Phase IIb study of pembrolizumab combined with S‐1 + oxaliplatin or S‐1 + cisplatin as first‐line chemotherapy for gastric cancer

Abstract The KEYNOTE‐659 study evaluated the efficacy and safety of first‐line pembrolizumab plus S‐1 and oxaliplatin (SOX) (cohort 1) or S‐1 and cisplatin (SP) (cohort 2) for advanced gastric/gastroesophageal junction (G/GEJ) cancer in Japan. Herein, we update the results of cohort 1 and describe the results of cohort 2. This open‐label phase IIb study enrolled patients with advanced programmed death‐ligand 1 (PD‐L1)‐positive (combined positive score ≥ 1) human epidermal growth factor receptor 2 (HER2)‐negative G/GEJ adenocarcinoma. The primary end‐point was the objective response rate (ORR). Other end‐points were duration of response (DOR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), and safety. One hundred patients were enrolled. In cohorts 1 and 2, median follow‐up time was 16.9 and 17.1 months; ORR (central review), 72.2% and 80.4%; DOR, 10.6 and 9.5 months; DCR (central review), 96.3% and 97.8%; median PFS (central review), 9.4 and 8.3 months; and median OS, 16.9 and 17.1 months, respectively. Treatment‐related adverse events (TRAEs) occurred in all patients, including peripheral sensory neuropathy (94.4%, cohort 1), decreased neutrophil count (82.6%, cohort 2), nausea (59.3% and 60.9% in cohorts 1 and 2), and decreased appetite (61.1% and 60.9% in cohorts 1 and 2). Grade 3 or higher TRAEs were reported by 59.3% (cohort 1) and 78.3% (cohort 2), including decreased platelet count (14.8%, cohort 1) and decreased neutrophil count (52.2%, cohort 2). Pembrolizumab in combination with SOX or SP showed favorable efficacy and safety in patients with PD‐L1‐positive, HER2‐negative G/GEJ adenocarcinoma.


| INTRODUC TI ON
Gastric cancer is the fifth most frequently diagnosed cancer worldwide and the second most common cancer in Japan. 1,2 In Japan, the standard first-line chemotherapy regimen for HER2-negative advanced G/GEJ cancer is combination therapy with platinum and fluoropyrimidine agents. [3][4][5][6][7] Of note, immune checkpoint blockade with Abs targeting the PD-1 pathway has therapeutic benefits in several cancers, including gastric cancer. 8 Pembrolizumab (MK-3475) is a potent, highly specific, humanized IgG4/kappa-isotype mAb that directly inhibits the binding of PD-1 and its ligands PD-L1 and PD-L2. Programmed cell death-L1 expression or PD-L1 CPS ≥ 1, calculated as the number of PD-L1positive cells (tumor cells, macrophages, and lymphocytes) divided by the total number of cells multiplied by 100, is detected in 67%-82% of gastric cancer patients. 9,10 The relationship between CPS and efficacy has been shown with pembrolizumab monotherapy. 11 The KEYNOTE-059 study evaluated the safety and efficacy of pembrolizumab plus fluoropyrimidine (5-FU) or capecitabine and cisplatin in chemotherapy-naïve patients with advanced gastric cancer. 12 The ORR, median PFS, and median OS were 60% (95% CI, 39%-79%), 6.6 months (95% CI, 5.9-10.6 months), and 13.8 months (95% CI, 8.6 months-not estimable), respectively. 12 In the subsequent KEYNOTE-062 phase III study in patients with HER2-negative advanced gastric or GEJ adenocarcinoma with PD-L1 CPS ≥1, OS with pembrolizumab alone as first-line therapy was noninferior to chemotherapy with 5-FU and cisplatin or capecitabine and cisplatin. However, OS with pembrolizumab plus 5-FU and cisplatin or capecitabine and cisplatin was not superior to 5-FU and cisplatin or capecitabine and cisplatin in patients with PD-L1 CPS ≥1 or PD-L1 CPS ≥10. 11 The current study (KEYNOTE-659) investigated the efficacy and safety of pembrolizumab in combination with S-1 (tegafurgimeracil-oteracil potassium) and oxaliplatin or S-1 and cisplatin as first-line therapy in Japanese patients with advanced G/GEJ adenocarcinoma. The results from cohort 1 (patients treated with pembrolizumab plus SOX) of this study have been reported previously and showed an ORR of 72.2% (95% CI, 58.4%-83.5%), DCR of 96.3% (95% CI, 87.3%-99.5%), PFS of 9.4 months (95% CI, 6.6 months-not evaluable), and the median OS was not reached (cut-off June 21). 13 In this article, we report the updated results for cohort 1 (patients treated with pembrolizumab plus SOX), as label phase IIb study enrolled patients with advanced programmed death-ligand 1 (PD-L1)-positive (combined positive score ≥ 1) human epidermal growth factor receptor 2 (HER2)-negative G/GEJ adenocarcinoma. The primary end-point was the objective response rate (ORR). Other end-points were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. One hundred patients were enrolled. In cohorts 1 and 2, median follow-up time was 16

| Study design and patients
Details of the study design have been previously published. 13 Briefly, this nonrandomized, multicenter, open-label, phase IIb trial (KEYNOTE-659, NCT03382600/JapicCTI-183829) targeted patients with advanced G/GEJ adenocarcinoma that was PD-L1 CPSpositive and HER2-negative and evaluated the efficacy and safety of SOX (cohort 1) or SP (cohort 2) with pembrolizumab as first-line treatment. Enrollment of cohort 2 commenced following completion of enrollment of cohort 1.
For cohorts 1 and 2, the key eligibility criteria were as follows:

| Treatment
Pembrolizumab 200 mg (a 30 min i.v. infusion) and oxaliplatin (130 mg/m 2 i.v.) or cisplatin (60 mg/m 2 i.v.) were given on day 1 of each 3-week cycle and S-1 was given orally twice daily for the first 2 weeks of each 3-week cycle at a dose of 40 mg for a BSA < 1.25 m 2 , 50 mg for a BSA from 1.25 to <1.5 m 2 , and 60 mg for a BSA ≥1.5 m 2 .
As prophylactic treatment for nausea and vomiting, patients were managed with palonosetron plus aprepitant or fosaprepitant.
Additionally, the use of steroids was allowed for oxaliplatin or cisplatin-associated antiemetic purposes.
Treatment with pembrolizumab plus chemotherapy was continued until disease progression, unacceptable AEs, withdrawal of consent, or until the patient had received 35 treatments with pembrolizumab.

| Assessments
Computed tomography was carried out at baseline within 21 days prior to enrollment. Subsequent tumor imaging was carried out every 6 weeks (42 days ± 7 days) or more frequently if clinically indicated.
Tumor response was assessed according to RECIST version 1.1 by central review as well as by the investigator. Tumor imaging to confirm PR or CR was carried out at least 4 weeks after the first indication of response was observed. In clinically stable patients, disease progression was confirmed based on iRECIST between 4 and 8 weeks after the first progression. 14

| End-points
The primary end-point was the ORR assessed by central review according to RECIST version 1.

| Statistical analysis
The target sample size was 90 patients, comprising 45 patients in cohort 1 and 45 patients in cohort 2, to account for a drop-off rate before treatment of 10%. No specific hypotheses were tested in this study. However, the planned sample sizes were considered appropriate to allow the estimation of the effect of pembrolizumab with SOX or SP according to the point estimate and 95% CI by the exact bino- In cohort 1, 42 patients were discontinued due to disease progression (40 had radiological disease progression, and two had clinical disease progression). Three patients discontinued due to TRAEs (enteritis, pancreatitis/pancreatic pseudocyst, and cardiac arrest).
Additionally, nine patients discontinued for other reasons, including six patients who completed 35 pembrolizumab treatments and two patients who underwent surgery for curative intent. Only one patient was lost to follow-up. In cohort 2, 35 patients discontinued due to disease progression: 31 had radiological disease progression, and four had clinical disease progression. Three patients discontinued due to an AE: two had treatment-related rash, and one had pancreatitis. One patient withdrew from treatment. Seven patients discontinued for other reasons, including three patients who completed 35 pembrolizumab treatments and three patients who underwent surgery for curative intent.
The baseline demographic and clinical characteristics of patients are shown in Table 1. More than half of the population were men (79.6% in cohort 1, 60.9% in cohort 2), the median age was 66.0 and 65.0 years in cohorts 1 and 2, respectively, and CPS was ≥10 in 31 (57.4%) and 27 (58.7%) patients in cohorts 1 and 2, respectively.

| Treatment delivery
In cohorts 1 and 2, the median treatment duration of pembrolizumab was 6.0 and 5.1 months, respectively. The median treatment duration of SOX (cohort 1) was 4.9 months and the median treatment duration of SP (cohort 2) was 4.4 months. The actual and relative dose intensities for each drug, along with the cumulative doses, are shown in Table 2

| Safety
Overall, TRAEs of any grade occurred in all patients in this study. The incidence of TRAEs that occurred in at least 10% of patients in this study are presented in Table 5 Regarding the safety profile of pembrolizumab in combination with SP, decreased neutrophil count (grade ≥ 3) was more frequently reported in cohort 2 (52.2%) than in cohort 1 (14.8%) ( Table 5).
Overall, the most frequently reported TRAEs in cohort 2 were anemia (2.2% and 0.0%, respectively). Study discontinuation because of rash was reported in two patients in this study, but treatment discontinuation due to rash was not reported in cohort 1. 13 Grade 3 colitis was observed in three patients (5.6%) in cohort 1, 13 but no grade ≥3 colitis was observed in cohort 2. The other TRAEs of interest were not notably different from those reported with pembrolizumab monotherapy. 10,11 Although SP is usually given every 5 weeks in Japan, in this study, SP3 treatment matched the timing of pembrolizumab treatment (every 3 weeks). In addition, the efficacy and safety of SP3 have previously been confirmed in the SOS study, a phase III study in Japan and Korea that investigated SP3 as first-line therapy in patients with advanced gastric cancer. 16 The incidence and profile of AEs in this study are consistent with the SP3 safety profile reported in the SOS study, showing no novel safety concern with the combination of SP3 with pembrolizumab. 10,11 Although the initial dose of oxaliplatin (130 mg/m 2 ) was higher than that in the G-SOX study (100 mg/m 2 ), an increase of hematological toxicities was not observed in this study. The relative dose intensity for oxaliplatin in this study (59.6%) was lower than that in the G-SOX study (79.0%). 17   Abbreviations: CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease. cell death. 18,19 In our study, regimens that included two different platinum agents were investigated, but no difference was suggested between cohorts by platinum agent. Although there are some differences in the safety profiles of the platinum agents, both SOX and SP could be candidates for use in pembrolizumab combination regimens.
In the KEYNOTE-062 study, no statistically significant ben-

ACK N OWLED G M ENTS
The authors thank the patients, their families, and caregivers for participating in this study, and the medical advisor for this study,