The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer

Abstract

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas^1-3. More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours⁴. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer⁵, there are preclinical^6-19 and clinical^20,21 rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma²² ( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.

Extended Data Fig. 1.. Treatment difference in objective response in subgroups of the efficacy population.

Response was assessed per RECIST, version 1.1, by blinded, independent central review. The estimated treatment difference between the pembrolizumab and placebo groups in the overall population was calculated using the Miettinen and Nurminen method stratified by geographic region (Australia/Europe/Israel/North America [Aus/Eur/Isr/NAm] vs Asia vs rest of world), PD-L1 combined positive score ([CPS]; ≥1 vs <1), and chemotherapy choice (5-fluorouracil plus cisplatin [FP] vs capecitabine plus oxaliplatin [CAPOX]); differences in subgroups were calculated using the unstratified Miettinen and Nurminen method. The efficacy population included the first 264 participants randomly allocated to treatment. The treatment regimen included trastuzumab and chemotherapy in both groups. Diamonds represent the estimated treatment difference in objective response, the error bars represent the 95% confidence interval (CI) of the estimated treatment difference, and the region shaded in dark grey represents the 95% CI for the treatment difference in the overall population. ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction; IHC, immunohistochemistry; ISH, in situ hybridization.

Fig. 1.. Best percentage change from baseline in the size of target lesions among participants in the efficacy population.

(a) pembrolizumab group; (b) placebo group. Only those participants in the efficacy population who had RECIST-measurable disease at baseline and at least one evaluable post-baseline measurement are evaluable for change from baseline (N=124 in the pembrolizumab group, N=122 in the chemotherapy group). The treatment regimen included trastuzumab and chemotherapy in both groups. Increases from baseline greater than 100% were truncated at 100%.