KEYNOTE-585 mPR, pDS Results Favor Pembrolizumab Plus Chemotherapy for G/GEJ Cancers

The randomized, phase 3 KEYNOTE-585 trial found that neoadjuvant or adjuvant pembrolizumab plus chemotherapy (cisplatin plus capecitabine [XP] or cisplatin plus 5-fluorouracil [FP]) was not superior to placebo plus chemotherapy (XP or FP) for event-free survival (EFS) in the intention-to-treat population of patients with locally advanced gastric or gastroesophageal (G/GEJ) adenocarcinoma. Pembrolizumab plus chemotherapy significantly improved pathologic complete response against placebo plus chemotherapy (difference, 10.9%; 95% CI, 7.5-14.8; P<.00001).

Patients who experience pathologic tumor downstaging (pDS) often have lower recurrence rates and improved overall survival (OS). While major pathologic response (mPR) serves as an important end point for certain types of cancer, data are lacking in gastric cancer.

At the 2024 American Society of Clinical Oncology Annual Meeting, Kohei Shitara, MD, presented a post hoc analysis of the KEYNOTE-585 trial examining the utility of mPR and pDS as surrogate end points.

The main cohort of KEYNOTE-585 included patients who received pembrolizumab or placebo plus XP or FP, while the safety cohort received pembrolizumab or placebo plus docetaxel, oxaliplatin, FP, and leucovorin.

The primary objectives of the post hoc analysis were the relationship between mPR (≤10% residual viable tumor, comparable with Mandard tumor regression grade 1 or 2) and EFS, and the percentage of patients who had improved survival by stage, compared with downstaging in the pTNM group.

Overall downstaging was derived by comparing answers to questions regarding primary tumor and nodal involvement from clinical and pathologic assessments for each patient. Patients could have tumor downstaging, nodal downstaging, or both. If both, the number of levels downstaged for tumor and nodes were added together to calculate the total number of levels downstaged.

Of 1007 patients analyzed (pembrolizumab plus chemotherapy, n=502; placebo plus chemotherapy, n=505), 44.0% and 34.1%, respectively, had pathologic nodal stage N0. The incidence of mPR (grade 1/2 tumor regression) was 31.5% with pembrolizumab plus chemotherapy versus 22.2% with placebo plus chemotherapy.

In patients with mPR, the hazard ratios (95% CI) for EFS and OS were 0.6 (0.4-1.0) and 0.7 (0.4-1.2), respectively, for pembrolizumab plus chemotherapy versus placebo plus chemotherapy.

In the pembrolizumab plus chemotherapy group, primary tumor downstaging and nodal status downstaging occurred in 234 (46.5%) and 203 (40.4%) patients, respectively, while 291 (58%) experienced primary tumor or nodal status downstaging.

In patients who received placebo plus chemotherapy, primary tumor downstaging and nodal status downstaging occurred in 176 (34.9%) and 146 (28.9%) patients, respectively, while 241 (47.7%) experienced primary tumor or nodal status downstaging.

This post hoc analysis shows that patients with mPR experienced improved PFS and OS with pembrolizumab plus chemotherapy over placebo plus chemotherapy. Further studies in this patient population are encouraged.