Immune checkpoint inhibitors have faced challenges in stomach cancer, and Merck's KEYTRUDA has now experienced a setback. The Phase III KEYNOTE-585 trial of neoadjuvant and adjuvant pembrolizumab plus chemotherapy, fell short on one of its primary endpoints, event-free survival (EFS). 

A total of 804 patients were assigned 1:1 to pembrolizumab (n = 402) or placebo (n = 402). A separate safety cohort included 203 patients assigned pembrolizumab (n = 100) or placebo (n = 103). In the main cohort, chemotherapy consisted of cisplatin plus either capecitabine or 5-FU. In the safety cohort, chemotherapy consisted of 5-FU, docetaxel, oxaliplatin and leucovorin (FLOT). Additionally, 1,007 patients were randomized to the main cohort combined with FLOT (fluorouracil plus cisplatin [FP] or fluorouracil, leucovorin, oxaliplatin plus docetaxel [FLOT]), with 502 receiving pembrolizumab and 505 receiving a placebo. The median follow-up periods were 47.7 months and 46.3 months, respectively. Randomization was stratified according to geographical region (Asia vs non-Asia). Gastric cancer is notably more prevalent in Asian countries compared to other regions. Particularly in Asian nations like Japan, China, Mongolia, and the Republic of Korea, Gastric cancer is a common disease (Ning et al., 2022).

As per the results presented in the ESMO 2023, within the main cohort, the addition of pembrolizumab to chemotherapy significantly increased the pathological complete response (pCR) rate to 12.9%, compared to 2.0 % with placebo and chemotherapy. 

On the other hand, within the main plus FLOT cohort, combination therapy showed an improved pCR rate to 13.0% compared to 2.4 % with placebo. Event-free survival (EFS) showed a longer duration with pembrolizumab than with placebo for the primary (median 44.4 vs 25.3 months) and main plus FLOT (median 45.8 vs 25.7 months) cohorts respectively, although this difference did not reach statistical significance. Overall survival (OS) is still under analysis, with median OS at 60.7 months with pembrolizumab and 58 months with placebo. Rates of Grade ≥3 drug-related adverse events were 65% with pembrolizumab plus chemotherapy and 63% with placebo plus chemotherapy.

KOL insights

“On the one hand it is perhaps surprising that the improvement in pCR seen in KEYNOTE-585 did not lead to prolonged survival because we know that, in chemotherapy trials, regimens associated with higher pCR rates tend to improve survival. But on the other hand, we know that immunotherapy in gastric cancer performs best in patients with PD-L1-positive disease and that patients in this trial were biomarker unselected. For patients with tumors that express high levels of PD-L1, the difference in EFS for those treated with pembrolizumab was meaningful (HR 0.70).” –MD, United Kingdom

“These findings are insufficient to recommend immune checkpoint inhibitors (ICIs) in perioperative therapy. Additional studies are needed to elucidate the effectiveness of ICI in this setting”–MD, Japan

Conclusion

According to phase III study results, the combination of KEYTRUDA and chemotherapy can induce high rates of response in patients with gastroesophageal junction adenocarcinoma while maintaining safety. Although perioperative KEYTRUDA demonstrated some enhancements in EFS in the ongoing stomach cancer trial, the degree of improvement did not reach statistical significance. While the PD-1 inhibitor did increase the number of patients with no evidence of cancer in resected tissue, fulfilling the trial's alternative primary endpoint of pCR, it is crucial to recognize that pCR is an early gauge of effectiveness. If the more established EFS marker does not show success, regulatory authorities are unlikely to view pCR as sufficient for potential approval. It is noteworthy that individuals in this trial were not selected based on biomarkers, and that immunotherapy for gastroesophageal junction adenocarcinoma often works better in patients with PD-L1-positive disease. In future, companies may proceed with biomarker-selected trials. At the ESMO Congress in 2023, preliminary findings from the global, phase III MATTERHORN study (#LBA73) also presented. The KEYNOTE-585 and the MATTERHORN study have nearly the same design. Based on the results of both studies, immune checkpoint inhibitors are still insufficient to be recommended as perioperative therapy options for gastric/gastro-esophageal junction malignancies.

The incidence of gastroesophageal junction cancer is on the rise. At the time of diagnosis, around 40% of patients have metastatic disease, and their 5-year overall survival is low. Owing to the high prevalence of H. pylori infection, certain dietary practices, smoking habits, and strong alcohol intake. Gastric Cancer is highly prevalent in Asian countries. 

For more insight into the patient's burden, epidemiological factors, treatment options, and evolving developments in the market landscape, refer to the Gastroesophageal Adenocarcinoma Market Report