Pembrolizumab addition benefits patients with HER2-positive gastric cancer

medwireNews: The addition of pembrolizumab to first-line trastuzumab plus chemotherapy significantly improves the progression-free survival (PFS) of patients with HER2-positive, advanced gastric or gastroesophageal junction adenocarcinoma, shows the KEYNOTE-811 trial presented at the ESMO Congress 2023 in Madrid, Spain. The researchers highlight in a simultaneous publication in The Lancet that the PFS benefit was observed in the subgroup of patients with a PD-L1 combined positive score (CPS) of 1 or more, but not those with a CPS below 1. In light of these results, the US FDA approval of this regimen “will be revised and limited to patients with tumours with a PD-L1 CPS of 1 or more,” they write. The authors of a linked commentary say that “[o]ne key lesson of KEYNOTE-811 is that when combining targeted therapy with immune-checkpoint inhibitors in patients with gastro-oesophageal adenocarcinoma, pre-existing immune activation might be crucial.” Elizabeth Smyth (Churchill Hospital, Oxford, UK) and Raghav Sundar (National University of Singapore) continue: “As treatment for gastro-oesophageal adenocarcinoma becomes increasingly complex with the introduction of novel biomarker-directed therapies, including CLDN18.2 and FGFR2b, the oncology community should carefully weigh the addition of immunotherapy to a treatment regimen.” In the double-blind, phase 3 trial, 698 patients with previously untreated locally advanced or metastatic disease were randomly assigned to receive either pembrolizumab 200 mg or placebo every 3 weeks alongside trastuzumab plus fluoropyrimidine and platinum-based chemotherapy for up to 35 cycles. Yelena Janjigian (Memorial Sloan Kettering Cancer Center, New York, USA) and colleagues note that the first interim analysis demonstrated “a superior objective response” with pembrolizumab versus placebo, with the current publication focusing on the second and third interim analyses, conducted at a median follow-up of 28.4–28.5 months and 38.5–38.6 months, respectively. The co-primary endpoint of PFS was significantly prolonged in the pembrolizumab compared with the placebo group at the second interim analysis, at a median of 10.0 versus 8.1 months, and a hazard ratio (HR) for progression or death of 0.60, which met the superiority criteria. The respective 24-month PFS rates were 25.1% and 14.2%. Overall survival (OS) – the other primary endpoint – was numerically longer in the pembrolizumab than placebo group, at a median of 20.0 and 16.9 months, respectively, but the HR for death of 0.87 was not statistically significant. The findings were similar at the third interim analysis, with the significant PFS benefit afforded by pembrolizumab maintained and median OS remaining numerically longer in the pembrolizumab arm. Although the investigators acknowledge the lack of a definitive OS gain as a “key limitation” of these interim analyses, they say: “As these data are still evolving, the independent data monitoring committee recommended that the study continue without changes to the prespecified final analysis of overall survival.” Of note, subgroup analysis showed that the PFS benefit of pembrolizumab was restricted to patients with a PD-L1 CPS of 1 or more (85% of patients in each treatment arm), with median durations of 10.8 versus 7.2 months with pembrolizumab and placebo, respectively, and a significant HR of 0.70. By contrast, the median PFS durations in patients with a CPS below 1 were nearly identical at 9.5 and 9.6 months, respectively, and the HR was a nonsignificant 1.17. Turning to the adverse event (AE) data, Janjigian and team say that “[n]o new safety concerns were observed.” Treatment-related AEs of grade 3 or worse occurred in 58% of participants in the pembrolizumab arm and 51% of those in the placebo arm, with the most common events being diarrhea (9 vs 8%) and decrease in neutrophil count (8 vs 9%). Four patients in the pembrolizumab group died as a result of a treatment-related AE, as did three patients in the placebo group. “The effect of this regimen on progression-free survival suggests that it could be considered as a first-line therapy option for patients with metastatic gastro-oesophageal cancer with co-occurring HER2 and PD-L1 overexpression; however, the overall survival benefit of this regimen is yet to be determined,” conclude the study authors. medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group ESMO Congress 2023; Madrid, Spain: 20–24 October Lancet 2023; doi:10.1016/S0140-6736(23)02033-0 Lancet 2023; doi:10.1016/S0140-6736(23)02296-1

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Pembrolizumab addition benefits patients with HER2-positive gastric cancer

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