KEYNOTE-062: Pembrolizumab combination fails to improve survival in gastric/GEJ cancer

Medical writer: Muriel Cunningham

Pembrolizumab plus chemotherapy failed to prolong overall survival (OS) and progression-free survival (PFS) among patients with PD-L1–positive gastric and gastroesophageal cancers, according to results from the phase III KEYNOTE-062 trial (Abstract LBA4007). Pembrolizumab monotherapy improved OS among patients with high PD-L1 expression but not PFS.

The objective of the KEYNOTE-062 trial (NCT02494583) was to determine the safety and efficacy of first-line treatment with pembrolizumab with and without chemotherapy in patients with gastric or gastroesophageal cancer. This study was conducted in patients with HER2-negative, advanced gastric or gastroesophageal cancer who had a PD-L1 combined positive score (CPS) of 1 or higher. Josep Tabernero, MD, PhD, of Vall d’Hebron University Hospital, Spain, presented the study results.

Patients who met eligibility criteria were randomly selected 1:1:1 to one of the following three groups: pembrolizumab 200 mg every 3 weeks (Q3W) for up to 2 years; pembrolizumab 200 mg Q3W plus chemotherapy (cisplatin 80 mg/m² + 5-fluorouracil [5-FU] 800 mg/m²/day for 5 days Q3W or capecitabine 1,000 mg/m²twice daily on days 1 to 14 Q3W according to local guidelines); or placebo Q3W plus chemotherapy. Patients were stratified by region, disease status, and fluoropyrimidine treatment. The primary endpoints were (1) OS in patients with CPS 1 or higher and patients with CPS 10 or higher for pembrolizumab plus chemotherapy vs. chemotherapy alone and pembrolizumab vs. chemotherapy alone; and (2) PFS using RECIST version 1.1 with central review in patients with a CPS of 1 or higher for pembrolizumab plus chemotherapy vs. chemotherapy alone. The secondary endpoint was the overall response rate (ORR) using RECIST version 1.1 with central review in patients with CPS 1 or higher for pembrolizumab plus chemotherapy vs. chemotherapy alone. The prespecified analysis plan allowed alpha passing from successful hypotheses.

A total of 763 patients were randomly assigned: 257 (33.7%) to pembrolizumab plus chemotherapy, 256 (33.6%) to pembrolizumab alone, and 250 (32.8%) to chemotherapy alone. The demographic characteristics were well balanced among the treatment groups. The median age was 62, and the majority of patients (> 95%) had metastatic disease.

The presented efficacy results are summarized in the Table. Pembrolizumab was noninferior to chemotherapy for OS in patients with CPS 1 or higher. Clinically meaningful improvement in OS was observed with pembrolizumab vs. chemotherapy in CPS 10 or higher (median OS = 17.4 vs. 10.8 months; HR 0.69, 95% CI [0.49, 0.97]). No significant differences were seen in subgroup analyses. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS 1 or higher (HR 0.85; P = 0.046) or CPS 10 or higher (HR 0.85; P = 0.158) per prespecified boundaries. A modest benefit in PFS and ORR was seen with pembrolizumab plus chemotherapy vs. chemotherapy alone.

The incidence of any-grade treatment-related adverse events was lower with pembrolizumab (54% pembrolizumab vs. 92% chemotherapy) as were grade 3/4 events (16% pembrolizumab vs. 68% chemotherapy). The safety profile of pembrolizumab plus chemotherapy was comparable to chemotherapy alone. “Patients receiving pembrolizumab had a better tolerability profile than those who received chemotherapy. There was a modest additional benefit of pembrolizumab plus chemotherapy vs. chemotherapy, and the safety profile of this combination was manageable as well,” Dr. Tabernero said.

Discussant Ian Chau, MD, of The Royal Marsden Hospital, United Kingdom, gave an overview of possible reasons why pembrolizumab combined with chemotherapy did not improve survival in patients with gastric cancer. Dr. Chau reviewed data from other studies and discussed the following elements: the combination of anti–PD-1 with chemotherapy, the chemotherapy backbone, whether gastric cancer is optimal for this combination, the choice of biomarker, and study design. He specifically noted the multiple endpoints, treatment groups, and populations of KEYNOTE-062, and referred to a recent review on multiplicity in clinical trials.1“There are many, many different facets in this clinical trial,” Dr. Chau said. These results and design considerations may have implications for future studies.

1. Dmitrienko A, et al. N Engl J Med. 2018;378:2115-22.

Posted on 15 July 201921 May 2024