First‐line pembrolizumab vs chemotherapy in metastatic non‐small‐cell lung cancer: KEYNOTE‐024 Japan subset

Abstract
 This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death‐ligand 1 (PD‐L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression‐free survival by independent central review (data cut‐off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10‐0.64; one‐sided, nominal P = .001). The HR for overall survival (data cut‐off date, 15 February 2019) was 0.39 (95% CI, 0.17‐0.91; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or greater. The trial is registered with ClinicalTrials.gov: NCT02142738.


| INTRODUC TI ON
A previous version of this article was published in Cancer Science Lung cancer is the leading cause of cancer-related deaths worldwide 2 and represents approximately 20% of all cancer-related deaths in Japan. 3 Platinum-based chemotherapy has historically been the standard first-line treatment for patients with advanced-stage NSCLC, particularly those without targetable EGFR or ALK alterations [4][5][6] ; however, immunotherapy directed at the PD-1 checkpoint pathway has more recently provided patients with a therapeutic option that can improve clinical outcomes over standard chemotherapy regimens. 7 The most recent updates to lung cancer clinical practice eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events.
Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or greater. The trial is registered with ClinicalTrials.gov: NCT02142738.

K E Y W O R D S
Japan, non-small-cell lung carcinoma, PD-L1 protein, pembrolizumab, treatment outcome Pembrolizumab is a humanized IgG4 mAb that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2, thereby promoting cytotoxic T cell-mediated antitumor responses. 9 The phase I KEYNOTE-001 trial was the first study to show an association between PD-L1 expression and response to pembrolizumab, showing a higher response rate among patients with advanced NSCLC and a PD-L1 TPS of 50% or greater. 10 The global phase III KEYNOTE-024 study subsequently found that patients with previously untreated metastatic NSCLC without EGFR mutations or ALK translocations and a PD-L1 TPS of 50% or greater had significantly longer OS (HR, 0.60; 95% CI, 0.41-0.89; P =.005) and favorable safety outcomes with pembrolizumab vs platinum-based chemotherapy. 11  All patients provided written informed consent before enrollment. The trial protocol and all amendments were approved by an institutional review board or independent ethics committee at each study site, and the trial was carried out in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.

| Endpoints
The end-points in this preplanned subgroup analysis of patients enrolled in KEYNOTE-024 in Japan were the same as for the overall study. The primary end-point in the KEYNOTE-024 study was PFS, defined as the time from randomization to the first of either documented disease progression (per RECIST version 1.1 by BICR) or death from any cause. Evaluation by BICR was discontinued after the second interim analysis (protocol amendment 8); therefore, PFS is reported by BICR with a data cut-off date of 10 July 2017, and additionally by investigator review with a data cut-off date of 15 February 2019. Secondary end-points were OS (defined as the time from randomization to death from any cause), ORR (defined as the proportion of patients with a confirmed complete or partial response), and safety. Objective response data are reported per RECIST version 1.1 by investigator review with a data cut-off date of 15 February 2019. Duration of response was an exploratory endpoint, and was defined as the time from the first documentation of a complete or partial response to disease progression. 11

| Statistical analysis
Statistical methods for this subanalysis of the KEYNOTE-024 study were the same as those of the primary analysis, 11 except that only those patients enrolled in Japan were included. Efficacy analyses included all randomized patients, according to the treatment assigned (intention-to-treat population); safety analyses included all patients who received at least one dose of treatment, according to the treatment received. Both PFS and OS were estimated using the Kaplan-Meier method. For the analysis of PFS, patients who were alive without disease progression and had not initiated new anticancer therapy or who were lost to follow-up were censored at the time of last tumor assessment. For the analysis of OS, patients without documented death were censored at the time of last follow-up. Between-group differences in PFS and OS were assessed using a stratified log-rank test. Hazard ratios and associated 95% CIs were assessed using a stratified Cox proportional hazards model with Efron's method of handling ties. The stratified Miettinen and Nurminen method was used to assess treatment differences in ORR; patients with missing data were considered nonresponders.
Stratification factors used for randomization were also applied to the analyses. One-sided nominal P values are provided for this subanalysis. The data cut-off date for response data by BICR was 10 July 2017; for all other data for this analysis, the cut-off date was 15 February 2019.

| Safety
Treatment-related AEs of any grade occurred in all 21 patients treated with pembrolizumab and 18 of the 19 patients (95%) treated with chemotherapy in this Japanese cohort ( Table 2). The most common treatment-related AEs in the pembrolizumab arm were pyrexia     32%). In addition, pembrolizumab had a manageable safety profile, and no new safety signals were identified in this subset of Japanese patients relative to previous studies evaluating pembrolizumab monotherapy in patients with advanced NSCLC. 10,11,16 The favorable efficacy observed with pembrolizumab in this Severe skin reactions 1 (5) 1 (5) 0 (0) 0 (0)

| D ISCUSS I ON
The as-treated population comprised all randomized patients who received at least one dose of study treatment, according to the treatment received. b AEs that were attributed to treatment by the investigator are listed.
c Treatment-related AEs that led to discontinuation were: pneumonitis (n = 2), fatigue (n = 1), and uveitis (n = 1) among four patients in the pembrolizumab group; and hypoxia (n = 1) and pulmonary alveolar hemorrhage (resulting in death) in one patient in the chemotherapy group. d Immune-mediated AEs and infusion reactions are listed irrespective of attribution to study treatment by the investigator.
0.69; P =.0003); and additionally showed OS benefit in the overall population with PD-L1 TPS of 1% or greater (HR, 0.81; P =.0018). 18 Together, these findings provide support for the use of pembrolizumab monotherapy as first-line treatment for PD-L1-positive (TPS ≥1%) advanced NSCLC, which has received regulatory approval in Japan. 19 Significant OS benefit has also been shown with pembroli-  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 datasharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the United States and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country-or region-specific regulations.
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