Gastroesophageal junction carcinoma (GEJ) is a difficult-to-treat malignancy that constitutes a large minority of all gastric cancers. One of the key difficulties in treating the disease is the high rate of chemoresistance acquired in response to first-line chemotherapies. Furthermore, the five-year survival of patients with metastatic GEJ (mGEJ) is less than 5%. There has been an emphasis in the clinical setting on maximising the efficacy of the first-line treatment to derive as much clinical benefit as possible before secondary resistance develops. Human epidermal growth factor receptor 2 (HER2+) is prevalent in roughly 20% of all GEJ, making it highly promising for more personalised therapeutic regimens.
At the European Society for Medical Oncology (ESMO), final data from KEYNOTE-811 was presented on 15 September. The study evaluated 698 patients with HER2+ mGEJ receiving either Merck & Co’s Keytruda (pembrolizumab) in combination with trastuzumab and chemotherapy (fluorouracil- or platinum-based) or trastuzumab and chemotherapy alone in the first line. The interim analysis demonstrated that the Keytruda arm significantly improved progression-free survival (PFS) and had a higher overall survival (OS) than the control arm.
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Adding Keytruda improved OS by 3.2 months (p=0.0201) in the intention-to-treat group and increased the overall response rate (ORR) by 12.5%. There was a slight increase in grade ≥3 drug-related adverse events in the Keytruda arm (59% vs 51%). Keytruda’s performance was even more pronounced in the PD-L1 combined positive score ≥1 patient sub-group analysis, with an OS improvement of 4.4 months. Keytruda’s long-term rival, Bristol Myers Squibb’s Opdivo (nivolumab), has received approval for first-line treatment in mGEJ, but this was only for HER2- patients following evidence presented in the CheckMate-649 trial.
Merck & Co’s position in this line and indication is not devoid of threats. Daiichi Sankyo also had data presented from its their Phase II DESTINY-Gastric03 trial with Enhertu (trastuzumab deruxtecan) at ESMO this year, which also used a HER2+ mGEJ patient cohort. The antibody-drug conjugate was evaluated in multiple arms, ranging from monotherapy to combinations with fluoropyrimidine chemotherapy (FP) and Keytruda. The highest ORR was reached in the Enhertu + FP arm (78%). The trial also revealed a high incidence of grade ≥3 adverse events, with 76% of the Enhertu + FP arm patients impacted. Keytruda is already indicated for mGEJ cancer in combination with chemotherapy, and these results instill confidence and will improve its sales in this indication. According to GlobalData’s Gastric and Gastroesophageal Junction Adenocarcinoma: Eight Market Drug Forecast and Market Analysis Update: 2019-2029 report, peak sales for Keytruda in gastric and GEJ cancer to reach $754m in the eight major markets (US, UK, France, Germany, Italy, Spain, Japan, China) by 2029. Comparatively, Opdivo is expected to reach $1.47bn in sales in the same year across the eight major markets owing to its larger accessibility in the HER2- disease.
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