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Programmed Cell Death Ligand 1 Expression in Untreated EGFR Mutated Advanced NSCLC and Response to Osimertinib Versus Comparator in FLAURA

Open AccessPublished:October 09, 2019DOI:https://doi.org/10.1016/j.jtho.2019.09.009

      Abstract

      Introduction

      EGFR mutated (EGFRm) NSCLC tumors occasionally express programmed cell death ligand 1 (PD-L1), although frequency and clinical relevance are not fully characterized. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following treatment with osimertinib or comparator EGFR tyrosine kinase inhibitors in the FLAURA trial (phase III, NCT02296125).

      Methods

      Of 231 tissue blocks available from the screened population (including EGFRm-positive and -negative samples), 197 had sufficient tissue for PD-L1 testing using the SP263 (Ventana, Tucson, Arizona) immunohistochemical assay. Tumor cell (TC) staining thresholds of PD-L1 TC greater than or equal to 1%, TC greater than or equal to 25%, and TC greater than or equal to 50% were applied. Progression-free survival (PFS) was investigator-assessed, per Response Evaluation Criteria in Solid Tumor, version 1.1, according to PD-L1 expressors (TC ≥ 1%) or negatives (TC < 1%) in randomized patients.

      Results

      PD-L1 staining was successful in 193 of 197 patient formalin-fixed paraffin-embedded blocks; of these, 128 of 193 were EGFRm-positive and 106 of 128 patients were randomized to treatment (osimertinib: 54; comparator: 52). At the PD-L1 TC greater than or equal to 25% threshold, 8% (10 of 128) of EGFRm-positive tumors expressed PD-L1 versus 35% (23 of 65) of EGFRm-negative tumors. With the TC greater than or equal to 1% threshold, 51% (65 of 128) versus 68% (44 of 65) were mutation-positive and –negative, respectively, and with the TC greater than or equal to 50% threshold, 5% (7 of 128) versus 28% (18 of 65), were mutation-positive and -negative, respectively. For PD-L1 expressors (TC ≥ 1%), median PFS was 18.4 months with osimertinib and 6.9 months with comparator (hazard ratio = 0.30; 95% confidence interval: 0.15–0.60). For PD-L1–negative patients (TC < 1%), median PFS was 18.9 months with osimertinib and 10.9 months with comparator (hazard ratio = 0.37; 95% confidence interval: 0.17–0.74).

      Conclusions

      Clinical benefit with osimertinib was unaffected by PD-L1 expression status.

      Keywords

      Introduction

      Osimertinib is a third-generation, irreversible, oral EGFR tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR TKI–sensitizing mutations and EGFR T790M and has shown efficacy in NSCLC central nervous system metastases.
      • Cross D.A.
      • Ashton S.E.
      • Ghiorghiu S.
      • et al.
      AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer.
      • Reungwetwattana T.
      • Nakagawa K.
      • Cho B.C.
      • et al.
      CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non–small-cell lung cancer.
      • Mok T.S.
      • Wu Y.-L.
      • Ahn M.-J.
      • et al.
      Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer.
      • Wu Y.L.
      • Ahn M.J.
      • Garassino M.C.
      • et al.
      CNS Efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3).
      In FLAURA (NCT02296125, phase III), patients with newly diagnosed EGFR mutation–positive (EGFRm) NSCLC treated with osimertinib had significantly improved progression-free survival (PFS) versus comparator EGFR TKIs (erlotinib/gefitinib).
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer.
      Median PFS was 18.9 months with osimertinib versus 10.2 months with comparator EGFR TKIs (hazard ratio [HR] = 0.46; 95% confidence interval [CI]: 0.37–0.57; p < 0.001).
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer.
      Separately from EGFR TKIs, the development of inhibitors targeting programmed cell death 1 (PD-1) receptor or programmed cell death ligand 1 (PD-L1) protein has resulted in a major advance in the treatment of NSCLC, with studies showing superior outcomes with PD-1/PD-L1 immunotherapies versus chemotherapy.
      • 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.
      However, the majority of the first-line immunotherapy trials have excluded EGFRm patients.
      • Carbone D.P.
      • Reck M.
      • Paz-Ares L.
      • et al.
      first-line nivolumab in stage iv or recurrent non-small-cell lung cancer.
      ,
      • 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.
      Additionally, in a phase II trial, pembrolizumab (a PD-1 inhibitor) failed to show efficacy (with no reported objective responses) in EGFR TKI–naive patients with EGFRm and PD-L1–positive advanced NSCLC.
      • Lisberg A.
      • Cummings A.
      • Goldman J.W.
      • et al.
      A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naive patients with advanced NSCLC.
      The biological basis for the lack of efficacy with immune checkpoint inhibitors in EGFRm patients is not known.
      • Soo R.A.
      • Lim S.M.
      • Syn N.L.
      • et al.
      Immune checkpoint inhibitors in epidermal growth factor receptor mutant non–small cell lung cancer: current controversies and future directions.
      With PD-L1 emerging as an important biomarker for immune checkpoint inhibition, interrogation of the interplay between PD-L1 expression and EGFRm is important. The relationship between PD-L1 expression level and sensitivity to EGFR TKIs in patients with EGFRm NSCLC is not firmly established.
      • Soo R.A.
      • Lim S.M.
      • Syn N.L.
      • et al.
      Immune checkpoint inhibitors in epidermal growth factor receptor mutant non–small cell lung cancer: current controversies and future directions.
      We report the prevalence and impact of PD-L1 expression in patients with EGFRm advanced NSCLC from the phase III FLAURA trial.

      Materials and Methods

      Patients, Trial Design, and Treatments

      Patients from the FLAURA study were included in this analysis; full details of this study, its patients, trial design, and treatments have been previously published.
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer.
      Briefly, patients had locally advanced or metastatic NSCLC and were treatment-naive for advanced disease. Local or central confirmation of EGFR Ex19del or L858R by tissue testing was required for enrollment. Patients were randomized to treatment with osimertinib 80 mg once daily or EGFR TKI comparator (gefitinib 250 mg once daily or erlotinib 150 mg once daily). Endpoints included PFS, objective response rate, and duration of response.
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer.

      Tumor Sample Analysis

      Tissue samples from 994 patients were screened in the FLAURA study for EGFR Ex19del or L858R as part of the enrollment criteria using central testing (cobas EGFR Mutation Test, Roche Molecular Systems, Pleasanton, California) or a local EGFR test in an accredited laboratory. Five hundred fifty-six patients were randomized to treatment. For tumor cell (TC) scoring, evaluable tissue blocks were tested for PD-L1 status/expression using the VENTANA PD-L1 (SP263) immunohistochemical assay (Ventana Medical Systems, Tucson, Arizona). Positive tumor cell staining thresholds for PD-L1 of 1% (TC ≥ 1%), 25% (TC ≥ 25%), and 50% (TC ≥ 50%) were applied. Clinical outcomes were available for those patients with PD-L1 TC staining data who were randomized to treatment.
      Immune cell (IC) scoring does not form part of the PD-L1 determination in NSCLC using the Ventana SP263 assay, but is incorporated into the VENTANA PD-L1 (SP142) Assay. Therefore, a purely exploratory IC analysis was conducted whereby the proportion of tumor area occupied by PD-L1 staining ICs was determined and thresholds of 1% (IC ≥ 1%) and 25% (IC ≥ 25%) were applied.

      Trial Oversight

      The trial was conducted in accordance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines (as defined by the International Conference on Harmonisation), applicable regulatory requirements, and the policy on bioethics and human biologic samples of the trial sponsor, AstraZeneca. This analysis was funded by the sponsor and was designed by the principal investigators and sponsor. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

      Results

      Patients

      Of 994 patients screened for EGFR mutations for inclusion in FLAURA, 231 tissue blocks were available from the screened population (including both mutation-positive and -negative samples), of which 197 had sufficient tumor content for PD-L1 testing (results were available from 193 of 197 samples as four failed post-staining) (Fig. 1). Among these, 128 of 193 were EGFRm-positive; of these 106 of 128 were randomized in FLAURA (54, osimertinib; 52, comparator), the remaining 22 of 128 failed screening and were not enrolled. In total, 450 randomized patients had unknown PD-L1 status (no tissue available). Baseline demographics are shown in Table 1.
      Figure thumbnail gr1
      Figure 1Flow chart of FLAURA study patients and PD-L1 testing in this analysis. *Central PD-L1 testing was carried out by Hematogenix (United Kingdom). #On inspection of the samples, 34 formalin-fixed paraffin-embedded blocks contained insufficient/no tissue for PD-L1 testing, an additional four samples were found to be insufficient for testing upon hematoxylin and eosin assessment. Tumors were required to harbor one or both of the Ex19del and L858R EGFR-TKI sensitizing mutations for randomization into the study. EGFRm, EGFR mutated; Ex19del, exon 19 deletion; PD-L1, programmed cell death ligand 1.
      Table 1Baseline Demographics and Disease Characteristics of Patients with EGFRm Advanced NSCLC Randomized in FLAURA, According to PD-L1 Expression Status
      CharacteristicPD-L1 Expressers (n = 52)PD-L1 Non-Expressers (n = 54)PD-L1 Unknown (n = 450)
      Median age (range), y64 (35–85)65 (40–85)64 (26–93)
      Sex
       Female36 (69)40 (74)274 (61)
       Male16 (31)14 (26)176 (39)
      Ethnicity
       White33 (63)43 (80)125 (28)
       Asian
      Most patients with PD-L1 status unknown were Asian (70%), due to several sites in Asia not providing tissue blocks for testing.
      19 (37)11 (20)317 (70)
       Other
      Other consisted of patients who were Black/African American, Native Hawaiian or other Pacific Islander, American Indian or Alaska Native, missing
      008 (2)
      EGFR mutation status
       L858R22 (42)18 (33)147 (33)
       Exon 19 deletion29 (56)34 (63)250 (56)
       EGFRm not detected1 (2)1 (2)4 (1)
       Invalid test01 (2)8 (2)
       No/inadequate sample0041 (9)
      Smoking status
       Never38 (73)38 (70)281 (62)
       Current2 (4)1 (2)14 (3)
       Former12 (23)15 (28)155 (34)
      CNS metastases
       Present12 (23)9 (17)95 (21)
       Not present40 (77)45 (83)355 (79)
      Visceral metastases
       Present18 (35)15 (28)164 (36)
       Not present34 (65)39 (72)286 (64)
      Values are n (%) unless otherwise stated.
      CNS, central nervous system; EGFRm, EGFR mutated; PD-L1, programmed cell death ligand 1.
      a Most patients with PD-L1 status unknown were Asian (70%), due to several sites in Asia not providing tissue blocks for testing.
      b Other consisted of patients who were Black/African American, Native Hawaiian or other Pacific Islander, American Indian or Alaska Native, missing

      PD-L1 Expression and Efficacy

      Expression of PD-L1 was less frequent in EGFRm-positive samples versus EGFRm-negative samples (51% versus 68% at a TC greater than or equal to 1% threshold) (Table 2). This difference was more pronounced at higher PD-L1 TC thresholds: 8% versus 35% at TC greater than or equal to 25% and 5% versus 28% at TC greater than or equal to 50%. Of these EGFRm-positive samples, prevalence of PD-L1 expression (TC ≥ 1%) for Ex19del and L858R was 49% and 53% of samples, respectively (Table 2).
      Table 2Tumor PD-L1 Expression According to EGFR Mutation Status
      Mutation StatusPD-L1 TC < 1%PD-L1 TC ≥ 1%PD-L1 TC ≥ 25%PD-L1 TC ≥ 50%
      EGFRm negative (n = 65)
       Screened population21/65 (32)44/65 (68)23/65 (35)18/65 (28)
      EGFRm positive (n = 128)
       Screened population63/128 (49)65/128 (51)10/128 (8)7/128 (5)
      Exon 19 deletions40/79 (51)39/79 (49)6/79 (8)5/79 (6)
      L858R23/49 (47)26/49 (53)4/49 (8)2/49 (4)
      Randomized to treatment (n = 106)54/106 (51)52/106 (49)8/106 (8)5/106 (5)
       Randomized to osimertinib26/54 (48)28/54 (52)3/54 (6)2/54 (4)
       Randomized to comparator EGFR TKI28/52 (54)24/52 (46)5/52 (10)3/52 (6)
      Values are n (%).
      EGFRm, EGFR mutated; PD-L1, programmed cell death ligand 1; TC, tumor cell; TKI, tyrosine kinase inhibitor.
      In PD-L1 expressors (TC ≥ 1%), median PFS was 18.4 months (95% CI: 10.9–noncalculable [NC]) with osimertinib and 6.9 months (95% CI: 5.3–12.5) with comparator (HR = 0.30; 95% CI: 0.15–0.60) (Fig. 2A). For PD-L1–negative patients (TC < 1%), median PFS was 18.9 months (95% CI: 12.4–NC) with osimertinib and 10.9 months (95% CI: 8.3–12.4) with comparator (HR = 0.37; 95% CI: 0.17–0.74) (Fig. 2B). In the PD-L1 status-unknown group, median PFS was 19.1 months (95% CI: 14.9–23.4) with osimertinib and 10.8 months (95% CI: 9.6–12.3) with comparator (HR = 0.49; 95% CI: 0.39–0.62) (Fig. 2C). For objective response rate and median duration of response results, see Table 3.
      Figure thumbnail gr2
      Figure 2PFS by treatment group according to tumor cell PD-L1 expression (TC 1% cutoff) in (A) PD-L1 expressors (TC ≥ 1%), (B) PD-L1 negatives (TC < 1%), and (C) PD-L1 unknown. CI, confidence interval; HR, hazard ratio; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; TC, tumor cell; NC, noncalculable.
      Table 3Response Rates Across Treatments and PD-L1 Status
      Osimertinib (n = 54)Comparator (n = 52)
      PD-L1 ExpressersPD-L1 Non-ExpressersPD-L1 Status UnknownPD-L1 ExpressersPD-L1 Non-ExpressersPD-L1 Status Unknown
      Response, n (%)n=28

      22 (79)
      n=26

      22 (85)
      n=225

      179 (80)
      n=24

      17 (71)
      n=28

      23 (82)
      n=225

      170 (76)
      Median DoR,

      mo (95% CI)
      n=22

      17.2 (10.0–NC)
      n=22

      NC (11.0–NC)
      n=179

      17.6 (12.5–21.9)
      n=17

      6.9 (2.9–13.8)
      n=23

      8.8 (6.9–11.1)
      n=170

      8.5 (7.2–11.0)
      CI, confidence interval; DoR, duration of response; NC, noncalculable; PD-L1, programmed cell death ligand 1.

      PD-L1 Immune Cell Scoring Outcomes

      Most randomized patients (98 of 106 [92%]) had some PD-L1 IC expression (IC≥1%). Outcomes of the exploratory IC analysis are in the Supplementary Data.

      Discussion

      In this analysis of PD-L1 expression among screened patients in the FLAURA trial, tumor EGFR mutations and PD-L1 expression were not mutually exclusive; however, a lower proportion of patients with EGFRm-positive tumors expressed PD-L1 versus patients with EGFRm-negative tumors. This difference was more pronounced above the threshold of PD-L1 TC greater than or equal to 25%. These data are in agreement with a pooled analysis of 18 studies that found a 41% lower likelihood of EGFRm-positive tumors expressing PD-L1 versus EGFRm-negative tumors (odds ratio = 0.59; 95% CI: 0.38–0.92; p < 0.02).
      • Soo R.A.
      • Lim S.M.
      • Syn N.L.
      • et al.
      Immune checkpoint inhibitors in epidermal growth factor receptor mutant non–small cell lung cancer: current controversies and future directions.
      PFS analysis showed benefit with osimertinib regardless of PD-L1 expression with both the SP263 assay TC classification (TC≥1%) and an exploratory IC classification (IC≥1%), suggesting that the PD-L1 status is not prognostic of outcomes with osimertinib therapy. Furthermore, median PFS with osimertinib was closely aligned across the PD-L1 subgroups, as well as to the median PFS of osimertinib for the overall FLAURA study population (18.9 months).
      • Soria J.C.
      • Ohe Y.
      • Vansteenkiste J.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer.
      Regarding response, results were similar to that of the overall FLAURA population for all PD-L1 subgroups, suggesting that expression of PD-L1 does not affect response, although this group size was small. Here, the scoring algorithm of the SP142 assay was chosen for the exploratory IC analysis as another study; using this assay had indicated that in patients with EGFRm advanced NSCLC and treated with an EGFR TKI, PD-L1 expression was associated with poor response and a significantly shorter PFS than in patients with no/low PD-L1 expression.
      • Su S.
      • Dong Z.Y.
      • Xie Z.
      • et al.
      Strong programmed death ligand 1 expression predicts poor response and de novo resistance to EGFR tyrosine kinase inhibitors among NSCLC patients with EGFR mutation.
      As shown previously, this is not the case in the present study.
      The numerical difference in PFS by PD-L1 expression in the EGFR TKI comparator group correlates with findings from retrospective analyses of studies in patients with EGFRm advanced NSCLC treated with EGFR TKIs, in which a shorter median PFS was observed in patients with PD-L1 expression versus no expression.
      • Su S.
      • Dong Z.Y.
      • Xie Z.
      • et al.
      Strong programmed death ligand 1 expression predicts poor response and de novo resistance to EGFR tyrosine kinase inhibitors among NSCLC patients with EGFR mutation.
      ,
      • Yoneshima Y.
      • Ijichi K.
      • Anai S.
      • et al.
      PD-L1 expression in lung adenocarcinoma harboring EGFR mutations or ALK rearrangements.
      However, the literature is inconsistent, with other studies showing high PD-L1 expression results and improved outcomes in patients with NSCLC treated with gefitinib or erlotinib.
      • Yoneshima Y.
      • Ijichi K.
      • Anai S.
      • et al.
      PD-L1 expression in lung adenocarcinoma harboring EGFR mutations or ALK rearrangements.
      ,
      • D'Incecco A.
      • Andreozzi M.
      • Ludovini V.
      • et al.
      PD-1 and PD-L1 expression in molecularly selected non–small-cell lung cancer patients.
      This inconsistency may be due to a number of factors, including differences in PD-L1 threshold cutoffs, and differences among patients, including previous treatments received.
      • Soo R.A.
      • Lim S.M.
      • Syn N.L.
      • et al.
      Immune checkpoint inhibitors in epidermal growth factor receptor mutant non–small cell lung cancer: current controversies and future directions.
      Because data on efficacy of EGFR TKIs in patients with EGFRm NSCLC and PD-L1 expressing tumors are inconsistent, and many trials in the first-line setting exclude patients with EGFRm NSCLC altogether, treating these patients with an immune checkpoint inhibitor as first-line therapy, instead of an EGFR TKI, may be a suboptimal option.
      • Carbone D.P.
      • Reck M.
      • Paz-Ares L.
      • et al.
      first-line nivolumab in stage iv or recurrent non-small-cell lung cancer.
      ,
      • 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.
      ,
      • Soo R.A.
      • Lim S.M.
      • Syn N.L.
      • et al.
      Immune checkpoint inhibitors in epidermal growth factor receptor mutant non–small cell lung cancer: current controversies and future directions.
      This has been shown in a phase II study investigating pembrolizumab monotherapy as first-line treatment for patients with EGFRm– and PD-L1–positive advanced NSCLC that closed enrollment early due to futility.
      • Lisberg A.
      • Cummings A.
      • Goldman J.W.
      • et al.
      A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naive patients with advanced NSCLC.
      Clinical practice guidelines recommend that patients who are EGFRm- positive should be treated with an EGFR TKI regardless of PD-L1 status.
      • Hanna N.
      • Johnson D.
      • Temin S.
      • et al.
      Systemic Therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update.
      Strengths of this study include that all data were from a single prospective global trial, and central testing was used for PD-L1 expression. As this was an exploratory endpoint of the FLAURA trial, a limitation was that viable tissue samples were only available in a subset of the randomized patients. Further limitations were that no data were captured on post-study immunotherapy for these patients and tumor mutational burden was not recorded; explorations of both would have provided further insight. Tumor mutational burden and immunotherapy response are now being investigated with samples from the FLAURA trial.
      In conclusion, our analysis of tissue samples from patients enrolled in the FLAURA study supports the use of osimertinib as first-line treatment for patients with EGFRm advanced NSCLC regardless of PD-L1 expression.

      Acknowledgments

      The study (NCT02296125) was funded by AstraZeneca, Cambridge, United Kingdom, the manufacturer of osimertinib. The authors thank all the patients involved in the FLAURA study and their families, the study investigators, and the team at AstraZeneca; Bernadette Tynan, MSc, of iMed Comms, Macclesfield, United Kingdom, an Ashfield Company, part of UDG Healthcare plc, for medical writing support that was funded by AstraZeneca, Cambridge, United Kingdom, in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3); and Maiyan Chau for study conception and interpretation, and Hiten Meisuria and the Tagrisso Information Exploitation Management Team for assistance in data analysis.

      Supplementary Data

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