.01. The preclinical and clinical activity of poziotinib, a potent, selective inhibitor of EGFR exon 20 mutant NSCLC. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      IIPoziotinib≥First1173%NANA
      ORR, overall response rate; OS, overall survival; PFS, progression-free survival; NA, not available; NR, not reached.
      a In T790M-positive patients.
      Figure thumbnail gr4
      Figure 4Sequential treatment strategies and cumulative progression-free survival (PFS) with first- and next-generation (gen) EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated NSCLC. ph, phase; Bvz, bevacizumab.

      First-Generation Inhibitors: Gefitinib, Erlotinib, Icotinib

      In the first-line setting, the phase III CONVINCE trial comparing icotinib, a first-generation TKI, with cisplatin-pemetrexed (with optional maintenance pemetrexed) in Chinese patients with EGFR-mutated NSCLC, showed a significant benefit in PFS (11.2 versus 7.9 months [p = 0.006]). No difference in OS was observed on account of poststudy therapy with an EGFR TKI, which was reported in 82% of chemotherapy-treated patients.
      • Shi Y.K.
      • Wang L.
      • Han B.H.
      • et al.
      First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study.
      When indirectly compared with other first-generation inhibitors such as gefitinib and erlotinib, icotinib did not outperform.
      • Yang J.J.
      • Zhou Q.
      • Yan H.H.
      • et al.
      A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations.
      Upon resistance to first-generation inhibitors, the updated results of the IMPRESS phase III trial confirmed the deleterious effect on OS of continuing gefitinib in addition to cisplatin-pemetrexed versus standard treatment of cisplatin-pemetrexed.
      • Mok T.S.K.
      • Kim S.-W.
      • Wu Y.-L.
      • et al.
      Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive non-small-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analyses.

      Second-Generation Inhibitors: Afatinib, Dacomitinib

      The benefit of second-generation over first-generation inhibitors has been strongly debated since publication of the LUX-LUNG 7 trial showing the absence of a clinically meaningful survival benefit with afatinib versus with gefitinib in patients with untreated EGFR-mutated NSCLC.
      • Paz-Ares L.
      • Tan E.-H.
      • O’Byrne K.
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.
      Significant data came from the ARCHER 1050 study, the first open-label phase III trial comparing dacomitinib with gefitinib in patients with NSCLC without brain metastases who harbored a common activating EGFR mutation (del19/L858R). After 14.7 months of follow-up, dacomitinib was found to have the longest PFS among first- or second-generation EGFR TKIs. Interestingly, the PFS curves in the ARCHER 1050 study separated relatively late, after at least 6 months, as in the LUX-LUNG-7 trial. ORR was similar between gefitinib and dacomitinib, suggesting that the PFS benefit was driven mainly by a greater depth of response with dacomitinib because of more potent EGFR inhibition. However, the attractiveness of dacomitinib was hampered by a high rate of treatment-related serious AEs (9.3%) leading to frequent dose reductions (66%) and treatment discontinuation (∼10%).
      • Wu Y.-L.
      • Cheng Y.
      • Zhou X.
      • et al.
      Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.
      The OS data are currently immature but will likely be influenced by subsequent therapies. Dacotiminib could be a potential first-line option after carefully weighing the toxicity-to-benefit ratio.

      Third-Generation Inhibitor: Osimertinib

      Osimertinib is a third-generation irreversible EGFR TKI that is selective for both EGFR and T790M mutations. In the AURA3 phase III trial, compared with platinum-pemetrexed chemotherapy, osimertinib significantly improved ORR (71% versus 31% [p < 0.001]) and PFS (10.1 versus 4.4 months [p < 0.001]) in patients with T790M-positive EGFR-mutated NSCLC previously treated with first- or second-generation EGFR TKIs.
      • Mok T.S.
      • Wu Y.-L.
      • Ahn M.-J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      In AURA3, baseline central nervous system (CNS) imaging was mandated only in patients with known or suspected brain metastases and follow-up imaging in patients with confirmed CNS disease. Of note, osimertinib was extremely active against brain metastases and leptomeningeal disease, with a significantly higher CNS ORR (70% versus 31%) and PFS (11.7 versus 5.6 months) compared with chemotherapy.
      • Mok T.S.
      • Ahn M.-J.
      • Han J.-Y.
      • et al.
      CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: data from a randomized phase III trial (AURA3).
      The activity was observed regardless of prior radiotherapy (RT) status (64% in patients with prior RT versus 34% in patients who did not receive prior brain RT). At the 2017 annual ASCO meeting, a phase III trial comparing third-line osimertinib with docetaxel plus bevacizumab in patients with T790M-positive EGFR-mutated NSCLC reported a remarkable improvement in PFS (10.2 versus 3 months [p < 0.0001]) and in ORR (62% versus 8%) in favor of osimertinib.
      • Alley E.W.
      • Lopez J.
      • Santoro A.
      • et al.
      Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
      Osimertinib had a manageable toxicity profile, the most common side effects being diarrhea and rash, with grade 3 or 4 in only 1% to 3% of patients.
      • Mok T.S.
      • Wu Y.-L.
      • Ahn M.-J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      • Nie K.
      • Zhang Z.
      • Zhou X.
      • et al.
      Osimertinib compared to docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated non-small cell lung cancer.
      On the basis of the AURA3 study, osimertinib received FDA and EMA approval in patients with pretreated T790M-positive EGFR-mutated NSCLC.
      The FLAURA study, a phase III trial comparing first-line osimertinib with gefitinib in patients with NSCLC harboring the common EGFR mutation del19/L858R was reported this year. Osimertinib significantly improved PFS (18.9 versus 10.0 months [p < 0.001]) compared with first-generation EGFR TKIs (gefitinib or erlotinib).
      • Soria J.-C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      The ORR was 80% for osimertinib and 76% for standard EGFR TKI. As in AURA3, in the FLAURA study, CNS baseline and follow-up imaging was mandatory only for patients with known brain metastases. In this subset of patients, osimertinib showed a 76% ORR, which is in line with that for the overall population. A nonsignificant OS benefit was observed in favor of osimertinib; the rate of crossover to osimertinib in the control arm was limited and the data are still immature. Approval of osimertinib in the first-line setting is expected on the basis of the PFS results, but the optimal strategy is still unknown. In particular, the control arm (gefitinib) might be considered suboptimal given the results of dacomitinib or other combinations such as erlotinib/bevacizumab (the BELIEF trial), with PFS ranging from 14.7 to 16.0 months.
      • Wu Y.-L.
      • Cheng Y.
      • Zhou X.
      • et al.
      Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.
      • Rosell R.
      • Dafni U.
      • Felip E.
      • et al.
      Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial.
      It is hoped that the APPLE phase II trial comparing osimertinib up front with gefitinib followed by osimertinib will give further insight into this issue.

      ClinicalTrials.gov. Osimertinib treatment on EGFR T790M plasma positive NSCLC patients (APPLE). https://clinicaltrials.gov/ct2/show/NCT02856893. Accessed November 6, 2017.

      Remarkable advances have been observed in the detection and monitoring of EGFR mutations in circulating tumor DNA (ctDNA). A large-scale study including patients with NSCLC with insufficient tumor tissue for EGFR analysis, showed that patients with EGFR positivity in ctDNA had outcomes similar to those with tissue diagnosis, with an ORR of 72% and PFS of 11 months with first-line EGFR TKIs.
      • Mayo-de-Las-Casas C.
      • Jordana-Ariza N.
      • Garzón-Ibañez M.
      • et al.
      Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions.
      In patients who failed therapy with a first- and/or second-generation EGFR TKI, the 50% rate of T790M mutation positivity in ctDNA was similar to that expected in tissue, as was the 62% ORR with osimertinib,
      • Remon J.
      • Caramella C.
      • Jovelet C.
      • et al.
      Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA.
      confirming the initial results from the phase I AURA study.
      • Oxnard G.R.
      • Thress K.S.
      • Alden R.S.
      • et al.
      Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer.
      Interestingly, an exploratory analysis of the AURA trial reported that clearance of EGFR mutations (del19/L858R or T790M) at 6 weeks after initiation of osimertinib was associated with improved ORR and PFS compared with absence of plasma clearance, highlighting the potential role of ctDNA monitoring to assess EGFR TKI efficacy.
      • Thress K.S.
      • Markovetz A.
      • Barrett J.C.
      • et al.
      Complete clearance of plasma EGFR mutations as a predictor of outcome on osimertinib in the AURA trial.
      In the AURA study, next-generation sequencing on ctDNA was used to characterize mechanisms of resistance to osimertinib in 33 patients: C797S mutation was identified in seven patients, MET amplification in three patients, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) in three patients, and KRAS and BRAF V600E mutations and FGFR3 and RET rearrangement in one patient each. Interestingly, loss of T790M was associated with early onset of resistance to osimertinib, and furthermore, the C797S mutation was found exclusively in patients maintaining the T790M mutation, whereas other competing mechanisms of resistance were more frequent in patients losing T790M.

      Oxnard GR, Hu Y, Mileham KF et al. OA 09.02. Osimertinib resistance mediated by loss of EGFR T790M is associated with early resistance and competing resistance mechanisms. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      Finally, SCLC transformation has been described as a mechanism of resistance to EGFR TKIs in 5% of patients with EGFR-mutant NSCLC.
      • Sequist L.V.
      • Waltman B.A.
      • Dias-Santagata D.
      • et al.
      Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.
      A recent study elegantly demonstrated that the clone responsible for SCLC transformation is present at baseline in patients with EGFR-mutated NSCLC, and biallelic loss of retinoblastoma 1 gene (RB1) and tumor protein p53 gene (TP53) correlates with a 43-fold increased risk of transformation to SCLC.
      • Lee J.-K.
      • Lee J.
      • Kim S.
      • et al.
      Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas.
      This study suggested that testing for tumor protein 53 and retinoblastoma 1 at diagnosis in EGFR-mutated NSCLC could be useful to predict tumors that are most likely to transform to SCLC, prompting clinicians to monitor this disease more frequently than in other patients.

      Exon 20 EGFR Mutations

      Exon 20 insertions represent 9% of all EGFR mutations and are not appropriate targets for current EGFR TKIs because of lack of activity.
      • Arcila M.E.
      • Nafa K.
      • Chaft J.E.
      • et al.
      EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics.
      The EGFR inhibitor poziotinib showed promising results in in vitro models of exon 20 EGFR-mutated NSCLC, whereas eight of 11 patients (73%) with exon 20 EGFR mutations experienced a response to poziotinib in a phase II study. Despite the promising activity, PFS results and further patient data are needed.

      Elamin YY, Robichaux J, Lam VK, et al. OA 12.01. The preclinical and clinical activity of poziotinib, a potent, selective inhibitor of EGFR exon 20 mutant NSCLC. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      ALK Rearrangement

      ALK-rearranged NSCLC is the oncogene-addicted setting showing the greatest evolution over the past year. This population experiences a remarkably long OS, up to 7.5 years, when appropriately treated.
      • Duruisseaux M.
      • Besse B.
      • Cadranel J.
      • et al.
      Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer (IFCT-1302 CLINALK): a French nationwide cohort retrospective study.
      Not all ALK fusions are alike, given that 3a/b variants were less sensitive to anaplastic lymphoma kinase (ALK) TKIs, probably because of higher protein stability.
      • Woo C.G.
      • Seo S.
      • Kim S.W.
      • et al.
      Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer.
      • Ou I.
      • Schrock A.
      • Gowen K.
      • et al.
      Association of ALK resistance mutations by EML4-ALK variant (v3 vs. non-v3) in ALK+ non-small cell lung cancer (NSCLC).
      • Yoshida T.
      • Oya Y.
      • Tanaka K.
      • et al.
      Differential crizotinib response duration among ALK fusion variants in ALK-positive non-small-cell lung cancer.
      Secondary ALK resistance mutations can be actively monitored in cell-free DNA to better characterize mechanisms of resistance.
      • Gettinger S.N.
      • Zhang S.
      • Hodgson G.
      • et al.
      Activity of brigatinib (BRG) in crizotinib (CRZ)-resistant ALK+ NSCLC patients (pts) according to ALK plasma mutation status.
      Table 2
      • Hida T.
      • Nokihara H.
      • Kondo M.
      • et al.
      Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.
      • Peters S.
      • Camidge D.R.
      • Shaw A.T.
      • et al.
      Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.
      • Mok T.S.
      • Kim D.
      • Wu Y.
      • et al.
      Overall survival (OS) for first-line crizotinib versus chemotherapy in ALK+ lung cancer: updated results from PROFILE 1014.
      • Shaw A.T.
      • Kim T.M.
      • Crinò L.
      • et al.
      Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial.
      • Soria J.-C.
      • Tan D.S.W.
      • Chiari R.
      • et al.
      First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.
      • Cho B.C.
      • Kim D.-W.
      • Bearz A.
      • et al.
      ASCEND-8: a randomized phase 1 study of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg in Fasted state in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC).
      • Novello S.
      • Mazieres J.
      • Ou S.
      • et al.
      Primary results from the phase III ALUR study of alectinib versus chemotherapy in previously treated ALK+ non-small-cell lung cancer (NSCLC).
      • Kim D.-W.
      • Tiseo M.
      • Ahn M.-J.
      • et al.
      Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial.

      Solomon BJ, Shaw A, Ou SH, et al. OA 05.06. Phase 2 study of lorlatinib in patients with advanced ALK+ROS1+ non-small-cell lung cancer. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      • Horn L.
      • Wakeele K.
      • Reckamp K.
      • et al.
      Plasma genotyping of patients enrolled on the expansion phase I/II trial of X-396 in patients (pts) with ALK+ non-small cell lung cancer (NSCLC).
      summarizes the major clinical trials in patients with ALK-rearranged NSCLC during 2017. Despite extremely encouraging results, a lot of questions regarding the best treatment strategies and combinations remain unanswered, as depicted in Figure 5.
      Table 2Clinical Trials in ALK-Rearranged NSCLC Performed or Published in 2017
      AuthorsTrialPhaseTreatmentLinePatients, nORRPFS, moOS, mo
      Mok et al.
      • Mok T.S.
      • Kim D.
      • Wu Y.
      • et al.
      Overall survival (OS) for first-line crizotinib versus chemotherapy in ALK+ lung cancer: updated results from PROFILE 1014.
      PROFILE 1014IIICrizotinib vs.

      cisplatin + pemetrexed
      First172

      171
      74% vs. 45%10.9 vs.

      7 (p < 0.001)
      NR vs.

      47.5 (p = 0.09)
      Shaw et al.
      • Shaw A.T.
      • Kim T.M.
      • Crinò L.
      • et al.
      Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial.
      ASCEND-5IIICeritinib vs.

      pemetrexed or docetaxel
      Second or third115

      116
      39% vs.

      7%
      5.4 vs.

      1.6 (p < 0.0001)
      18.1 vs. 20.1 (p = 0.5)
      Soria et al.
      • Soria J.-C.
      • Tan D.S.W.
      • Chiari R.
      • et al.
      First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.
      ASCEND-4IIICeritinib vs.

      platinum + pemetrexed
      First189

      187
      72% vs.

      27%
      16.6 vs.

      8.1 (p < 0.00001)
      Not mature
      Cho et al.
      • Cho B.C.
      • Kim D.-W.
      • Bearz A.
      • et al.
      ASCEND-8: a randomized phase 1 study of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg in Fasted state in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC).
      ASCEND-8IIICeritinib, 450 mg/d (low-fat meal), vs.

      ceritinib, 600 mg/d (low-fat meal), vs.

      ceritinib, 750 mg/d (fasting)
      ≥First89

      87

      91
      78%

      75%

      70%
      17.6 vs.

      NE vs.

      10.9
      NA
      Hida et al.
      • Hida T.
      • Nokihara H.
      • Kondo M.
      • et al.
      Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.
      J-ALEXIIIAlectinib vs.

      crizotinib
      First or second103

      104
      85% vs.

      70%
      NR vs.

      10.2 (p < 0.0001)
      Not mature
      Peters et al.
      • Peters S.
      • Camidge D.R.
      • Shaw A.T.
      • et al.
      Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.
      ALEXIIIAlectinib vs.

      crizotinib
      First152

      151
      83% vs.

      75%
      25.7 vs.

      10.4 (p < 0.001)
      Not mature
      Novello et al.
      • Novello S.
      • Mazieres J.
      • Ou S.
      • et al.
      Primary results from the phase III ALUR study of alectinib versus chemotherapy in previously treated ALK+ non-small-cell lung cancer (NSCLC).
      ALURIIIAlectinib vs.

      pemetrexed or docetaxel
      Third72

      35
      36% vs.

      11%
      9.6 vs.

      1.4 (p < 0.001)
      NA
      Kim et al.
      • Kim D.-W.
      • Tiseo M.
      • Ahn M.-J.
      • et al.
      Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial.
      ALTAIIBrigatinib, 90 mg, vs. brigatinib, 180 mg/90 mgSecond or third
      Seventy-five percent of patients received a first-line chemotherapy regimen; all patients were pretreated with crizotinib.
      112

      109
      45% vs.

      54%
      9.2 vs.

      12.9
      NA
      Solomon et al.

      Solomon BJ, Shaw A, Ou SH, et al. OA 05.06. Phase 2 study of lorlatinib in patients with advanced ALK+ROS1+ non-small-cell lung cancer. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      I/IILorlatinib≥First111
      Patients treated with lorlatinib after two or three previous anaplastic lymphoma kinase tyrosine kinase inhibitors.
      39%6.9NA
      Horn et al.
      • Horn L.
      • Wakeele K.
      • Reckamp K.
      • et al.
      Plasma genotyping of patients enrolled on the expansion phase I/II trial of X-396 in patients (pts) with ALK+ non-small cell lung cancer (NSCLC).
      I/IIEnsartinibCrizotinib naive888%NANA
      Crizotinib pretreated1283%
      ALK, ALK receptor tyrosine kinase gene; ORR, overall response rate; PFS, progression-free survival; OS, overall survival; NR, not reached; NA, not available.
      a Seventy-five percent of patients received a first-line chemotherapy regimen; all patients were pretreated with crizotinib.
      b Patients treated with lorlatinib after two or three previous anaplastic lymphoma kinase tyrosine kinase inhibitors.
      Figure thumbnail gr5
      Figure 5Sequential treatment strategies and cumulative progression-free survival (PFS) with first- and next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in patients with ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC. ph, phase; NR, not reached.

      First-Generation Inhibitor: Crizotinib

      At the 2017 ESMO meeting, the updated OS analysis of PROFILE 1014, a phase III trial comparing first-line crizotinib with platinum-pemetrexed chemotherapy in patients with ALK-rearranged NSCLC, reported an impressive 56% 4-year OS with crizotinib. OS was not statistically different because of the high crossover rate (∼85%). Patients receiving crizotinib followed by other ALK TKIs had a very long median OS compared with those receiving first-line crizotinib followed by chemotherapy (NR versus 49 months).
      • Mok T.S.
      • Kim D.
      • Wu Y.
      • et al.
      Overall survival (OS) for first-line crizotinib versus chemotherapy in ALK+ lung cancer: updated results from PROFILE 1014.

      Second-Generation Inhibitors: Ceritinib, Alectinib, Brigatinib

      Compared with second- or third-line chemotherapy (docetaxel or pemetrexed), ceritinib significantly improved ORR (39% versus 7%) and PFS (5.4 versus 1.6 months [p < 0.0001]) in patients with crizotinib-resistant ALK-rearranged NSCLC in the phase III trial ASCEND-5. No significant difference was seen in OS, likely because of the 75% rate of crossover from chemotherapy.
      • Shaw A.T.
      • Kim T.M.
      • Crinò L.
      • et al.
      Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial.
      Ceritinib also showed dramatically improved ORR (72% versus 27%) and PFS (16.6 versus 8.1 months [HR = 0.55, p < 0.00001]) compared with first-line platinum-pemetrexed chemotherapy with maintenance pemetrexed in the phase III trial ASCEND-4.
      • Soria J.-C.
      • Tan D.S.W.
      • Chiari R.
      • et al.
      First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.
      As observed in PROFILE 1014 and ASCEND-5, a significant difference in OS was not expected owing to the 72% crossover rate. In 2017, ceritinib obtained FDA and EMA approval in patients with untreated ALK-positive NSCLC. Activity in brain metastases was reported, with an intracranial ORR of 73% in first-line treatment and 35% in second-line treatment.
      • Shaw A.T.
      • Kim T.M.
      • Crinò L.
      • et al.
      Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial.
      • Soria J.-C.
      • Tan D.S.W.
      • Chiari R.
      • et al.
      First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.
      Interestingly, around 60% of patients enrolled in ASCEND 4 and 40% of patients in ASCEND 5 had not received any brain RT before. Ceritinib, 750 mg/d, led to grade 3 or 4 AEs in 65% of patients in ASCEND-4 (mostly asymptomatic increases in alanine transaminase [ALT], aspartate transaminase, or γ-glutamyl transferase levels), and dose reductions or discontinuation were common (in 80% of patients) in both ASCEND-4
      • Soria J.-C.
      • Tan D.S.W.
      • Chiari R.
      • et al.
      First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.
      and ASCEND-5.
      • Shaw A.T.
      • Kim T.M.
      • Crinò L.
      • et al.
      Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial.
      The phase I study ASCEND-8 recently showed that ceritinib, 450 mg/d with a low-fat meal, had a similar pharmacokinetic profile and the same efficacy (an ORR of 78% and PFS of 17.6 months) as ceritinib, 750 mg/d under fasting conditions.
      • Cho B.C.
      • Kim D.-W.
      • Bearz A.
      • et al.
      ASCEND-8: a randomized phase 1 study of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg in Fasted state in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC).
      Although increased aspartate transaminase and ALT levels were similar for the two doses, the lower dose was associated with almost no grade 3 gastrointestinal toxicities, half as many grade 2 toxicities, and a similar rate of grade 1 toxicities. Ceritinib, 450 mg with a low-fat meal, is thus a valid alternative regimen for routine practice.
      Two phase III studies, ALEX and J-ALEX, recently compared alectinib with crizotinib in white and Japanese patients with ALK-positive NSCLC, respectively. In the J-ALEX, alectinib at 300 mg daily significantly improved ORR (85% versus 70%) and PFS (HR = 0.34) after adjustment for potential imbalance of prognostic factors and time to brain progression (HR = 0.16) compared with crizotinib.
      • Hida T.
      • Nokihara H.
      • Kondo M.
      • et al.
      Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.
      Alectinib showed a significant improvement in PFS also in patients with baseline brain metastases (NR versus 10.2 [p = 0.006]); however, the presence of CNS disease was not a stratification factor in J-ALEX, and only 29 and 14 patients had baseline brain metastases in the crizotinib and alectinib arms, respectively. The OS data were still immature; however, crossover from crizotinib to alectinib was allowed. Similarly, the ALEX trial confirmed the superiority of alectinib, 600 mg daily, compared with crizotinib in ORR (83% versus 75%) and in PFS (26 versus 10 months [HR = 0.50, p < 0.001]). The OS data were immature, and surprisingly, crossover was not allowed.
      • Peters S.
      • Camidge D.R.
      • Shaw A.T.
      • et al.
      Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer.
      Grade 3 to 5 AEs occurred in 26% and 41% of patients in J-ALEX and ALEX, respectively and alectinib had a more favorable AE profile than crizotinib. In both arms, approximately 85% of patients with brain metastases did not receive previous brain RT, and alectinib was clearly superior to crizotinib in CNS responses (intracranial ORR 79% versus 40% [HR = 0.4 for PFS]) and had a remarkable neuroprotective effect, with 5% of patients without CNS involvement having brain progression compared with 31% in the crizotinib arm.
      • Gadgeel S.
      • Peters S.
      • Mok T.S.
      • et al.
      Alectinib vs crizotinib in treatment-naive ALK+ NSCLC: CNS efficacy results from the ALEX study.
      Despite the undoubted beneficial effect on the CNS with alectinib, in the ALEX trial a brain evaluation at baseline and every 2 months was mandated for all the patients regardless of the presence of brain metastases, and for this reason, patients were probably overmonitored for brain metastases compared with in other studies performing a CNS evaluation only in patients with known brain metastases at baseline. Finally, on the basis of ORR (36% versus 11%) and PFS (9.6 versus 1.4 months [p < 0.001]) in the phase III ALUR trial, alectinib was more active than third-line chemotherapy in crizotinib-refractory patients.
      • Novello S.
      • Mazieres J.
      • Ou S.
      • et al.
      Primary results from the phase III ALUR study of alectinib versus chemotherapy in previously treated ALK+ non-small-cell lung cancer (NSCLC).
      Brigatinib was tested after crizotinib progression with two schedules (90 mg/d or 180 mg/d with a 7-day lead-in at 90 mg/daily) in the randomized phase II trial ALTA. At 180 mg/d, brigatinib showed an ORR of 54%, intracranial ORR of 67%, and PFS of 13 months (investigator assessment).
      • Kim D.-W.
      • Tiseo M.
      • Ahn M.-J.
      • et al.
      Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial.
      In a crizotinib-resistant setting, these results compared favorably with the PFS times of 5.4 and 9.6 months with ceritinib and alectinib in ASCEND-5
      • Shaw A.T.
      • Kim T.M.
      • Crinò L.
      • et al.
      Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial.
      and ALUR,
      • Novello S.
      • Mazieres J.
      • Ou S.
      • et al.
      Primary results from the phase III ALUR study of alectinib versus chemotherapy in previously treated ALK+ non-small-cell lung cancer (NSCLC).
      respectively. Brigatinib also performed well in a patient with a G1202R ALK mutation, which is a common mechanism of resistance to crizotinib, ceritinib, and alectinib. One of the specific toxicities associated with brigatinib is early-onset pneumonia, which was reported in 6% (all grades) of patients starting treatment with brigatinib at 90 mg/d. Brigatinib is currently being compared with crizotinib in the phase III trial ALTA 1L.

      ClinicalTrials.gov. ALTA-1L study: a phase 3 study of brigatinib versus crizotinib in ALK-positive advanced non-small cell lung cancer patients. https://clinicaltrials.gov/ct2/show/NCT02737501. Accessed November 6, 2017.

      Third-Generation Inhibitor: Lorlatinib

      Lorlatinib is a potent ALK and ROS1 inhibitor with high CNS penetration and activity against mutations driving resistance to crizotinib, ceritinib, and alectinib, including G1202R.
      • Gainor J.F.
      • Dardaei L.
      • Yoda S.
      • et al.
      Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer.
      In a nonrandomized multicohort phase I/II trial, the ORR with lorlatinib was 90% in 30 TKI-naive patients (PFS NR), 69% in 59 crizotinib-treated patients (PFS NR), and 39% in 111 patients who had received two or three previous ALK TKIs (PFS 6.9 months). Impressive intracranial responses are reported, including a 48% ORR in the latter heavily pretreated cohort. Grade 3 or 4 treatment-related AEs were reported in 41% of patients (notably hyperlipidemia), and cognitive effects were present but mainly mild and reversible.

      Solomon BJ, Shaw A, Ou SH, et al. OA 05.06. Phase 2 study of lorlatinib in patients with advanced ALK+ROS1+ non-small-cell lung cancer. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      A phase III trial (CROWN) comparing lorlatinib with crizotinib is ongoing.

      ClinicalTrials.gov. A study of lorlatinib versus crizotinib in first line treatment of patients with ALK-positive NSCLC. https://clinicaltrials.gov/ct2/show/NCT03052608. Accessed November 6, 2017.

      Ensartinib, a potent ALK, tyrosine-protein kinase met (MET), and ROS1 inhibitor, gave an ORR of 87% and PFS of 26 months in a cohort of patients with TKI-naive ALK-positive NSCLC.
      • Horn L.
      • Wakeele K.
      • Reckamp K.
      • et al.
      Plasma genotyping of patients enrolled on the expansion phase I/II trial of X-396 in patients (pts) with ALK+ non-small cell lung cancer (NSCLC).
      The phase III eXalt3 trial is currently testing ensartinib versus crizotinib in the first-line setting.

      ClinicalTrials.gov. eXalt3: study comparing X-396 (ensartinib) to crizotinib in ALK positive non-small cell lung cancer (NSCLC) patients. https://clinicaltrials.gov/ct2/show/NCT02767804. Accessed November 6, 2017.

      ROS1 and NTRK Rearrangements

      Crizotinib is the current standard treatment in ROS1-rearranged NSCLC, after a 72% ORR and median PFS of 19.2 months reported in 50 TKI-naive patients.
      • Shaw A.T.
      • Ou S.-H.I.
      • Bang Y.-J.
      • et al.
      Crizotinib in ROS1-rearranged non-small-cell lung cancer.
      Ceritinib also showed a promising ORR and PFS (62% and 19 months, respectively) in a TKI-naive population.
      • Lim S.M.
      • Kim H.R.
      • Lee J.-S.
      • et al.
      Open-label, multicenter, phase II study of ceritinib in patients with non–small-cell lung cancer harboring ROS1 rearrangement.
      In 32 patients with untreated ROS1-rearranged NSCLC, entrectinib, a ROS and neurotropic tropomyosin receptor kinase (NTRK) TKI, showed an ORR of 78%, an intracranial response of 83%, and an impressive preliminary PFS of 29.6 months.

      Ahn MJ, Cho B, Siena S, et al. OA 14.06. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      Second-line TKIs are being developed. In 47 ROS1-positive patients, 70% of whom were crizotinib resistant, lorlatinib gave an ORR of 36%, an intracranial ORR of 56%, and a PFS of 9.6 months.

      ClinicalTrials.gov. ALTA-1L study: a phase 3 study of brigatinib versus crizotinib in ALK-positive advanced non-small cell lung cancer patients. https://clinicaltrials.gov/ct2/show/NCT02737501. Accessed November 6, 2017.

      G2032R mutations were recently identified in several small series as one of the most frequent mechanisms of resistance to ROS1 inhibition,
      • Gainor G.S.
      • Friboulet L.
      • Yoda S.
      • et al.
      Frequency and spectrum of ROS1 resistance mutations in ROS1-positive lung cancer patients progressing on crizotinib.
      and in preclinical studies most ROS1 next-generation TKIs (ceritinib
      • Awad M.M.
      • Katayama R.
      • McTigue M.
      • et al.
      Acquired resistance to crizotinib from a mutation in CD74-ROS1.
      , lorlatinib,
      • Facchinetti F.
      • Loriot Y.
      • Kuo M.-S.
      • et al.
      Crizotinib-resistant ROS1 mutations reveal a predictive kinase inhibitor sensitivity model for ROS1- and ALK-rearranged lung cancers.
      and entrectinib
      • Chong C.R.
      • Bahcall M.
      • Capelletti M.
      • et al.
      Identification of existing drugs that effectively target NTRK1 and ROS1 rearrangements in lung cancer.
      ) poorly inhibited G2032R-mutant tumors. On the contrary, cabozantinib, which is a multikinase inhibitor with ROS1 activity, demonstrated encouraging concentrations that inhibit 50% in ROS1 G2032R–mutant models.
      • Katayama R.
      • Kobayashi Y.
      • Friboulet L.
      • et al.
      Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer.
      The results of a phase II trial testing cabozantinib in patients with ROS1-rearranged NSCLC are awaited.

      ClinicalTrials.gov. Cabozantinib in patients with RET fusion-positive advanced non-small cell lung cancer and those with other genotypes: ROS1 or NTRK fusions or increased MET or AXL activity. https://clinicaltrials.gov/ct2/show/NCT01639508. Accessed November 6, 2017.

      The NTRK fusion gene was recently reported in up to 3.3% of patients with NSCLC negative for other common molecular drivers, but the results are preliminary and the incidence might be overestimated.
      • Vaishnavi A.
      • Capelletti M.
      • Le A.T.
      • et al.
      Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer.
      In addition to entrectinib, which showed impressive activity with complete intracranial response in a patient with sequestosome 1 gene (SQSTM1)–neurotrophic receptor tyrosine kinase 1 gene (NTRK1)–rearranged NSCLC included in the pooled analysis of the ALKA and STARTRK studies,
      • Drilon A.
      • Siena S.
      • Ou S.-H.I.
      • et al.
      Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1).
      larotrectinib (LOXO-101), which is a pan-TRK inhibitor, gave an ORR of 78% in adult and pediatric patients with different tumor types in a phase II study; all five patients with lung cancer had a partial response.
      • Hyman D.M.
      • Laetsch W.T.
      • Kummar S.
      The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers.
      These results led the FDA to grant orphan drug designation to larotrectinib for the treatment of solid tumors with neurotropic tropomyosin receptor kinase fusion proteins. Table 3

      Solomon BJ, Shaw A, Ou SH, et al. OA 05.06. Phase 2 study of lorlatinib in patients with advanced ALK+ROS1+ non-small-cell lung cancer. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      • Lim S.M.
      • Kim H.R.
      • Lee J.-S.
      • et al.
      Open-label, multicenter, phase II study of ceritinib in patients with non–small-cell lung cancer harboring ROS1 rearrangement.

      Ahn MJ, Cho B, Siena S, et al. OA 14.06. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      • Drilon A.
      • Siena S.
      • Ou S.-H.I.
      • et al.
      Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1).
      • Hyman D.M.
      • Laetsch W.T.
      • Kummar S.
      The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers.
      • Planchard D.
      • Smit E.F.
      • Groen H.J.M.
      • et al.
      Phase 2 trial (BRF113928) of dabrafenib (D) plus trametinib (T) in patients (pts) with previously untreated BRAF V600E–mutant metastatic non-small cell lung cancer.
      • Jänne P.A.
      • van den Heuvel M.M.
      • Barlesi F.
      • et al.
      Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial.
      • Yoh K.
      • Seto T.
      • Satouchi M.
      • et al.
      Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial.
      • Lee S.-H.
      • Lee J.-K.
      • Ahn M.-J.
      • et al.
      Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial.
      • Spigel D.R.
      • Edelman M.J.
      • O’Byrne K.
      • et al.
      Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung.
      • Scagliotti G.V.
      • MOro-Sibilot D.
      • Kollmeier J.
      • et al.
      A randomized, controlled, open label phase II study of erlotinib (E) with or without the MET antibody emibetuzumab (Emi) as first-line treatment for EGFRmt non-small cell lung cancer (NSCLC) patients who have disease control after an 8-week lead-in treatment with erlotinib.

      Ahn MJ, Han JY, Sequist L, et al. OA 09.03. TATTON Ph Ib expansion cohort: osimertinib plus savolitinib for Pts with EGFR-mutant MET-amplified NSCLC after progression on prior EGFR-TKI. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      • Smit E.
      • Peters S.
      • Dziadziuszko R.
      • et al.
      A single-arm phase II trial of afatinib in pretreated patients with advanced NSCLC harboring a HER2 mutation: the ETOP NICHE trial.
      • Stinchcombe T.
      • Stahel R.
      • Bubendorf L.
      • et al.
      Efficacy, safety, and biomarker results of trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-overexpressing locally advanced or metastatic non-small cell lung cancer (mNSCLC).

      Li B, Shen L, Buonocore D, et al. OA 14.05. Phase 2 basket trial of ado-trastuzumab emtansine in patients with HER2 mutant or amplified lung cancers. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      summarizes the major clinical trials in patients with ROS1- or NRTK-rearranged NSCLC during 2017.
      Table 3Clinical Trials in Non-EGFR or ALK-Positive, Oncogenic-Addicted NSCLC in 2017
      DriverDrugAuthorsPhaseTreatmentLinePatients, nORRPFS, moOS, mo
      ROS1LorlatinibSolomon et al.

      Solomon BJ, Shaw A, Ou SH, et al. OA 05.06. Phase 2 study of lorlatinib in patients with advanced ALK+ROS1+ non-small-cell lung cancer. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      I/IILorlatinibTKI exposed
      Seventy percent of patients were crizotinib resistant.
      4736%9.6NA
      EntrectinibAhn et al.

      Ahn MJ, Cho B, Siena S, et al. OA 14.06. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      IEntrectinibTKI naive3278%29.6NA
      CeritinibLim et al.
      • Lim S.M.
      • Kim H.R.
      • Lee J.-S.
      • et al.
      Open-label, multicenter, phase II study of ceritinib in patients with non–small-cell lung cancer harboring ROS1 rearrangement.
      IICeritinibTKI naive327219NA
      NTRKLarotrectinibHyman et al.
      • Hyman D.M.
      • Laetsch W.T.
      • Kummar S.
      The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers.
      ILarotrectinibNA5100%NANA
      EntrectinibDrilon et al.
      • Drilon A.
      • Siena S.
      • Ou S.-H.I.
      • et al.
      Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1).
      IEntrectinibNA1100%NANA
      BRAFDabrafenibPlanchard et al.
      • Planchard D.
      • Smit E.F.
      • Groen H.J.M.
      • et al.
      Phase 2 trial (BRF113928) of dabrafenib (D) plus trametinib (T) in patients (pts) with previously untreated BRAF V600E–mutant metastatic non-small cell lung cancer.
      IIDabrafenib + trametinibFirst3664%1125
      KRASSelumetinibJänne et al.
      • Jänne P.A.
      • van den Heuvel M.M.
      • Barlesi F.
      • et al.
      Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial.
      IIISelumetinib + docetaxel vs.

      placebo + docetaxel
      Second251

      254
      20% vs.

      13%
      3.9 vs.

      2.8 (p = 0.4)
      8.7 vs.

      7.9 (p = 0.6)
      RETVandetanibYoh et al.
      • Yoh K.
      • Seto T.
      • Satouchi M.
      • et al.
      Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial.
      IIVandetanib≥Third
      Forty-two percent of patients in third line.
      1947%4.711.1
      Lee et al.
      • Lee S.-H.
      • Lee J.-K.
      • Ahn M.-J.
      • et al.
      Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial.
      IIVandetanib≥Third
      Sixty-one percent of patients in the third line.
      1818%4.511.6
      METOnartuzumabSpigel et al.
      • Spigel D.R.
      • Edelman M.J.
      • O’Byrne K.
      • et al.
      Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung.
      IIIOnartuzumab + erlotinib vs. placebo + erlotinibSecond-3rd71 vs. 858.4 vs. 9.6%2.7 vs. 2.6 (p = 0.92)6.8 vs. 9.1 (p = 0.06)
      EmibetuzumabScagliotti et al.
      • Scagliotti G.V.
      • MOro-Sibilot D.
      • Kollmeier J.
      • et al.
      A randomized, controlled, open label phase II study of erlotinib (E) with or without the MET antibody emibetuzumab (Emi) as first-line treatment for EGFRmt non-small cell lung cancer (NSCLC) patients who have disease control after an 8-week lead-in treatment with erlotinib.
      IIEmibetuzumab + erlotinib vs. placebo + erlotinibFirst71 vs. 70NA9.3 vs. 9.5 (p = 0.54)NA
      SavolitinibAhn et al.

      Ahn MJ, Han JY, Sequist L, et al. OA 09.03. TATTON Ph Ib expansion cohort: osimertinib plus savolitinib for Pts with EGFR-mutant MET-amplified NSCLC after progression on prior EGFR-TKI. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      Savolitinib + osimertinib≥First
      All patients received one or more 1 EGFR tyrosine kinase inhibitors.
      4740%NANA
      HER2AfatinibSmit et al.
      • Smit E.
      • Peters S.
      • Dziadziuszko R.
      • et al.
      A single-arm phase II trial of afatinib in pretreated patients with advanced NSCLC harboring a HER2 mutation: the ETOP NICHE trial.
      IIAfatinib>First130%NANA
      T-DM1Stinchcombe et al.
      • Stinchcombe T.
      • Stahel R.
      • Bubendorf L.
      • et al.
      Efficacy, safety, and biomarker results of trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-overexpressing locally advanced or metastatic non-small cell lung cancer (mNSCLC).
      IIT-DM1>First4920%
      In IHC 3+ HER2-expressing patients.
      2.7
      In IHC 3+ HER2-expressing patients.
      12.1
      In IHC 3+ HER2-expressing patients.
      Li et al.

      Li B, Shen L, Buonocore D, et al. OA 14.05. Phase 2 basket trial of ado-trastuzumab emtansine in patients with HER2 mutant or amplified lung cancers. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      IIT-DM1>First1844%5NA
      ALK, ALK receptor tyrosine kinase gene; ORR, overall response rate; PFS, progression-free survival; OS, overall survival; TKI, tyrosine kinase inhibitor; NA, not available; NTRK, neurotrophic receptor tyrosine kinase gene; RET, ret proto-oncogene; MET, tyrosine-protein kinase met gene; HER2, erb-b2 receptor tyrosine kinase 2 gene; T-DM1, trastuzumab emtansine.
      a Seventy percent of patients were crizotinib resistant.
      b Forty-two percent of patients in third line.
      c Sixty-one percent of patients in the third line.
      d All patients received one or more 1 EGFR tyrosine kinase inhibitors.
      e In IHC 3+ HER2-expressing patients.

      BRAF and KRAS Mutations

      The BRAF V600E mutation, which has been identified in 1% to 2% of lung adenocarcinomas,
      • Kris M.G.
      • Johnson B.E.
      • Berry L.D.
      • et al.
      Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
      recently joined the list of targetable oncogenic drivers. The combination dabrafenib plus trametinib was highly active in patients with pretreated BRAF V600E–mutated NSCLC, with an updated OS of 18 months.
      • Planchard D.
      • Besse B.
      • Kim T.M.
      • et al.
      Updated survival of patients (pts) with previously treated BRAF V600E–mutant advanced non-small cell lung cancer (NSCLC) who received dabrafenib (D) or D + trametinib (T) in the phase II BRF113928 study.
      Recently, the combination showed an ORR of 64% and PFS of 11 months and a preliminary OS of 25 months in 36 treatment-naive patients. The toxicity profile was similar to that of equivalent agents, with drug-related grade 3 or 4 AEs in 36% of patients, the most common being pyrexia.
      • Planchard D.
      • Smit E.F.
      • Groen H.J.M.
      • et al.
      Phase 2 trial (BRF113928) of dabrafenib (D) plus trametinib (T) in patients (pts) with previously untreated BRAF V600E–mutant metastatic non-small cell lung cancer.
      On the basis of these results, the combination of dabrafenib and trametinib recently obtained EMA and FDA approval in patients with BRAF V600E–mutated NSCLC regardless of prior treatment.
      In contrast, the use of single-agent MEK inhibitors combined with chemotherapy in patients with KRAS-mutated NSCLC has been unsuccessful. Selumetinib, a highly selective MEK1/2 inhibitor was tested in combination with docetaxel in the phase III SELECT-1 trial.
      • Jänne P.A.
      • van den Heuvel M.M.
      • Barlesi F.
      • et al.
      Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial.
      No significant improvements were seen in ORR, PFS, or OS for the combination compared with docetaxel monotherapy in patients with previously treated KRAS-mutated NSCLC. More recently, abemaciclib, a selective inhibitor of cyclin-dependent kinase 4 and cyclin-dependent kinase 6, has been compared with erlotinib in a phase III trial (JUPINER) enrolling patients with KRAS-mutated pretreated NSCLC.

      ClinicalTrials.gov. A study of abemaciclib (LY2835219) in participants with previously treated KRAS mutated lung cancer. https://clinicaltrials.gov/ct2/show/NCT02152631. Accessed November 6, 2017.

      Results have not been published yet; however, JUPINER did not meet the primary end point of OS. Table 3 summarizes the results of major clinical trials in patients with BRAF- and KRAS-mutated NSCLC from 2017.

      RET Rearrangement

      RET rearrangements are found in 1% to 2% of lung adenocarcinomas.
      • Lipson D.
      • Capelletti M.
      • Yelensky R.
      • et al.
      Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.
      Several multitarget agents with anti-RET activity, including vandetanib, cabozantinib, lenvatinib, alectinib, and sunitinib, have been evaluated, with ORRs ranging from 16% to 47% and median PFS from 2.3 to 7.3 months.
      • Yoh K.
      • Seto T.
      • Satouchi M.
      • et al.
      Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial.
      • Lee S.-H.
      • Lee J.-K.
      • Ahn M.-J.
      • et al.
      Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial.
      • Drilon A.
      • Rekhtman N.
      • Arcila M.
      • et al.
      Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial.
      • Velcheti V.
      • Hida T.
      • Reckamp K.L.
      • et al.
      Phase 2 study of lenvatinib (LN) in patients (Pts) with RET fusion-positive adenocarcinoma of the lung.
      In 2017, two nonrandomized phase II trials investigated vandetanib in Japanese (LURET)
      • Yoh K.
      • Seto T.
      • Satouchi M.
      • et al.
      Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial.
      and Korean
      • Lee S.-H.
      • Lee J.-K.
      • Ahn M.-J.
      • et al.
      Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial.
      populations with RET-rearranged NSCLC. The ORR, median PFS, and OS were 53% and 5 and 11 months in the LURET study and 18% and 4.5 and 11.6 months in the Korean trial. In both studies the ORR was higher in patients with kinesin family member 5B gene (KIF5B)-RET fusion than in patients with the KIF5B-RET fusion (83% versus 20% in LURET and 33% versus 0% in the Korean trial) and the main treatment-related grade 3 to 4 AEs were hypertension and QT prolongation. A large retrospective worldwide analysis (GLORY) including 165 patients with RET-rearranged NSCLC treated with multitarget agents (vandetanib, cabozantinib, lenvatinib, sunitinib, sorafenib, alectinib, ponantinib, or regorafenib) also reported a disappointing ORR (26%), PFS (2.3 months), and OS (6.8 months).
      • Gautschi O.
      • Milia J.
      • Filleron T.
      • et al.
      Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry.
      Different mechanisms of escape to RET inhibition and some potential treatment strategies to overcome resistance have recently been described.
      • Ferrara R.
      • Auger N.
      • Auclin E.
      • et al.
      Clinical and translational implications of RET rearrangements in non-small cell lung cancer.
      The early onset of acquired resistance (as described for MDM2 proto-oncogene [MDM2] amplification
      • Somwar R.
      • Smith R.
      • Hayashi T.
      • et al.
      MDM2 amplification (Amp) to mediate cabozantinib resistance in patients (Pts) with advanced RET-rearranged lung cancers.
      ) and the existence of concomitant molecular alterations
      • Kim J.-O.
      • Lee J.
      • Shin J.-Y.
      • et al.
      The clinical characteristics of RET rearranged lung adenocarcinoma patients.
      • Klempner S.J.
      • Bazhenova L.A.
      • Braiteh F.S.
      • et al.
      Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR-mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI.
      • Michels S.
      • Scheel A.H.
      • Scheffler M.
      • et al.
      Clinicopathological characteristics of RET rearranged lung cancer in European patients.
      suggest that a combinatorial treatment strategy could be more effective than single-agent RET inhibition. This was also confirmed in a phase I study testing vandetanib and everolimus, which showed a preliminary ORR of 83% in a small series of patients with RET-rearranged NSCLC.
      • Cascone T.
      • Subbiah V.
      • Hess K.R.
      • et al.
      Significant systemic and CNS activity of RET inhibitor vandetanib combined with mTOR inhibitor everolimus in patients with advanced NSCLC with RET fusion.
      In addition, selective RET inhibitors such as LOXO-292 or BLU-667 are being developed with promising activity in both in vitro and in vivo models and in patients with KIF5B-RET fusions.

      Velcheti M, Bauer TM, Subbiah V et al. OA 12.07. LOXO-292, a potent, highly selective RET inhibitor, in MKI-resistant RET fusion-positive lung cancer patients with and without brain metastases. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      Table 3 summarizes the major clinical trials in patients with RET-rearranged NSCLC from 2017.

      MET Deregulation

      MET amplification and exon 14 mutations were initially detected in 3.3% of NSCLC, and both were negative prognostic factors for OS.
      • Tong J.H.
      • Yeung S.F.
      • Chan A.W.H.
      • et al.
      MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis.
      The existence of an overlap between EGFR and MET signaling in preclinical models
      • Matsubara D.
      • Ishikawa S.
      • Sachiko O.
      • Aburatani H.
      • Fukayama M.
      • Niki T.
      Co-activation of epidermal growth factor receptor and c-MET defines a distinct subset of lung adenocarcinomas.
      brought combined approaches blocking EGFR and MET in the absence of EGFR activating mutations. However, two phase III trials (ATTENTION
      • Yoshioka H.
      • Azuma K.
      • Yamamoto N.
      • et al.
      A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study).
      and METlung
      • Spigel D.R.
      • Edelman M.J.
      • O’Byrne K.
      • et al.
      Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung.
      ) testing erlotinib in combination with a MET inhibitor (tivantinib and onartuzumab, respectively) recently failed to show meaningful benefit. These results were confirmed by a negative randomized phase II trial exploring first-line erlotinib in combination with the MET inhibitor emibetuzumab in patients with EGFR-mutated NSCLC, although an exploratory analysis suggested a potential PFS benefit in high expressors of MET.
      • Scagliotti G.V.
      • MOro-Sibilot D.
      • Kollmeier J.
      • et al.
      A randomized, controlled, open label phase II study of erlotinib (E) with or without the MET antibody emibetuzumab (Emi) as first-line treatment for EGFRmt non-small cell lung cancer (NSCLC) patients who have disease control after an 8-week lead-in treatment with erlotinib.
      MET amplification was recently found to be a mechanism of resistance to osimertinib in EGFR-mutated NSCLC.
      • Piotrowska Z.
      • Thress K.S.
      • Mooradian M.
      • et al.
      MET amplification (amp) as a resistance mechanism to osimertinib.
      The expansion cohort of the phase Ib TATTON trial testing combined osimertinib and savolitinib, which is a MET inhibitor, in patients with EGFR-mutated and MET-positive NSCLC was presented at the 2017 World Conference on Lung Cancer. In patients centrally confirmed as MET positive by fluorescence in situ hybridization (MET gene copy ≥5 or MET/centrometer chromosome 7 ratio ≥2), the ORR was 40% in the overall population, 53% to 57% in patients who had not received a third EGFR TKI, and 28% in patients previously treated with a third-generation TKI.

      Ahn MJ, Han JY, Sequist L, et al. OA 09.03. TATTON Ph Ib expansion cohort: osimertinib plus savolitinib for Pts with EGFR-mutant MET-amplified NSCLC after progression on prior EGFR-TKI. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      The MET exon 14 skipping mutation is an oncogenic driver that can be successfully targeted with MET TKIs, as recently described in a multicentric retrospective study in patients with MET-mutated NSCLC, with OS extended to 25 months in patients treated with a MET TKI compared with 8 months in patients who were not.
      • Awad M.M.
      • Leonardi G.C.
      • Kravetz S.
      • et al.
      Impact of MET inhibitors on survival among patients (pts) with MET exon 14 mutant (METdel14) non-small cell lung cancer (NSCLC).
      This result confirmed reports from the expansion cohort of the PROFILE 1001 trial, which showed clinical activity of crizotinib in 10 of 15 patients with NSCLC with the MET exon 14 mutation.
      • Drilon A.E.
      • Camidge D.R.
      • Ou I.
      • et al.
      Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC).
      Table 3 summarizes the major clinical trials in patients with MET-deregulated NSCLC from 2017.

      HER2 Deregulation

      HER2 amplifications and mutations are present in 2% to 6% and 1% to 5% of NSCLC, respectively.
      • Liu L.
      • Shao X.
      • Gao W.
      • et al.
      The role of human epidermal growth factor receptor 2 as a prognostic factor in lung cancer: a meta-analysis of published data.
      • Heinmöller P.
      • Gross C.
      • Beyser K.
      • et al.
      HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin.
      Attempts to target it have been mostly unsuccessful. A phase II trial
      • Smit E.
      • Peters S.
      • Dziadziuszko R.
      • et al.
      A single-arm phase II trial of afatinib in pretreated patients with advanced NSCLC harboring a HER2 mutation: the ETOP NICHE trial.
      and a retrospective multicentric analysis
      • Lai V.
      • Lebas L.
      • Milia J.
      • et al.
      Afatinib in patients with metastatic HER2-mutant lung cancers: an international multicenter study.
      of afatinib in patients with HER2-mutated NSCLC showed ORRs of 0% and 15%, respectively, confirming the previous low ORR reported with dacomitinib (12%),
      • Kris M.G.
      • Camidge D.R.
      • Giaccone G.
      • et al.
      Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.
      neratinib (0%), and neratinib plus temsirolimus (19%).
      • Gandhi L.
      • Besse B.
      • Mazieres J.
      • et al.
      Neratinib ± tlimus in HER2-mutant lung cancers: an international, randomized phase II study.
      Furthermore, in tumors overexpressing erb-b2 receptor tyrosine kinase 2 (HER2) (immunohistochemistry [IHC] score of 2+ or 3+), the ORR of trastuzumab emtansine (TDM-1) was also disappointing (0% and 20%, respectively).
      • Stinchcombe T.
      • Stahel R.
      • Bubendorf L.
      • et al.
      Efficacy, safety, and biomarker results of trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-overexpressing locally advanced or metastatic non-small cell lung cancer (mNSCLC).
      However, in 18 HER2-mutant patients enrolled in a phase II trial the ORR was 44% and the median PFS was 5 months.

      Li B, Shen L, Buonocore D, et al. OA 14.05. Phase 2 basket trial of ado-trastuzumab emtansine in patients with HER2 mutant or amplified lung cancers. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      Interestingly, among responders, HER2 expression with IHC varied widely and was not predictive of benefit with T-DM1, suggesting that HER2 mutation may be a more promising target for TDM-1 therapy than HER2 overexpression. Table 3 summarizes the major clinical trials in patients with HER2-deregulated NSCLC from 2017.

      Advances in NSCLC: Chemotherapy

      The year 2017 did not bring any major revolutions in chemotherapy for patients with NSCLC. A combined analysis of the MILES-3 and MILES-4 trials evaluated the addition of first-line cisplatin, 60 mg/m2 every 3 weeks, to gemcitabine or pemetrexed in patients with NSCLC who are older than 70 years.
      • Gridelli C.
      • Morabito A.
      • Cavanna L.
      • et al.
      Efficacy of the addition of cisplatin to single-agent first-line chemotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC): a joint analysis of the multicenter, randomized phase III MILES-3 and MILES-4 studies.
      Unfortunately, these two trials were closed prematurely, with a trend to a worse OS in elderly patients with NSCLC when cisplatin was added.
      The AvaALL phase III trial showed no difference in OS (primary end point) when first-line bevacizumab was continued beyond progression in patients with NSCLC treated with a chemotherapy platinum doublet.
      • Benounna J.
      • De Castro J.
      • Dingemans A.E.
      • et al.
      Efficacy and safety results from AvaALL: an open-label, randomized phase III trial of standard of care (SOC) with or without continuous bevacizumab (Bev) treatment beyond progression (PD) in patients (pts) with advanced non-small cell lung cancer (NSCLC) progressing after first-line bev and chemotherapy (chemo).
      A subgroup analysis of ULTIMATE IFCT 1103 phase III trial, comparing second or third-line paclitaxel plus bevacizumab with docetaxel showed prolonged OS (>12 months) with the combination in patients naive to bevacizumab.
      • Cortot A.
      • Audigier-Vallette C.
      • Molinier O.
      • et al.
      Prolonged OS of patients exposed to weekly paclitaxel and bevacizumab: impact of the cross-over in the IFCT-1103 ULTIMATE study.
      Additionally, the activity of second-line antiangiogenic treatment is particularly valuable in patients who are refractory to first-line platinum-based chemotherapy. In an exploratory analysis of the REVEL trial, the OS benefit with ramucirumab plus docetaxel compared with single-agent docetaxel was higher in patients who relapsed within 9 weeks after starting first-line chemotherapy (8.3 versus 4.6 months).

      Reck M, Shepherd F, Perol M, et al. MA 03.06. Effect of 2L ramucirumab after rapid time to progression on 1L therapy: subgroup analysis of REVEL in advanced NSCLC. Paper presented at: IASLC 18th World Conference on Lung Cancer. October 15–18, 2017; Yokohama, Japan.

      Finally, the IFCT-GFPC 1101 trial showed no OS difference between pemetrexed continuation maintenance after cisplatin-pemetrexed treatment compared with a maintenance regimen (switch to pemetrexed or continuous gemcitabine) based on the ORR to cisplatin-gemcitabine induction chemotherapy.
      • Perol M.
      • Audigier-Vallette C.
      • Molinier O.
      • et al.
      IFCT-GFPC-1101 trial: a multicenter phase III assessing a maintenance strategy determined by response to induction chemotherapy compared to continuation maintenance with pemetrexed in patients (pts) with advanced non-squamous (NSCLC).

      Advances in SCLC and Mesothelioma: Targeted Therapy and Chemotherapy

      SCLC

      The phase III CONVERT trial compared the standard regimen of RT consisting of 45 Gy twice daily over 3 weeks to 66 Gy once daily over 45 days in combination with cisplatin-etoposide in limited-stage SCLC.
      • Faivre-Finn C.
      • Snee M.
      • Ashcroft L.
      • et al.
      Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.
      No significant survival benefit was observed, and twice-daily concurrent RT remains the standard. The 2-year OS rate was similar in both arms (50%–56%), which is numerically higher than the historical rates with concurrent RT (41%–47%),
      • Turrisi A.T.
      • Kim K.
      • Blum R.
      • et al.
      Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide.
      whereas the rates of radiation esophagitis and pneumonitis were remarkably inferior to those in previous studies of concurrent RT. These findings highlight improvements in staging procedures (i.e., positron emission tomography/computed tomography scan) and the use of modern and precise RT techniques in limited-stage SCLC.
      Several ongoing studies are exploring the activity of ICIs in the population of those with SCLC. In the phase Ib KEYNOTE-028 trial, the safety and efficacy of pembrolizumab at 10 mg/kg every 2 weeks for 2 years was assessed in 24 patients with advanced SCLC with at least 1% PD-L1 expression.
      • Ott P.A.
      • Elez E.
      • Hiret S.
      • et al.
      Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study.
      The safety profile was similar to that in previous studies, and grade 3 or 4 AEs occurred in 8% of patients. The ORR was 33% (95% CI: 16% to 55%) with one complete and seven partial responses, suggesting promising activity in patients with previously treated SCLC. Similarly, the randomized expansion cohort of the phase I/II CHECKMATE 032 trial showed that nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg every 3 weeks) for four cycles nearly doubled ORR (21% versus 11%) compared with nivolumab (3 mg/kg every 2 weeks) in patients with platinum-treated SCLC. However, the rate of grade 3 or 4 toxicities was also higher in the combination arm (37% versus 12%).
      • Hellmann M.D.
      • Ott P.A.
      • Zugazagoitia J.
      • et al.
      Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): first report of a randomized expansion cohort from CheckMate 032.
      Rovalpituzumab tesirine (Rova-T) is a delta like Notch canonical ligand 3 (DLL3)-targeted antibody drug conjugate that was developed in patients with recurrent SCLC.
      • Rudin C.M.
      • Pietanza M.C.
      • Bauer T.M.
      • et al.
      Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study.
      Rova-T showed a promising ORR (35%), PFS (4.3 months), and 1-year OS rate (30%) in patients with high DLL3 expression (≥50%) by IHC, representing 67% of the overall population. The main grade 3 and 4 treatment-related AEs were thrombocytopenia (12%), serosal effusions (11%), and skin toxicities (8%), and the recommended dose was two cycles at 0.3 mg/kg every 6 weeks. The nonrandomized phase II TRINITY study of Rova-T in patients with heavily pretreated DLL3-positive SCLC is ongoing, as are phase III trials of Rova-T as second-line and maintenance therapy.

      ClinicalTrials.gov. Study of rovalpituzumab tesirine (SC16LD6.5) for third-line and later treatment of subjects with relapsed or refractory delta-like protein 3-expressing small cell lung cancer (TRINITY). https://clinicaltrials.gov/ct2/show/NCT02674568. Accessed November 6, 2017.

      DLL3 is part of the Notch pathway, which is yet to be successfully targeted. A randomized phase II trial testing tarextumab, a Notch-inhibitor, in combination with platinum-etoposide chemotherapy in patients with extensive-stage SCLC, failed to show any significant improvement in PFS, ORR, or OS, and no predictive value was found for Notch pathway activation.
      • Daniel D.B.
      • Rudin C.M.
      • Hart L.
      • et al.
      Results of a randomized, placebo-controlled, phase 2 study of tarextumab (TRXT, anti-Notch2/3) in combination with etoposide and platinum (EP) in patients with untreated extensive small cell lung cancer.
      Other combinations have recently been tested in patients with SCLC. A randomized trial demonstrated that veliparib, a poly(ADP-ribose) polymerase 1 inhibitor, combined with platinum-based chemotherapy, slightly improved PFS over chemotherapy alone, without any significant difference in OS.
      • Owonikoko T.K.
      • Dahlberg S.E.
      • Sica G.
      • et al.
      Randomized trial of cisplatin and etoposide in combination with veliparib or placebo for extensive stage small cell lung cancer: ECOG-ACRIN 2511 study.
      Trilaciclib,
      • Lima C.
      • Robert P.
      • Priego V.
      • et al.
      Trilaciclib (G1T28): a cyclin dependent kinase 4/6 inhibitor, in combination with etoposide and carboplatin (EP) for extensive stage small cell lung cancer (ES-SCLC)—phase 1b results.
      a cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibitor, combined with chemotherapy showed a confirmed 88% ORR in 19 patients with extensive-stage SCLC, but these results are too preliminary to draw definitive conclusions. A drug that deserves further exploration is lurbinectedin, a DNA-damaging agent that has been tested in a multicohort study as monotherapy or in combination with doxorubicin or paclitaxel.
      • Garcia Olmedo M.E.
      • Forster M.
      • Calvo E.
      Activity of lurbinectedin as single agent and in combination in patients with advanced small cell lung cancer (SCLC).
      Lurbinectedin gave an ORR of 36% to 67% and median PFS of 3 to 5 months; however, toxicity was quite high, with a febrile neutropenia rate of 11% to 36%. In patients with pretreated extended-stage SCLC, the association of lurbinectedin and doxorubicin is currently being compared with topotecan or a cyclophosphamide-doxorubicin-vincristine combination in the phase III ATLANTIS trial.

      ClinicalTrials.gov. Clinical trial of lurbinectedin (PM01183)/doxorubicin (DOX) versus cyclophosphamide (CTX), doxorubicin (DOX) and vincristine (VCR) (CAV) or topotecan as treatment in patients with small-cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT02566993. Accessed November 6, 2017.

      MPM

      This year, interesting studies have been reported in patients with advanced malignant pleural mesothelioma (MPM), highlighting the promising role of ICIs in this population. In the IFCT-1501 MAPS2 phase II study, 125 patients with pretreated advanced mesothelioma (≥2 lines or ≥1 with platinum-pemetrexed) were randomized to receive nivolumab versus nivolumab plus ipilimumab (1 mg/kg every 6 weeks) in two noncomparative arms. The primary end point was disease control rate (DCR) at 12 weeks. Both arms reached their primary end point, with DCRs of 44% and 50% for the nivolumab and combination arms, respectively; toxicity was higher in the combination arm, but globally manageable. With a median follow-up of 10.4 months, the median PFS was 4.0 months with nivolumab and 5.6 months with the combination, and the median OS times were 10.4 months and NR, respectively.
      • Zalcman G.
      • Mazieres J.
      • Greillier L.
      • et al.
      Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: updated results of the IFCT-1501 MAPS2 randomized phase II trial.
      To date, the DETERMINE study is the only comparative study testing ICIs in MPM. This randomized, double-blind phase IIb trial compared tremelimumab, a CTLA4 inhibitor, with placebo as second- or third-line treatment in advanced MPM. Of 571 patients randomized, 569 received treatment (380 with 10 mg/kg of tremelimumab and 189 with placebo every 4 weeks times seven doses and then every 12 weeks). No significant differences in OS (primary end point) were observed (7–8 months for both treatment arms), and higher toxicity was reported with tremelimumab.
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      Finally, the KEYNOTE-028 phase Ib trial, assessed the safety and efficacy of pembrolizumab in 25 patients with previously treated MPM with PD-L1 expression of 1% or higher. The ORR was 20% (95% CI: 6.8–40.7) and the DCR was 72%. Responses were durable, with a median duration of 12 months (95% CI: 3.7–NR).
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      The role of antiangiogenic agents in MPM was confirmed by the LUME-Meso phase II trial which compared nintedanib plus platinum-pemetrexed to placebo plus platinum-pemetrexed in epithelioid or biphasic MPM.
      • Grosso F.
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      The updated analysis showed meaningful improvements in PFS (9.4 versus 5.7 months [p = 0.01], primarily in the epithelioid histologic type) and ORR (57% versus 44%), with a nonsignificant trend in OS benefit (18 versus 14 months [p = 0.31]). Treatment-related grade 3 or 4 toxicities were increased ALT level (14%) and diarrhea (7%).
      Finally, the expansion cohort of the phase I TRAP study testing ADI-PEG20, an arginine-degrading agent in combination with cisplatin-pemetrexed showed an encouraging ORR (35%), PFS (5.6 months), and OS (10.1 months) in MPM with loss of argininosuccinate synthase 1.
      • Phillips M.
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      Expansion study of ADI-PEG 20, pemetrexed and cisplatin in patients with ASS1-deficient malignant pleural mesothelioma (TRAP).
      However, hematologic grade 3 or 4 treatment-related AEs occurred in around 30% of patients. On the basis of these results, the ATOMIC-meso randomized phase II/III study is currently testing the combination of ADI-PEG20 and cisplatin-pemetrexed versus first-line platinum-pemetrexed chemotherapy in patients with MPM with argininosuccinate synthase 1 loss.

      ClinicalTrials.gov. Ph 2/3 study in subjects with MPM w/low ASS 1 expression to assess ADI-PEG 20 with pemetrexed and cisplatin. https://clinicaltrials.gov/ct2/show/NCT02709512. Accessed November 6, 2017.

      Thymic Malignancies

      In the phase Ia JAVELIN study, eight patients with thymic epithelial tumors (thymoma and thymic carcinoma) received durvalumab, five at 10 mg/kg and three at 20 mg/kg. Three of the eight patients (38%) experienced a partial response.
      • Heery C.R.
      • O’Sullivan-Coyne G.
      • Madan R.A.
      • et al.
      Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.
      A phase II study of pembrolizumab in patients with refractory thymic epithelial tumors was recently presented. Patients who progressed after platinum-containing chemotherapy received 200 mg of pembrolizumab every 3 weeks. A total of 33 patients were enrolled (26 with thymic carcinoma and seven with thymoma). The ORR and DCR were 24% and 76%, respectively. Observed grade 3 or 4 irAEs included hepatitis (12%), myocarditis (9%), myasthenia gravis (6%), and thyroiditis (3%). The rate of discontinuation due to irAEs was 24%.
      • Cho J.
      • Ahn M.J.
      • Yoo K.H.
      • et al.
      A phase II study of pembrolizumab for patients with previously treated advanced thymic epithelial tumor.
      A twin phase II study testing pembrolizumab in patients with thymic carcinoma showed an ORR of 22.5% and again a high incidence of irAEs (myocarditis, hepatitis, and thyroid disfunctions) probably because of a worsening of autoimmune disorders typically observed in patients with thymic malignancies.
      • Giaccone G.
      • Thompson J.
      • McCuire C.
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      Pembrolizumab in patients with recurrent thymic carcinoma: results from a phase II study.

      Conclusion

      During the course of 2017, several studies reshaped the treatment paradigm of advanced NSCLC. ICIs have a confirmed long-term survival benefit in pretreated patients and in untreated patients with PD-L1 expression of 50% or higher. In the first-line setting, anti–PD-1/PD-L1 agents in combination with chemotherapy or anti-CTLA4 showed promising preliminary results. In patients with EGFR or ALK-positive NSCLC, efficacy of ICIs was limited; however, predictive biomarkers (notably PD-L1) could be useful to identify potential responders. In addition, preliminary data suggest a benefit from continuing immune checkpoint blockade until disease progression, and correlations between drug exposure or AEs and activity of ICIs were recently reported. PD-L1 was not a reliable biomarker for atezolizumab efficacy in second or further lines, and different competitive predictive biomarkers such as TMB came of age. Finally, acceleration of tumor growth during ICI treatment was described for the first time in a subgroup of patients with NSCLC and appeared to correlate with poor survival.
      Regarding oncogene-addicted NSCLC, next-generation TKIs for EGFR (osimertinib) and ALK (alectinib) showed promising activity and PFS compared with first-generation drugs; however, given the lack of mature OS data the best treatment strategy is yet to be determined. New potent drugs (lorlatinib, entrectinib, and larotrectinib) showed encouraging results in ROS1- or NTRK-rearranged NSCLC. Finally, RET-rearrangements and BRAF, MET exon 14, and HER2 mutations joined the list of targetable oncogenic drivers, with favorable responses for different TKIs as monotherapy or in combination (dabrafenib plus trametinib in patients with BRAF-mutated NSCLC).
      On the other hand, treatment of SCLC, MPM, and thymic malignancies did not experience any major changes in 2017. For SCLC, preliminary data suggest a potential benefit with ICIs, and remarkable clinical activity was seen with anti-DDL3 therapies (Rova-T) and novel chemotherapeutic agents (lurbinectedin). Finally, ICIs showed compelling results in MPM or thymic malignancies, and it is hoped that future studies will provide physicians and patients with promising new therapeutic options.

      Acknowledgments

      Dr. Ferrara was the recipient of the Diploma in Clinical and Translational Research in Oncology grant for the year 2016–2017. Dr. Ferrara was also the recipient of the of the International Association for the Study of Lung Cancer Young Investigator Award for 2017–2018. We thank Dr. Sarah MacKenzie, PhD, for medical writing support in the preparation of this manuscript.

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