Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non–small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non–small-cell lung cancer without EGFR/ALK alterations.

INTRODUCTION

In the phase 3 KEYNOTE-189 study, pembrolizumab (an anti–programmed cell death protein-1 monoclonal antibody) plus pemetrexed and carboplatin/cisplatin significantly prolonged overall survival (OS; hazard ratio [HR], 0.49; 95% CI, 0.38 to 0.64; P < .001) and progression-free survival (PFS; 0.52; 0.43 to 0.64; P < .001) versus placebo plus pemetrexed-platinum in previously untreated metastatic nonsquamous non–small-cell lung cancer (NSCLC) without EGFR/ALK alterations.¹ In the protocol-specified final analysis, OS and PFS continued to improve with HRs (95% CI) of 0.56 (0.46 to 0.69) and 0.49 (0.41 to 0.59), respectively.² We present a 5-year exploratory analysis from KEYNOTE-189.

CONTEXT

• Key Objective

• We examined whether patients with previously untreated metastatic nonsquamous non–small-cell lung cancer without EGFR/ALK alterations treated with pembrolizumab plus pemetrexed and platinum chemotherapy continue to experience improved survival outcomes versus placebo plus pemetrexed and platinum chemotherapy after 5 years of follow-up.

• Knowledge Generated

• After 5 years, pembrolizumab plus pemetrexed-platinum was associated with improved overall survival (OS) and progression-free survival compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non–small-cell lung cancer, regardless of programmed cell death ligand-1 expression. Five-year OS rates were 19.4% versus 11.3% in the intention-to-treat population.

• Relevance (T.E. Stinchcombe)

• The 5-year follow-up demonstrates durable benefit for the combination of platinum-pemetrexed and pembrolizumab and the benefit in the subsets of patients on the basis of tumor programmed cell death ligand-1 expression. In the future, the landmark analyses of progression-free survival or OS at 3 or 5 years may be used to assess the long-term benefit of novel immunotherapies.*

  *Relevance section written by JCO Associate Editor Thomas E. Stinchcombe, MD.

METHODS

Study Design and Patients

The study design for KEYNOTE-189 (ClinicalTrials.gov identifier: NCT02578680) has been previously described.^1-3 The Protocol (online only) and its amendments were approved by the appropriate institutional review boards and ethics committees. Patients provided written informed consent before enrollment.

Patients were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles (approximately 2 years). Patients also received pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min once every 3 weeks for four cycles followed by pemetrexed maintenance therapy. Treatment continued until the maximum number of cycles or until radiographic progression, unacceptable toxicity, investigator's decision, or patient withdrawal. Patients in the placebo plus pemetrexed-platinum group could cross over to receive pembrolizumab monotherapy upon documented progressive disease (PD) per RECIST v1.1 by blinded independent central review (BICR) if eligibility criteria were met. Patients could receive a second course of pembrolizumab monotherapy for up to 17 cycles (approximately 1 year) upon PD after either completing 35 cycles of pembrolizumab with a best overall response of stable disease or better or having achieved confirmed investigator-assessed complete response (CR) after receiving ≥ 8 cycles of pembrolizumab and ≥ 2 cycles beyond the initial CR assessment.

End Points and Statistical Analysis

Primary end points were PFS per RECIST v1.1 by BICR and OS. Secondary end points were objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 by BICR and safety. Exploratory end points included PFS2 (time from random assignment to second/subsequent PD on next-line treatment or death from any cause). No alpha was assigned to this analysis.

RESULTS

Patients

Overall, 616 patients were randomly assigned to pembrolizumab plus pemetrexed-platinum (n = 410) or placebo plus pemetrexed-platinum (n = 206; Table 1). At data cutoff (March 8, 2022), seven patients (all in the pembrolizumab plus pemetrexed-platinum group) were continuing to receive pemetrexed. Among patients randomly assigned to pembrolizumab plus pemetrexed-platinum, 224 (54.6%) received subsequent anticancer therapy (103 received anti–PD-1 or anti–programmed cell death ligand 1 [PD-L1] therapy, including nine who began on-study second-course pembrolizumab; Appendix Table A1, online only). In the placebo plus pemetrexed-platinum group, 84 patients crossed over to pembrolizumab monotherapy on-study; an additional 34 patients received subsequent anti–PD-(L)1 therapy outside the study for an effective crossover rate of 57.3%.

TABLE 1.

Patient Baseline Characteristics

Efficacy Outcomes

Median time from random assignment to data cutoff was 64.6 (range, 60.1-72.4) months. In the intention-to-treat (ITT) population, HRs (95% CI) for pembrolizumab plus pemetrexed-platinum versus placebo plus pemetrexed-platinum were 0.60 (0.50 to 0.72) for OS and 0.50 (0.42 to 0.60) for PFS (Figs 1A and 1E). Five-year OS rates were 19.4% versus 11.3%, and 5-year PFS rates were 7.5% versus 0.6%. ORR (95% CI) was 48.3% (43.4 to 53.2) and 19.9% (14.7 to 26.0), respectively. Median (range) DOR was 12.7 (1.1+ to 68.3+) and 7.1 (2.4 to 31.5) months, respectively (Fig 2A). Similar trends were observed across the PD-L1 subgroups analyzed (Figs 1B‐1D, 1F‐1H; Appendix Table A2 [online only]; and Appendix Fig A1 [online only]).

FIG 1.

Kaplan-Meier estimates of OS in the (A) ITT, (B) PD-L1 TPS ≥ 50%, (C) PD-L1 TPS 1%-49%, and (D) PD-L1 TPS < 1% populations and PFS by RECIST version 1.1 by blinded independent central review in the (E) ITT, (F) PD-L1 TPS ≥ 50%, (G) PD-L1 TPS 1%-49%, and (H) PD-L1 TPS < 1% populations. Chemo, chemotherapy; ITT, intention-to-treat; OS, overall survival; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; TPS, tumor proportion score.

FIG 2.

(A) Duration of response in the ITT population and (B) treatment duration and time to response in patients who completed 35 cycles of pembrolizumab. Response assessments are shown per RECIST version 1.1 by BICR. Median PFS was not reached (95% CI, 14.7 months to not reached). PFS rate 3 years after completion of 35 cycles was 56.2% (95% CI, 39.7 to 69.8). BICR, blinded independent central review; chemo, chemotherapy; CR, complete response; ITT, intention-to-treat; PD, progressive disease; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.

Median (95% CI) PFS2 was 17.0 (15.0 to 19.2) months in the pembrolizumab plus pemetrexed-platinum group versus 9.1 (7.6 to 10.8) months in the placebo plus pemetrexed-platinum group (HR, 0.54; 95% CI, 0.45 to 0.65). Five-year PFS2 rates (95% CI) were 16.7% (13.2 to 20.5) versus 7.8% (4.7 to 12.1).

Safety

Overall, 404 patients (99.8%) in the pembrolizumab plus pemetrexed-platinum group and 200 (99.0%) in the placebo plus pemetrexed-platinum group experienced adverse events (AEs). All fatal AEs were previously reported.^2,3 Immune-mediated AEs and infusion reactions occurred in 113 (27.9%) and 27 (13.4%) patients, respectively (Appendix Table A3, online only).

Patients Who Completed 35 Cycles of Pembrolizumab

Of the patients randomly assigned to pembrolizumab plus pemetrexed-platinum, 57 (13.9%) completed 35 cycles of pembrolizumab (Table 1) and received a median of 35 (range, 2-98) cycles of pemetrexed. ORR was 86.0% (8 CRs, 41 partial responses) and eight patients had best response of stable disease (Fig 2B). Median DOR was 57.7 (range, 4.2 to 68.3+) months. Estimated OS rate 3 years after completion of 35 cycles (ie, approximately 5 years from random assignment) was 71.9% (95% CI, 58.3 to 81.8). At data cutoff, 23 of 57 patients (40.4%) were alive without PD or subsequent therapy.

All patients experienced ≥ 1 AE (grade 3/4 AEs, 38 [66.7%]); none were grade 5. Immune-mediated AEs and infusion reactions occurred in 23 patients (40.4%; grade 3/4 in 7 [12.3%]).

DISCUSSION

In this 5-year update from KEYNOTE-189, pembrolizumab plus pemetrexed-platinum continued to prolong OS and PFS regardless of PD-L1 expression versus placebo plus pemetrexed-platinum with manageable toxicity (consistent with previous reports)^2,3 in patients with previously untreated metastatic nonsquamous NSCLC without EGFR/ALK alterations. Five-year OS rate was approximately 20% with pembrolizumab plus pemetrexed-platinum in the ITT population (v 11% with placebo plus pemetrexed-platinum) and was higher in patients with higher PD-L1 tumor proportion score (TPS), especially in the TPS ≥ 50% subgroup (29.6% v 21.4%; similar to the 5-year OS rates in the KEYNOTE-024 study of pembrolizumab monotherapy v chemotherapy [31.9% v 16.3%]⁴). However, there were a limited number of patients at risk at 5 years in some subgroups. Importantly, benefits were also observed in the PD-L1 TPS < 1% subgroup, for whom pembrolizumab monotherapy is not indicated.

Sustained improvements in OS were observed with pembrolizumab plus pemetrexed-platinum versus placebo plus pemetrexed-platinum despite an effective crossover rate of 57% from placebo plus pemetrexed-platinum to subsequent anti–PD-(L)1 therapy, which is reflected in the plateauing of the placebo plus pemetrexed-platinum Kaplan-Meier curve and was not previously observed in studies of chemotherapy alone.⁵ These factors likely attenuated the differences in 5-year OS rates in the ITT population and in OS HR observed in later analyses compared with the first interim analysis.¹ The improvement in PFS2 with pembrolizumab plus pemetrexed-platinum versus placebo plus pemetrexed-platinum also suggests the benefit of pembrolizumab plus pemetrexed-platinum is maintained after initial disease progression, further supporting its use as first-line treatment.

Pembrolizumab demonstrated robust and durable antitumor activity in patients who completed 35 cycles of pembrolizumab, with a majority of patients (72%) alive 3 years after completion (approximately 5 years after random assignment). These data support the feasibility of a 2-year treatment duration with pembrolizumab plus pemetrexed-platinum and are consistent with the outcomes reported in patients who completed 35 cycles of pembrolizumab monotherapy^6,7 and in the KEYNOTE-407 study of pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel versus placebo plus carboplatin and paclitaxel/nab-paclitaxel in previously untreated metastatic squamous NSCLC.⁸ Although this is the first report of 5-year outcomes for anti–PD-(L)1 therapy plus chemotherapy from a phase 3 study, improved survival outcomes at 5 years were reported with nivolumab (anti–PD-1) plus ipilimumab (anti–CTLA-4) versus chemotherapy in the CheckMate 227 study.⁹

In conclusion, pembrolizumab plus pemetrexed-platinum continued to demonstrate prolonged survival and durable antitumor activity versus placebo plus pemetrexed-platinum after 5 years of follow-up, with manageable toxicity,² in patients with previously untreated metastatic nonsquamous NSCLC without EGFR/ALK alterations. These results continue to support the combination of first-line pembrolizumab plus a platinum and pemetrexed as a standard of care for these patients.

APPENDIX

TABLE A1.

Subsequent Anticancer Therapy

TABLE A2.

Tumor Response

TABLE A3.

Summary of AEs in Patients Who Received ≥ 1 Dose of Study Treatment

FIG A1.

Kaplan-Meier estimates of (A) OS and (B) PFS per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review in patients with PD-L1 TPS ≥ 1%. Chemo, chemotherapy; OS, overall survival; PD-L1, programmed cell death ligand 1; pembro, pembrolizumab; PFS, progression-free survival; TPS, tumor proportion score.

DATA SHARING STATEMENT

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ (MSD), is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the United States and European Union or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country- or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.

AUTHOR CONTRIBUTIONS

Conception and design: Maximilian J. Hochmair, Helge G. Bischoff, Martin Reck, Jhanelle E. Gray, Paul Schwarzenberger, M. Catherine Pietanza, Delvys Rodríguez-Abreu

Administrative support: Enriqueta Felip, Maximilian J. Hochmair, Helge G. Bischoff

Provision of study materials or patients: Shirish Gadgeel, Giovanna Speranza, Enriqueta Felip, Manuel Dómine, Steven F. Powell, Helge G. Bischoff, Nir Peled, Francesco Grossi, Ross R. Jennens, Martin Reck, Rina Hui, Edward B. Garon, Takayasu Kurata, Jhanelle E. Gray, Delvys Rodríguez-Abreu

Collection and assembly of data: Marina C. Garassino, Shirish Gadgeel, Giovanna Speranza, Enriqueta Felip, Maximilian J. Hochmair, Steven F. Powell, Helge G. Bischoff, Nir Peled, Francesco Grossi, Ross R. Jennens, Martin Reck, Rina Hui, Edward B. Garon, Takayasu Kurata, Paul Schwarzenberger, M. Catherine Pietanza, Delvys Rodríguez-Abreu

Data analysis and interpretation: Marina C. Garassino, Shirish Gadgeel, Enriqueta Felip, Manuel Dómine, Maximilian J. Hochmair, Steven F. Powell, Helge G. Bischoff, Nir Peled, Ross R. Jennens, Martin Reck, Rina Hui, Jhanelle E. Gray, Paul Schwarzenberger, Erin Jensen, M. Catherine Pietanza, Delvys Rodríguez-Abreu

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study

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