In a discussion between prof Jeroen Dekervel from UZ Leuven and Dr Janjigian from Memorial Sloan Kettering Cancer Center in New York, both distinguished gastrointestinal oncologists, the focus centered on the findings from the phase 3 results of the KEYNOTE811 trial. This study delved into the effectiveness of combining pembrolizumab with trastuzumab and chemotherapy in patients suffering from HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) cancer.
Dr Janjigian initially provided an overview of the established treatment approach for these patients. Over the past decade, HER2 has served as a validated target and a crucial biomarker in this context, as substantiated by the ToGA study. The combination of trastuzumab with fluoropyrimidine and platinum-based chemotherapy demonstrated an impressive overall response rate (ORR) of 47%, a median progression-free survival (PFS) of 6.7 months, and a median overall survival (OS) of 13.8 months. Consequently, this combination has stood as the standard first-line therapy since 2009. For several years, attempts to employ dual HER2 inhibition proved unsuccessful.
The rationale behind KEYNOTE811 stemmed from internal phase 2 data and preclinical investigations, which highlighted the synergistic effects of dual PD-L1 and HER2 blockade. Notably, approximately 85% of HER2+ tumours exhibited PD-L1 overexpression, making them responsive to pembrolizumab. A phase 2 trial incorporating pembrolizumab yielded outstanding results in terms of ORR and OS.
Upon conducting an interim analysis of the phase 3 trial, incorporating pembrolizumab into the standard regimen led to a remarkable 74% increase in ORR. Consequently, this innovative approach received accelerated approval from the US FDA as a first-line therapy for locally advanced, unresectable, or metastatic HER2+ G/GEJ cancer patients.
During the ESMO2023 interim analysis presentation, it was revealed that the ORR was exceptionally high at 74%. Notably, the control arm also demonstrated commendable efficacy. Prof Dekervel and Dr Janjigian agreed that this could be attributed to improved HER2 testing methodologies and the utilization of oxaliplatin instead of cisplatin as the backbone therapy. While the results for OS endpoints are pending, the interim analysis confirmed the achievement of the primary endpoint, PFS, for all patients, particularly in the subgroup with PD-L1 combined positive score (CPS) greater than 1.
This subgroup analysis raised questions about the potential benefits of the therapy for patients with PD-L1 CPS>1, contrasting with potential risks for HER2+ CPS0 patients. Dr Janjigian acknowledged these concerns, emphasizing the rarity and small size of this subgroup, making definitive conclusions challenging. Both experts acknowledged that these findings might also hold significance for HER2-negative patients.
Addressing the pivotal question of whether this novel therapeutic approach could lead to the cure of patients with metastatic disease, Dr Janjigian revealed that 17% of patients exhibited a complete clinical response. This subset could be considered ‘cured’ under the definition of durable remission, offering a promising prospect for patients battling this condition.
Reference
Yelena Janjigian – Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Survival results from the phase III, randomized, double-blind, placebo-controlled KEYNOTE-811 study. ESMO2023 – 1511O
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