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Durvalumab for Stage III EGFR-Mutated NSCLC After Definitive Chemoradiotherapy

Open ArchivePublished:February 11, 2021DOI:https://doi.org/10.1016/j.jtho.2021.01.1628

      Abstract

      Introduction

      In 2018, durvalumab was approved by the U.S. Food and Drug Administration as consolidation immunotherapy for patients with stage III NSCLC after definitive chemoradiotherapy (CRT). However, whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown.

      Methods

      We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab.

      Results

      Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab owing to progression and five owing to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and eight completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKIs). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank p = 0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 mo) compared with CRT and durvalumab or CRT alone (log-rank p = 0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib.

      Conclusions

      In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction or consolidation EGFR TKIs further investigated as definitive treatment.

      Keywords

      Introduction

      Approximately one-third of patients with NSCLC are diagnosed with having locally advanced disease. For patients with unresectable stage III NSCLC, the standard of care is platinum-based concurrent chemoradiotherapy (CRT) followed by 1 year of consolidation durvalumab (anti–programmed death-ligand 1 [PD-L1] immunotherapy) on the basis of the results of the PACIFIC trial.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      Historically, median progression-free survival (PFS) after CRT alone has been low despite its administration with curative intent, ranging from 9 to 12 months after CRT initiation.
      • Senan S.
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      PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer.
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      Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: cancer and leukemia group B trial 30407.
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      Long-term results of NRG oncology RTOG 0617: standard- versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage III non-small-cell lung cancer.
      Furthermore, PFS after CRT alone may be even lower among patients with tumors that harbor activating EGFR mutations, ranging from 6 to 9 months in retrospective studies.
      • Tanaka K.
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      EGFR mutation impact on definitive concurrent chemoradiation therapy for inoperable stage III adenocarcinoma.
      • Ishihara M.
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      Evaluation of concurrent chemoradiotherapy for locally advanced NSCLC according to EGFR mutation status.
      • Park S.E.
      • Noh J.M.
      • Kim Y.J.
      • et al.
      EGFR mutation is associated with short progression-free survival in patients with stage III non-squamous cell lung cancer treated with concurrent chemoradiotherapy.
      Studies have also shown that patients with EGFR-mutated NSCLC experience recurrence with higher rates of distant metastases,
      • Tanaka K.
      • Hida T.
      • Oya Y.
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      EGFR mutation impact on definitive concurrent chemoradiation therapy for inoperable stage III adenocarcinoma.
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      • Ishihara M.
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      Evaluation of concurrent chemoradiotherapy for locally advanced NSCLC according to EGFR mutation status.
      underscoring the need for definitive treatments that enhance both local and systemic control.
      The PACIFIC trial was a phase 3 clinical trial in which 713 patients with unresectable stage III NSCLC who completed platinum-based concurrent CRT were randomized to receive consolidation durvalumab versus placebo every 2 weeks for up to 12 months.
      • Antonia S.J.
      • Villegas A.
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      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      ,
      • Antonia S.J.
      • Villegas A.
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      • et al.
      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      The trial met its coprimary end points, with durvalumab demonstrating a 45% reduction in risk of recurrence and a 29% reduction in risk of overall mortality compared with placebo.
      • Faivre-Finn C.
      • Vicente D.
      • Kurata T.
      • et al.
      Brief report: four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC - an update from the PACIFIC trial.
      Within the trial population, only 43 patients (6%) had tumors harboring confirmed EGFR mutations. Accordingly, the subset analyses evaluating PFS (hazard ratio [HR] = 0.84, 95% confidence interval [CI]: 0.40–1.75) and overall survival (OS) (HR = 0.97, 95% CI: 0.40–2.33) between durvalumab and placebo were inconclusive in these patients.
      • Faivre-Finn C.
      • Vicente D.
      • Kurata T.
      • et al.
      Brief report: four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC - an update from the PACIFIC trial.
      As a result, the impact of durvalumab remains unknown in patients with EGFR-mutated NSCLC.
      To further complicate this assessment, recent data have raised concerns on the safety of EGFR tyrosine kinase inhibitors (TKIs) after recent immunotherapy administration. TATTON was a phase 1b clinical trial evaluating the concurrent administration of osimertinib, a third-generation EGFR TKI, and durvalumab in patients with EGFR-mutated NSCLC.
      • Ahn M.J.
      • Yang J.
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      Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: results from the TATTON phase Ib trial.
      The trial was halted owing to 38% and 15% of patients experiencing any grade and grade 3 to 4 interstitial lung disease, respectively. Subsequently, a retrospective review of patients with advanced EGFR-mutated NSCLC found that 15% of patients who received sequential immunotherapy followed by osimertinib experienced severe immune-related adverse events (irAEs), which most often occurred if osimertinib was initiated within 3 months of immunotherapy.
      • Schoenfeld A.J.
      • Arbour K.C.
      • Rizvi H.
      • et al.
      Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib.
      As patients with stage III EGFR-mutated NSCLC remain at high risk of recurrence after definitive treatment, a fair proportion may need to initiate EGFR TKIs soon after durvalumab. Thus, the long-term safety and efficacy of durvalumab for these patients need to be elucidated.
      In this multi-institutional retrospective study, we describe the experiences of patients with unresectable stage III EGFR-mutated NSCLC who received consolidation durvalumab after concurrent CRT. We evaluated the clinical outcomes of patients who completed CRT and durvalumab compared with CRT alone and a subset of patients who received CRT with induction or consolidation EGFR TKIs. Finally, we evaluated the impact of durvalumab on toxicities and outcomes with subsequent EGFR TKI treatment in patients who experienced disease recurrence.

      Materials and Methods

      Study Design

      Patients with unresectable stage III NSCLC with activating EGFR mutations who completed concurrent platinum-based CRT between January 2017 and November 2020 were identified from the following four academic medical centers: Stanford Cancer Institute, City of Hope, University of California, San Francisco, and University of California, Davis. All sites obtained local Institutional Review Board approval for participating in this study. Patients had EGFR molecular testing performed in their standard-of-care evaluation at baseline through next-generation sequencing panels or targeted gene assays (Supplementary Table 1). Patients were classified as receiving durvalumab if they received at least one cycle of durvalumab after completing CRT. All other patients who did not receive durvalumab were classified as completing CRT without durvalumab. In a subgroup analysis, patients who received EGFR TKIs for the purposes of induction or consolidation treatment with CRT were further distinguished from those who received CRT alone (without durvalumab or EGFR TKI).
      Baseline demographic, clinical, and pathologic data were abstracted from patients’ electronic health records. NSCLC histology was classified according to WHO criteria.
      • Travis W.D.
      • Brambilla E.
      • Nicholson A.G.
      • et al.
      The 2015 World Health Organization Classification of Lung Tumors: impact of genetic, clinical and radiologic advances since the 2004 classification.
      Disease staging was based on the eighth edition of the American Joint Committee on Cancer and International Union Against Cancer TNM stage classification for lung cancer.
      • Detterbeck F.C.
      • Boffa D.J.
      • Kim A.W.
      • Tanoue L.T.
      The eighth edition lung cancer stage classification.
      The PD-L1 tumor proportion score (TPS) was ascertained from pathological or molecular sequencing reports in patients who had anti–PD-L1 immunohistochemistry performed.

      Study Outcomes

      PFS was measured from the date of CRT completion (unless otherwise stated) to the date of recurrence, death from any cause, or last follow-up, whichever came first. Recurrence was evaluated pathologically or radiographically on the basis of the Response Evaluation Criteria in Solid Tumors version 1.1.
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      OS was measured from the date of CRT completion to the date of death from any cause or last follow-up. Adverse events (AEs) owing to durvalumab were classified according to the Common Terminology Criteria for Adverse Events version 5.0. We defined severe irAEs as AEs that were attributed to durvalumab by the treating clinician, required immunosuppression (i.e., oral corticosteroids), and were treated as irAEs according to standard oncologic guidelines.

      National Comprehensive Cancer Network. Management of immunotherapy-related toxicities (version 1.2020). https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed October 4, 2020.

      ,
      • Brahmer J.R.
      • Lacchetti C.
      • Schneider B.J.
      • et al.
      Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline.
      High-dose corticosteroids were defined as greater than 20 mg/day of oral prednisone.

      Statistical Analysis

      Kaplan-Meier survival curves were generated to evaluate PFS and OS across treatment groups, and the log-rank test was used for subgroup comparisons. Survival analyses were supplemented with Cox proportional hazards regression models which estimated HRs for PFS in treatment group comparisons. The proportional hazards assumption was confirmed for all Cox models. Patient characteristics were evaluated between treatment groups using Fisher’s exact test for categorical variables and the t test or Wilcoxon ranked sum test for continuous variables. Statistical significance was defined at a two-sided p value less than 0.05. All statistical analyses were performed using R version 4.0.2 (Vienna, Austria).

      Results

      Patient Characteristics

      In total, 37 patients were included in the cohort (Table 1). The mean age at CRT completion was 68.1 years, and most patients were of female sex (78.4%) and never smoking (73.0%). The lung cancers were predominantly adenocarcinoma (91.9%), and most patients had stage IIIA (43.2%) or IIIB (45.9%) disease at CRT initiation. Eastern Cooperative Oncology Group performance status was 0 to 1 at CRT completion in most cases (86.5%). Patients who received CRT without durvalumab compared with CRT and durvalumab were more likely to be white (70.8% versus 38.5%) and of female sex (87.5% versus 61.5%), otherwise the baseline characteristics were similar between the two groups.
      Table 1Patient Characteristics
      CharacteristicsAll

      N = 37
      CRT + Durvalumab n = 13CRT Wo Durvalumab n = 24p Value
      p value was calculated across treatment groups for categorical data using Fisher’s exact test and for continuous data using the t test or Wilcoxon ranked sum test.
      Age at CRT completion (y), mean (SD)68.1 (9.6)67.6 (12.1)68.3 (8.3)0.832
      Sex, n (%)0.158
       Male8 (21.6)5 (38.5)3 (12.5)
       Female29 (78.4)8 (61.5)21 (87.5)
      Race/ethnicity, n (%)0.038
       White22 (59.5)5 (38.5)17 (70.8)
       Asian13 (35.1)8 (61.5)5 (20.8)
       Hispanic/Latino2 (5.4)0 (0.0)2 (8.3)
      Smoking status, n (%)0.992
       Never27 (73.0)10 (76.9)17 (70.8)
       Former10 (27.0)3 (23.1)7 (29.2)
      Histology, n (%)0.340
       Adenocarcinoma34 (91.9)11 (84.6)23 (95.8)
       Squamous1 (2.7)1 (7.7)0 (0.0)
       Adenosquamous2 (5.4)1 (7.7)1 (4.2)
      Stage at CRT initiation, n (%)0.756
       IIIA16 (43.2)5 (38.5)11 (45.8)
       IIIB17 (45.9)7 (53.8)10 (41.7)
       IIIC4 (10.8)1 (7.7)3 (12.5)
      EGFR mutation, n (%)0.484
       Exon 19 deletion14 (37.8)4 (30.8)10 (41.7)
       L858R18 (48.6)8 (61.5)10 (41.7)
       Other5 (13.5)1 (7.7)4 (16.7)
      PD-L1 expression, n (%)0.002
       Negative (0% TPS)7 (18.9)2 (15.4)5 (20.8)
       Low (1%–49% TPS)8 (21.6)4 (30.8)4 (16.7)
       High (≥50% TPS)9 (24.3)7 (53.8)2 (8.3)
       Not tested13 (35.1)0 (0.0)13 (54.2)
      Induction therapy before CRT, n (%)
       EGFR TKI4 (10.8)0 (0.0)4 (16.7)0.315
      CRT chemotherapy regimen, n (%)0.880
       Cisplatin/etoposide4 (10.8)2 (15.4)2 (8.3)
       Cisplatin/pemetrexed7 (18.9)2 (15.4)5 (20.8)
       Carboplatin/pemetrexed15 (40.5)5 (38.5)10 (41.7)
       Carboplatin/paclitaxel10 (27.0)4 (30.8)6 (25.0)
       Carboplatin/nab-paclitaxel1 (2.7)0 (0.0)1 (4.2)
      Radiotherapy dose (Gy), n (%)0.443
       441 (2.7)0 (0.0)1 (4.2)
       451 (2.7)0 (0.0)1 (4.2)
       501 (2.7)1 (7.7)0 (0.0)
       542 (5.4)0 (0.0)2 (8.3)
       6019 (51.4)6 (46.2)13 (54.2)
       6612 (32.4)6 (46.2)6 (25.0)
       69.61 (2.7)0 (0.0)1 (4.2)
      ECOG PS at CRT completion, n (%)0.142
       0–132 (86.5)10 (76.9)22 (91.7)
       22 (5.4)2 (15.4)0 (0.0)
       Unknown3 (8.1)1 (7.7)2 (8.3)
      Consolidation therapy after CRT, n (%)
       Chemotherapy10 (27.0)1 (7.7)9 (37.5)0.118
       EGFR TKI4 (10.8)0 (0.0)4 (16.7)0.315
      Follow-up (mo), median (IQR)21.8 (11–37)18.6 (15–27)23.0 (11–39)0.324
      Note: Percentages may not sum to 100% owing to rounding.
      CRT, chemoradiotherapy; ECOG, Eastern Cooperative Oncology Group; IQR, interquartile range; PD-L1, programmed death-ligand 1; PS, performance status; TKI, tyrosine kinase inhibitor; TPS, tumor proportion score; Wo, without.
      a p value was calculated across treatment groups for categorical data using Fisher’s exact test and for continuous data using the t test or Wilcoxon ranked sum test.
      Overall, 18 patients (48.6%) had EGFR L858R mutations and 14 (37.8%) had exon 19 deletions (Table 1 and Fig. 1). Uncommon EGFR driver mutations included exon 20 insertions (n = 2), G719A (n = 1), exon 19 insertion (n = 1), and L747P (n = 1). No significant differences in EGFR mutation subtypes were observed between the CRT treatment groups (p = 0.484). Co-occurring mutations most often occurred in TP53 and CTNNB1, and the frequencies did not substantially differ among those tested between treatment groups. Among patients with available PD-L1 expression (N = 24), nine (37.5%) had high (≥50% TPS), eight (33.3%) had low (1%–49% TPS), and seven (29.2%) had no PD-L1 expression. There were no significant differences in PD-L1 expression between CRT treatment groups among those tested for PD-L1 (p = 0.141). However, PD-L1 expression significantly differed between CRT treatment groups overall as all patients who completed CRT and durvalumab had PD-L1 testing performed whereas most patients who had CRT without durvalumab did not have PD-L1 testing (Table 1).
      Figure thumbnail gr1
      Figure 1Molecular features of the EGFR-mutated NSCLC cohort (N = 37). OncoPrint summarizes the definitive treatment regimen that patients received, PD-L1 expression, and co-occurring mutations in the upper panel and EGFR mutation subtypes or copy number variation in the lower panel. Each column represents one patient. The bar graphs and percentages correspond to the frequencies of the EGFR mutations across the cohort. Amp, amplification; CRT, chemoradiotherapy; del, deletion; ins, insertion; PD-L1, programmed death-ligand 1; VUS, variant of unknown significance; wo, without.
      Most patients received carboplatin/pemetrexed (40.5%) as their chemotherapy regimen during CRT (Table 1). Furthermore, most patients completed a radiotherapy dose totaling 60 Gy (51.4%) or 66 Gy (32.4%). There were no major differences in CRT treatment regimens between the CRT treatment groups. As expected, a higher frequency of patients who completed CRT without durvalumab versus with durvalumab received consolidation chemotherapy, though the difference was not statistically significant (37.5% versus 7.7%, p = 0.118). Four patients who completed CRT without durvalumab received induction EGFR TKIs before CRT, and another four patients received EGFR TKIs as consolidation treatment after CRT per the standard practice of their treating physicians. None who received CRT and durvalumab had induction or consolidation EGFR TKIs.

      CRT With Consolidation Durvalumab

      A total of 13 patients initiated consolidation durvalumab a median of 20 days (interquartile range [IQR]: 17–49) after completing CRT (Fig. 2A). Patients received a median of six cycles (IQR: 4–14) of durvalumab (Fig. 2B), with one patient (7.7%) receiving durvalumab every 4 weeks and all others receiving durvalumab every 2 weeks. Only two patients (15.4%) completed 12 months of durvalumab. Reasons for durvalumab discontinuation included severe irAEs (n = 5, 38.5%), disease progression (n = 5, 38.5%), and cognitive decline (n = 1, 7.7%). One patient developed a severe irAE at the time of disease progression (patient no. 3), but the primary reason for durvalumab discontinuation was owing to progression.
      Figure thumbnail gr2
      Figure 2Time intervals surrounding consolidation durvalumab and EGFR TKI initiation. (A) The median time from CRT completion to durvalumab initiation was 20 days (IQR: 17–49; 2.9 wk). (B) Patients received a median of six cycles (IQR: 4–14) of durvalumab. (C) Median time from durvalumab initiation to severe irAE was 95 days (IQR: 33–151). (D) Median time from the last durvalumab dose to EGFR TKI initiation was 71 days (IQR: 51–168). ∗Patient completed 12 months of consolidation durvalumab but only 24 cycles were recorded in the available documentation. ∗∗One patient experienced a severe irAE (colitis) a few days after completing the second cycle of durvalumab; thus, the patient was included in the 0- to 30-day bin and a close approximation (20 d) was used when calculating the median time to severe irAE. ∗∗∗One patient initiated osimertinib 588 days after the last dose of durvalumab and experienced an incident grade 4 pneumonitis while on osimertinib. CRT, chemoradiotherapy, IQR, interquartile range, irAE, immune-related adverse event; TKI, tyrosine kinase inhibitor.
      Among 12 assessable patients, all experienced AEs (Supplementary Table 2). The most common all-grade AEs included fatigue (n = 7, 58.3%), cough (n = 6, 50.0%), dyspnea (n = 3, 25.0%), and pneumonitis (n = 3, 25.0%). Severe irAEs occurred in six patients overall (46.2%), with three patients experiencing pneumonitis (one grade 2, two grade 3) and one patient each developing myocarditis (grade 3), hepatitis (grade 2), and colitis (grade 3) (Table 2). The median time from durvalumab initiation to onset of the severe irAE was 95 days (IQR: 33–151; Fig. 2C). Although two patients experienced severe irAEs within 1 month of starting durvalumab, most had these events after multiple cycles of treatment. All patients with severe irAEs were hospitalized for their symptoms, where the irAEs were adjudicated by specialists (Table 2). Although it is possible that the grade 3 pneumonitis in the patient who initiated durvalumab 2 days before (patient no. 2) was radiation induced,
      • Choi Y.W.
      • Munden R.F.
      • Erasmus J.J.
      • et al.
      Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis.
      ,
      • Naidoo J.
      • Nishino M.
      • Patel S.P.
      • et al.
      Immune-related pneumonitis after chemoradiotherapy and subsequent immune checkpoint blockade in unresectable stage III non-small-cell lung cancer.
      the patient’s records indicate that the onset of symptoms was distinctly after the infusion, suggesting at least a component of the pneumonitis was due to durvalumab. All initiated oral corticosteroids for treatment, with all except one patient requiring high-dose corticosteroids. No additional forms of immunosuppression were administered. None had obvious risk factors, such as a history of autoimmune disease. EGFR mutations, co-occurring alterations, and PD-L1 expression varied within this group. All recovered from the severe irAE, and none resumed further treatment with durvalumab.
      Table 2Characteristics of Patients Who Developed Severe irAEs While Receiving Durvalumab (n = 6)
      Patient No.EGFR MutationCoalterationsPD-L1 Expression (% TPS)Cycle(s) of DurvalumabTime From First Cycle of Durvalumab to irAE Onset, dirAECTCAE GradeRequired Hospitalization?Required High-Dose Steroids?PFS From CRT Completion, mo
      1L858RTP53mut, APCmut09120Pneumonitis3YesYes21.5
      2Exon 20 insertionCTNNB1mut, U2AF1mut012Pneumonitis3YesYes12.0
      3L858RTP53mut, ATMmut, EGFR amp206
      Patient received one cycle of durvalumab every 4 weeks. All other patients received one cycle of durvalumab every 2 weeks.
      161Pneumonitis2YesNo
      Patient initiated oral corticosteroids for the treatment of pneumonitis but did not initiate high-dose corticosteroids (>20 mg/d of oral prednisone).
      7.6
      4L858RSMAD4mut1570Myocarditis3YesYes16.3 (censored)
      5Exon 19 deletionTP53mut10014201Hepatitis2YesYes8.5
      6Exon 19 deletionNot tested602∼20
      Patient experienced grade 3 colitis a few days after receiving the second cycle of durvalumab. Exact date of event was unavailable; thus, a close approximation was provided.
      Colitis3YesYes10.3
      Note: Severe irAEs were defined as AEs attributed to durvalumab, required oral corticosteroids, and were treated as irAEs according to standard oncologic guidelines. High-dose steroids were defined as greater than 20 mg/day of oral prednisone.
      AE, adverse event; amp, amplification; CRT, chemoradiotherapy; CTCAE, Common Terminology Criteria for Adverse Events version 5.0; irAE, immune-related adverse event; mut, mutated; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TPS, tumor proportion score.
      a Patient received one cycle of durvalumab every 4 weeks. All other patients received one cycle of durvalumab every 2 weeks.
      b Patient initiated oral corticosteroids for the treatment of pneumonitis but did not initiate high-dose corticosteroids (>20 mg/d of oral prednisone).
      c Patient experienced grade 3 colitis a few days after receiving the second cycle of durvalumab. Exact date of event was unavailable; thus, a close approximation was provided.

      CRT Alone or With EGFR TKI

      A total of 24 patients completed concurrent CRT without durvalumab. The two most common documented reasons for withholding durvalumab included the oncologist’s concerns on the efficacy or safety of durvalumab with EGFR-mutated NSCLC (n = 9) and because patients received consolidation EGFR TKIs instead per the physician’s standard treatment preference (n = 4; Supplementary Fig. 1).
      Within this group, eight patients completed CRT with EGFR TKIs as either induction (n = 4) or consolidation (n = 4) therapy (Supplementary Table 3). As induction therapy, patients received either osimertinib (n = 3) or erlotinib (n = 1) for a median of 4.5 months (IQR: 3–7) and one patient received consolidation chemotherapy after CRT. As consolidation therapy, patients received erlotinib (n = 2), gefitinib (n = 1), or afatinib (n = 1) for a median of 17 months (IQR: 8–30), with one patient continuing erlotinib after progression.

      Progression-Free Survival

      In the overall cohort, the median follow-up time was 21.8 months (IQR: 11–37) after concurrent CRT. A total of 23 patients (62.2%) experienced recurrence after concurrent CRT. Median PFS was 12.0 months (95% CI: 7.6–not reached [NR]), and OS data were immature at data cutoff (Supplementary Fig. 2). Median PFS among patients who received CRT and durvalumab compared with CRT without durvalumab (but with or without EGFR TKI) was 10.3 months versus 22.8 months (HR = 1.78, 95% CI: 0.76–4.16, log-rank p = 0.180; Fig. 3A). Recurrence occurred most frequently in the ipsilateral lung (29.7%) followed by the brain (27.0%) and contralateral lung (21.6%) among all patients (Supplementary Table 4). Patients who received CRT and durvalumab experienced recurrence most frequently in the brain (38.5%), whereas patients who received CRT without durvalumab (but some with EGFR TKI) had relatively higher recurrence in the ipsilateral and contralateral lungs than in the brain (29.2% versus 25.0% versus 20.8%).
      Figure thumbnail gr3
      Figure 3PFS after chemoradiotherapy with or wo durvalumab. (A) Median PFS among patients who completed CRT and durvalumab versus CRT wo durvalumab was 10.3 months versus 22.8 months (log-rank p = 0.180). (B) Median PFS among patients who completed CRT alone versus CRT and durvalumab versus CRT and induction or consolidation EGFR TKI was 6.9 months versus 10.3 months versus 26.1 months (log-rank p = 0.023). CRT, chemoradiotherapy; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; wo, without.
      When distinguishing patients who received induction or consolidation EGFR TKIs from those who completed CRT alone (Supplementary Table 5), median PFS did not significantly differ between those who received CRT and durvalumab and CRT alone (10.3 mo versus 6.9 mo, log-rank p = 0.993; Supplementary Fig. 3), whereas those who received CRT and EGFR TKI had a significantly longer median PFS (26.1 mo) than the other two CRT treatment groups (log-rank p = 0.023; Fig. 3B). Cox analysis confirmed the negligible difference in recurrence risk between CRT and durvalumab and CRT alone (HR = 1.06, 95% CI: 0.44–2.52). However, treatment with CRT and EGFR TKI was associated with a significantly reduced risk of recurrence compared with CRT alone (HR = 0.16, 95% CI: 0.03–0.73) and CRT and durvalumab (HR = 0.15, 95% CI: 0.03–0.72).
      Among the 13 patients who received CRT and durvalumab, exploratory analyses were conducted to identify factors associated with differences in PFS (Supplementary Fig. 4). From the date of durvalumab initiation, the overall median PFS was 8.0 months (95% CI: 2.3–NR). There were no significant differences in median PFS in these patients when stratified by PD-L1 expression, severe irAEs, and EGFR mutation subtype. However, given the small sample size of this subset analysis, further validation of these results is required.

      EGFR TKIs After CRT

      Among six patients who progressed on CRT and durvalumab and subsequently initiated EGFR TKIs, the median time from the last durvalumab dose to EGFR TKI initiation was 71 days (IQR: 51–168; Fig. 2D). EGFR TKIs included osimertinib (n = 5) and erlotinib (n = 1). With a median follow-up of 15.3 months (IQR: 14–18), one patient (16.7%) experienced an incident grade 4 pneumonitis 17 days after initiating osimertinib. Notably, this patient had previously experienced a grade 3 pneumonitis while on durvalumab (Table 2, patient no. 1) and had a nearly 20-month treatment-free interval between durvalumab and osimertinib (Fig. 2D).
      Within the CRT alone group, 11 patients initiated EGFR TKIs after progression on CRT (osimertinib n = 6, erlotinib n = 3, afatinib n = 2), and these treatments were distinct from the consolidation EGFR TKIs administered to some patients. There were no significant PFS differences from EGFR TKI initiation between patients who received CRT and durvalumab versus CRT without durvalumab (median = 16.1 mo versus NR; HR = 1.39, 95% CI: 0.30–6.31, log-rank p = 0.655; Supplementary Fig. 5), though a definitive conclusion is limited owing to the small sample sizes.

      Discussion

      In this study, we presented an in-depth assessment of patients with unresectable stage III EGFR-mutated NSCLC who received consolidation durvalumab after concurrent CRT. These patients experienced a high frequency of severe irAEs and did not obtain improvements in PFS when compared with those who completed CRT alone, in line with the negligible PFS difference in the PACIFIC trial subset analysis.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      To the best of our knowledge, this retrospective analysis is also the first to suggest that EGFR TKIs administered as induction or consolidation therapy with concurrent CRT may achieve a greater PFS compared with CRT with durvalumab or alone in patients with EGFR-mutated NSCLC. Altogether, these data suggest that an alternative definitive treatment approach may be more appropriate for patients with EGFR-mutated NSCLC.
      The PACIFIC trial has revolutionized the treatment of patients with locally advanced NSCLC. Yet, the median PFS of 10.3 months among EGFR-mutated NSCLC patients treated with durvalumab in this cohort was lower than the 17.2 months among those in PACIFIC.
      • Faivre-Finn C.
      • Vicente D.
      • Kurata T.
      • et al.
      Brief report: four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC - an update from the PACIFIC trial.
      The PFS in this study was also lower than that reported in retrospective analyses of unselected patients, which reached at least 14 months.
      • Sita T.
      • Hassanzadeh C.
      • Savoor R.
      • et al.
      OA03.03 multi-institutional study of pneumonitis after treatment with durvalumab and chemoradiotherapy for non-small cell lung cancer.
      • Offin M.
      • Shaverdian N.
      • Rimner A.
      • et al.
      Locoregional control, failure patterns and clinical outcomes in patients with stage III non-small cell lung cancers treated with chemoradiation and durvalumab.
      • Jung H.A.
      • Noh J.M.
      • Sun J.M.
      • et al.
      Real world data of durvalumab consolidation after chemoradiotherapy in stage III non-small-cell lung cancer.
      Although the median PFS with CRT and durvalumab was numerically higher than that with CRT alone, the Kaplan-Meier plot reveals that the survival curves are largely overlapping, indicating a lack of benefit with durvalumab. This finding is in accordance with previous assessments of anti–PD-(L)1 immunotherapy among patients with EGFR-mutated NSCLC, which have consistently revealed suboptimal outcomes.
      • Lee C.K.
      • Man J.
      • Lord S.
      • et al.
      Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis.
      Although the exact cause for this response pattern remains unknown, studies suggest that low rates of PD-L1 expression and CD8+ tumor-infiltrating lymphocytes may play a role.
      • Gainor J.F.
      • Shaw A.T.
      • Sequist L.V.
      • et al.
      EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis.
      ,
      • Dong Z.Y.
      • Zhang J.T.
      • Liu S.Y.
      • et al.
      EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer.
      After recurrence, PFS with first-line EGFR TKIs did not significantly differ between patients who received CRT with or without durvalumab, suggesting EGFR TKIs could have similar effects as salvage therapy after either approach. As the OS data were immature, we were unable to compare the OS between treatment groups, which would provide a more definitive answer on the clinical benefit with durvalumab or the absence thereof in this setting.
      When considering the administration of any immune checkpoint inhibitor, the potential benefits must always be balanced with the risks of irAEs. In PACIFIC, 30% of patients experienced grade 3 or 4 AEs with durvalumab (3% with grade 3 or 4 pneumonitis) and 15% discontinued treatment owing to AEs,
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      consistent with previous studies of immunotherapy for advanced NSCLC.
      • Reck M.
      • Rodriguez-Abreu D.
      • Robinson A.G.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
      • 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.
      In this study, 42% of assessable patients experienced grade 3 AEs and 39% discontinued durvalumab owing to AEs. In addition, 25% of assessable patients developed a grade greater than or equal to 2 pneumonitis and required oral corticosteroids. A PACIFIC trial subgroup analysis revealed that all-grade pneumonitis (including radiation pneumonitis) occurred more frequently in patients treated with durvalumab who were EGFR-positive versus EGFR-negative (59% versus 36%).
      • Vansteenkiste J.
      • Naidoo J.
      • Faivre-Finn C.
      • et al.
      MA05.02 PACIFIC subgroup analysis: pneumonitis in stage III, unresectable NSCLC patients treated with durvalumab vs. placebo after CRT.
      In a separate analysis, all-grade nonpneumonitis irAEs occurred at similar frequencies in the EGFR-positive and EGFR-negative durvalumab subgroups (14% versus 15%).
      • Naidoo J.
      • Vansteenkiste J.F.
      • Faivre-Finn C.
      • et al.
      Non-pneumonitis immune-mediated adverse events (imAEs) with durvalumab in patients with unresectable stage III NSCLC (PACIFIC).
      However, small retrospective studies have revealed higher rates of toxicity with durvalumab overall,
      • Sita T.
      • Hassanzadeh C.
      • Savoor R.
      • et al.
      OA03.03 multi-institutional study of pneumonitis after treatment with durvalumab and chemoradiotherapy for non-small cell lung cancer.
      ,
      • Jung H.A.
      • Noh J.M.
      • Sun J.M.
      • et al.
      Real world data of durvalumab consolidation after chemoradiotherapy in stage III non-small-cell lung cancer.
      ,
      • Jafri S.I.M.
      • Lopetegui-Lia N.
      • Reddy A.
      • Vredenburgh J.
      Real-world incidence of grade III/IV side effects, emergency room visits, and hospital admissions after treatment with adjuvant durvalumab in locally advanced non-small cell lung cancer.
      suggesting outside of a selected clinical trial population, the risk of irAEs may be higher. Previous data have indicated that patients who experience high-grade irAEs may derive greater clinical benefit from immunotherapy
      • Teraoka S.
      • Fujimoto D.
      • Morimoto T.
      • et al.
      Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study.
      • Ricciuti B.
      • Genova C.
      • De Giglio A.
      • et al.
      Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis.
      • Grangeon M.
      • Tomasini P.
      • Chaleat S.
      • et al.
      Association between immune-related adverse events and efficacy of immune checkpoint inhibitors in non-small-cell lung cancer.
      ; however, we did not observe this pattern in our cohort. As the number of EGFR-positive patients who received durvalumab was relatively small, we cannot definitively conclude that these patients are at a higher risk of irAE development with durvalumab, only that nearly half experienced severe irAEs and most had negligible PFS benefits compared with patients receiving CRT alone.
      The question of whether to administer durvalumab to patients with EGFR-mutated NSCLC is compounded by the concerns of irAEs when initiating osimertinib after immunotherapy.
      • Schoenfeld A.J.
      • Arbour K.C.
      • Rizvi H.
      • et al.
      Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib.
      In this study, one patient who developed pneumonitis while on durvalumab unfortunately redeveloped a grade 4 pneumonitis shortly after initiation of osimertinib. Previous analyses have revealed that anti–PD-(L)1 antibodies may persist in the bloodstream for months after treatment and can cause delayed onset of irAEs
      • Schoenfeld A.J.
      • Arbour K.C.
      • Rizvi H.
      • et al.
      Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib.
      ,
      • Shinno Y.
      • Goto Y.
      • Ohuchi M.
      • et al.
      The long half-life of programmed cell death Protein 1 inhibitors may increase the frequency of immune-related adverse events after subsequent EGFR tyrosine kinase inhibitor therapy.
      ; however, it is unlikely that the durvalumab antibodies persisted after the patient’s 20-month treatment-free interval. It is possible that the patient’s previous episode of pneumonitis had “primed” the immune system to overactivation on exposure to osimertinib, which would raise additional concerns given the frequency of pneumonitis associated with CRT and durvalumab.
      • Vansteenkiste J.
      • Naidoo J.
      • Faivre-Finn C.
      • et al.
      MA05.02 PACIFIC subgroup analysis: pneumonitis in stage III, unresectable NSCLC patients treated with durvalumab vs. placebo after CRT.
      None of the other five patients who initiated EGFR TKIs after durvalumab experienced irAEs despite having shorter between-treatment time intervals. In one retrospective study, four of six patients who developed severe irAEs received osimertinib within 30 days of their last immunotherapy dose and only one of our patients fit within this 30-day between-treatment time interval.
      • Schoenfeld A.J.
      • Arbour K.C.
      • Rizvi H.
      • et al.
      Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib.
      Finally, this retrospective analysis suggests that there may be a significant PFS benefit among patients who receive EGFR TKIs as induction or consolidation therapy with CRT. Previous investigations of EGFR TKIs in the locally advanced setting have been limited. The phase 2 RTOG-1306 trial sought to evaluate erlotinib hydrochloride as induction therapy for 12 weeks followed by concurrent CRT for patients with stage III EGFR-mutated NSCLC (NCT01822496), but unfortunately it terminated early owing to slow accrual. Maintenance gefitinib was evaluated after CRT in the randomized phase 3 SWOG 0023 trial, which revealed that gefitinib was associated with poorer OS compared with placebo (23 mo versus 35 mo, p = 0.013) in a molecularly unselected population.
      • Kelly K.
      • Chansky K.
      • Gaspar L.E.
      • et al.
      Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023.
      However, recent data from the phase 3 ADAURA trial indicate that EGFR TKIs may have a role in the definitive treatment of early-stage EGFR-mutated NSCLC.
      • Herbst R.S.
      • Tsuboi M.
      • John T.
      • et al.
      LBA5 Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA.
      Currently, the randomized phase 3 LAURA trial is underway which will evaluate osimertinib administered until progression, toxicity, or other reasons for discontinuation in patients with stage III EGFR-mutated NSCLC after CRT (NCT03521154). Whether the optimal definitive strategy for these patients involves EGFR TKIs as induction or consolidation therapy with CRT remains to be determined. Although the subgroup analysis was small, the induction EGFR TKI data in this study are provocative in that none of these patients had recurrence over 7 months and this strategy could enable EGFR TKI rechallenge in case of recurrence.
      Although this retrospective analysis has inherent limitations, this design enabled us to evaluate a spectrum of patient experiences during CRT and with EGFR TKIs after recurrence. The multi-institutional nature of this study could introduce heterogeneity but found consistent results between institutions. The sample size of this study was small, especially in the subset analyses; yet, the main findings corroborated those observed in PACIFIC. Nonetheless, further investigation with larger cohorts will be insightful. Although all patients in the CRT and durvalumab group had PD-L1 testing performed, PD-L1 expression was missing for more than half of the patients in the CRT-alone group. As oncologists may be more likely to recommend consolidation durvalumab for patients with high PD-L1 expression, this could potentially induce a selection bias. Patients with high PD-L1 expression had better outcomes after CRT and durvalumab in PACIFIC
      • Paz-Ares L.
      • Spira A.
      • Raben D.
      • et al.
      Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial.
      ; however, whether this applies to patients with EGFR-mutated NSCLC remains unknown.
      In summary, patients with EGFR-mutated NSCLC did not derive PFS benefits with consolidation durvalumab and experienced a high frequency of severe irAEs. Although most patients did not experience incident irAEs when initiating EGFR TKIs after recurrence, one patient who had pneumonitis on durvalumab redeveloped severe pneumonitis on osimertinib, suggesting potentially multiple mechanisms for increased susceptibility to irAEs with EGFR TKIs after immunotherapy. Given the growing body of literature suggesting a lack of benefit and the current evidence of harm, consolidation durvalumab in the setting of EGFR-mutated NSCLC should be approached with caution. Alternatively, induction or consolidation EGFR TKIs may offer a more durable definitive treatment strategy for these patients and further investigation of these approaches is warranted.

      Acknowledgments

      The authors thank Laura Lundi, Angel Baroz, and Jeremy Fricke for administrative and regulatory support of this retrospective study.

      Supplementary Data

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      Linked Article

      • To Give or Not to Give: Consolidative Durvalumab in EGFR-Mutant NSCLC
        Journal of Thoracic OncologyVol. 16Issue 6
        • Preview
          The standard treatment for stage III, unresectable NSCLC now involves combination chemoradiation therapy (CRT) followed by 1 year of consolidative durvalumab in patients who do not progress after CRT. The addition of durvalumab came as a result of the PACIFIC trial, which revealed that patients with unresectable stage III NSCLC who received CRT followed by durvalumab as compared with patients who received CRT followed by placebo had an improved median progression-free survival (PFS) of 17.2 months versus 5.6 months and an improved median overall survival (OS) of 48 months versus 29 months, with a remarkable 50% of patients still alive at 48 months on the durvalumab arm in the intention-to-treat population.
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