No OS benefit for perioperative pembrolizumab in patients with untreated, locally-advanced, resectable gastric and gastroesophageal junction cancer

Checkpoint inhibition with PD-1/PD-L1 inhibitors was proven to be beneficial for the treatment of patients with resectable gastric and gastroesophageal junction (G/GEJ) cancer in the first line.¹ Whether such positive effects are also seen in a neoadjuvante/adjuvant setting, remains unknown. The previous and third interim analysis of the KEYNOTE-585 study has shown that the addition of pembrolizumab to perioperative chemotherapy does not significantly improve the event-free survival (EFS) in patients with untreated locally-advanced, resectable G/GEJ cancer, when compared to placebo plus chemotherapy (p=0.0198). Despite this lack of benefit in EFS, the previous analysis of KEYNOTE-585 did reveal a positive effect for perioperative pembrolizumab on the pathological complete response (pathCR) rate (p<0.0001). During ESMO GI 2024, dr. Kohei Shitara presented the final analysis of the KEYNOTE-585 study.²

Study design

This phase III, multicentric, randomised study enrolled patients with untreated, locally advanced, resectable G/GEJ cancer. In the main cohort, patients were randomised 1:1 to receive neoadjuvant pembrolizumab (200 mg, IV, Q3W) or placebo, in addition to 3 cycles of chemotherapy (either cisplatin plus capecitabine or cisplatin plus 5-FU). After surgery, patients in the main cohort either received 3 cycles of adjuvant pembrolizumab plus chemotherapy or placebo plus chemotherapy (Q3W), followed by 11 cycles of adjuvant pembrolizumab or placebo (Q3W). In addition, the KEYNOTE-585 study contained a FLOT cohort, in which patients were randomised 1:1 to a perioperative treatment regimen consisting of docetaxel, oxaliplatin, leucovorin and 5-FU (FLOT) plus either pembrolizumab or placebo. For analysis purposes, the FLOT cohort was combined with the main cohort. Primary endpoints were pathCR (assessed by blinded, independent central review), EFS, overall survival (OS) and safety.

Results

A total of 804 patients were randomised to the main cohort (pembrolizumab: n=402; placebo: n=402) and 203 patients were randomised to the FLOT cohort (pembrolizumab: n=100; placebo: n=103). At a median follow-up of 59.9 months in the main cohort, the pathCR rate was 13.4% in the pembrolizumab arm and 2.0% in the placebo arm (difference [95% CI]: 11.4% [8.0-15.3]). At a median follow-up of 58.6 months in the combined main + FLOT cohort, the pathCR rate was 14.2% and 2.8% with pembrolizumab or placebo, respectively (difference [95% CI]: 11.4% [8.1-15.0]). In the main cohort, the median EFS was 44.4 months with pembrolizumab and 25.7 months with placebo (HR [95% CI]: 0.81 [0.67-0.98]). The median EFS was 47.0 months in the pembrolizumab arm and 26.9 months in the placebo arm of the main + FLOT cohort (HR [95% CI]: 0.80 [0.67-0.95]). The median OS was 71.8 months with pembrolizumab, versus 55.7 months for placebo (HR [95% CI]: 0.86 [0.71-1.06]) in the main cohort. In the FLOT cohort, the median OS was not reached in the pembrolizumab arm and 55.7 months in the placebo arm (HR [95% CI]: 0.86 [0.71-1.03]). Grade ≥3 drug-related adverse events (AEs) were reported for 65% and 63% of patients that were treated with pembrolizumab or placebo, respectively, in the main cohort. In the FLOT cohort these values were 67% with pembrolizumab and 63% with placebo. Immune-mediated AEs were more frequently observed in patients that received pembrolizumab (29%) than placebo (10%).

Conclusions

In conclusion, the results of the final analysis of the KEYNOTE-585 study confirm what was found in the earlier interim analyses: addition of neoadjuvant and adjuvant treatment with pembrolizumab to chemotherapy in patients with untreated, locally advanced, resectable G/GEJ cancer significantly increases the pathCR rate, but not the OS compared to placebo. The safety profile of pembrolizumab was consistent with previous reports regarding pembrolizumab treatment in a similar setting.

References

1. Rha SY, Wyrwicz LS, Weber PEY, et al. VP1-2023: Pembrolizumab (pembro) plus chemotherapy (chemo) as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: Phase III KEYNOTE-859 study. Ann of Oncol 2023;34:319-20.
2. Shitara K, et al. Final analysis of the phase III KEYNOTE-585 study of pembrolizumab plus chemotherapy vs chemotherapy as perioperative therapy in locally-advanced gastric and gastroesophageal junction cancer. Presented at ESMO GI 2024; Abstract LBA3.