Josep Tabernero, MD, PhD
Frontline pembrolizumab (Keytruda) demonstrated non-inferior overall survival (OS) compared with standard chemotherapy among patients with PD-L1–positive, HER2-negative, advanced gastric or gastroesophageal junction (G/GEJ) cancer, according to results from the phase III KEYNOTE-062 trial presented in a press briefing at the 2019 ASCO Annual Meeting.
Moreover, the PD-1 inhibitor showed a clinically meaningful improvement in OS among patients with tumors that had high levels of PD-L1 expression: at 2 years, 39% of patients in this subgroup were alive versus 22% of those on standard chemotherapy. In addition, the agent showed an improved safety profile compared with chemotherapy.
Lead study author Josep Tabernero, MD, PhD, head of the Medical Oncology Department, Vall d’Hebron University Hospital and Institute of Oncology in Barcelona, Spain, noted these trial results are significant in offering patients a new, effective treatment option. “There remains a significant unmet need for treatments for these cancers and our results reinforce the importance of continued research in this field,” he said in a press release.
In the randomized, active controlled phase III KEYNOTE-062 trial (NCT02494583), 763 patients with a PD-L1 combined positive score of ≥1 (CPS ≥1) who had HER2-negative, advanced gastric cancer were randomized 1:1:1 to receive one of the following treatment regimens:
- 200 mg pembrolizumab every 3 weeks for up to 2 years (n = 256);
- the pembrolizumab regimen plus chemotherapy (80 mg/m2 cisplatin plus 800 mg/m2/day fluorouracil [5-FU] on days 1 through 5 every 3 weeks or 1000 mg/m2 capecitabine twice daily on days 1 through 14 every 3 weeks per local guidelines (n = 257); or
- placebo every 3 weeks plus chemotherapy (n = 250).
Patients received treatment until unacceptable toxicity, disease progression, or patient/physician withdrawal decision. Key eligibility criteria included locally advanced, unresectable or metastatic gastric or gastroesophageal adenocarcinoma, HER2/neu negative, PD-L1–positive disease (CPS ≥1), and an ECOG score of 0 or 1. Patients were stratified by geographic region, locally advanced or metastatic disease, and whether they received 5-FU or capecitabine.
Primary endpoints were OS in CPS ≥1 and CPS ≥10 patients for the pembrolizumab plus chemotherapy regimen versus chemotherapy, and for pembrolizumab versus chemotherapy; and progression-free survival (PFS) per RECIST central review in CPS ≥1 patients for the pembrolizumab plus chemotherapy regimen versus chemotherapy. The secondary endpoints were overall response rate (ORR) per RECIST central review in CPS ≥1 patients for the pembrolizumab plus chemotherapy regimen versus chemotherapy, and safety.
Patients were a median age of 62 and 26% had previous gastric surgery to remove a tumor. In total, 69% had gastric cancer and 30% had GEJ cancer. All patients had a PD-L1 CPS ≥1 and 281 (37%) had a CPS ≥10.
Data cutoff was March 26, 2019. After a median follow-up of 11.3 months (range, 0.2-41.2), the trial reached its primary endpoint of demonstrating that OS for pembrolizumab monotherapy was comparable to standard chemotherapy. The 2-year OS rates in CPS ≥1 patients were 27% and 19%, respectively. The median OS was non-inferior to chemotherapy (10.6 [95% CI, 7.7-13.8] vs 11.1 months [95% CI, 9.2-12.8]; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18; non-inferiority margin, 1.2).
There were no major differences between arms in terms of OS in key subgroups of patients with CPS ≥1, Tabernero noted.
However, median OS was superior in the pembrolizumab arm for those with CPS ≥10 compared with standard chemotherapy (17.4 [95% CI, 9.1-23.1] vs 10.8 months [95% CI, 8.5-13.8]; HR, 0.69; 95% CI, 0.49-0.97). The 2-year OS rates were 39% and 22%, respectively.
OS in the CPS ≥1 group (12.5 months [95% CI, 10.8-13.9] vs 11.1 months [95% CI, 9.2-12.8]; HR, 0.85; 95% CI, 0.70-1.03; P
= .046) and CPS ≥ 10 group (12.3 months [95% CI, 9.5-14.8] vs 10.8 months [95% CI, 8.5-13.8]; HR, 0.85; 95% CI, 0.62-1.17; P
= .158) were comparable between the pembrolizumab plus chemotherapy arm and chemotherapy alone arm, respectively.
However, the ORR was higher among those who received pembrolizumab in addition to chemotherapy.
The rates of serious adverse events (AEs) were lowest among those treated with pembrolizumab alone (16.9%), followed by chemotherapy alone (69.3%), and pembrolizumab plus chemotherapy (73.2%).
The most common AEs included nausea and fatigue. In total, 22% of patients experienced immune-related toxicities, Tabernero said, adding that the safety profile of pembrolizumab was consistent with previous reports of the agent.
“Together with a substantially improved safety profile, I think it would be pretty clear to me that this would be a preferred treatment for this patient population. It also seems to be clear that pembrolizumab is superior to chemotherapy (from a clinical standpoint) in the high biomarker-positive population,” said Richard L. Schilsky, MD, FACP, FSCT, FASCO, senior vice president and chief medical officer of ASCO.
“What I take away from this study is for patients with advanced gastric/gastroesophageal cancer, pembrolizumab should really, in many cases, replace chemotherapy in the first-line treatment of this population,” he added.
Tabernero J, Van Cutsem E, Bang YJ, et al. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. Presented at: 2019 ASCO Annual Meeting; Chicago, IL; May 31-June 4, 2019. Abstract LBA4007.