Neoadjuvant/adjuvant pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo for gastric/gastroesophageal junction (G/GEJ) adenocarcinoma: Major pathologic response (mPR) in KEYNOTE-585.
Authors: Shitara Kohei , Bang Yung-Jue , Wyrwicz Lucjan S. , Rha Sun Young , Oshima Takashi , Di Bartolomeo Maria , Park Young-Kyu , Lonardi Sara , Yanez Weber Patricio Eduardo , Yen Chia-Jui , Metges Jean-Philippe , Garrido Marcelo , Moehler Markus H. , Pelles-Avraham Sharon , Yong Wei-Peng , Spallanzani Andrea , Jensen Erin , Krishnan Radha , Shih Chie-Schin , Al-Batran Salah-Eddin 
Published: June 2024

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Background: Pathologic tumor downstaging (pDS) is more accurate than clinical staging for prognosis; generally, patients (pts) with downstaged tumors have lower recurrence rates and improved overall survival (OS). mPR is an important surrogate end point in non–small cell lung cancer, but data are scarce in gastric cancer. In the randomized phase 3 KEYNOTE-585 trial (NCT03221426), neoadjuvant or adjuvant pembro + chemo (cisplatin + capecitabine [XP] or cisplatin + 5-fluorouracil [FP]) was not superior to pbo + chemo (XP or FP) for event-free survival (EFS) in the intention-to-treat (ITT) population of pts with locally advanced G/GEJ adenocarcinoma; pembro + chemo significantly improved pathologic complete response (pCR) vs pbo + chemo (difference, 10.9%; 95% CI, 7.5-14.8; P<0.00001). In this post hoc analysis we examined the utility of mPR and pDS as surrogate end points in KEYNOTE-585. Methods: Pts with untreated localized G/GEJ adenocarcinoma (including Siewert type 2 or 3 tumors) and ECOG PS 0 or 1 who planned to undergo surgery after preoperative chemo were eligible. The main cohort of KEYNOTE-585 received pembro or pbo + XP or FP; the safety cohort received pembro or pbo + docetaxel, oxaliplatin, FP, and leucovorin (FLOT). Objectives for the post hoc analysis were the relation between mPR (≤10% residual viable tumor, comparable to Mandard tumor regression grade 1 or 2) and EFS per RECIST v1.1 per investigator and OS, plus the percentage of pts 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 pt. Pts could have tumor downstaging, nodal downstaging, or both. If both, the number of levels downstaged for tumor and nodes were added together to calculate a total number of levels downstaged. The database cutoff was February 9, 2023. Results: A total of 1007 pts were analyzed (n=502, pembro + chemo; n=505, pbo + chemo); 44.0% and 34.1%, respectively, had pathologic nodal stage N0. The incidence of mPR (grade 1/2 tumor regression) was 31.5% with pembro + chemo vs 22.2% with pbo + chemo. In pts who had mPR, the HRs (95% CI) for EFS and OS were 0.6 (0.4-1.0) and 0.7 (0.4-1.2), respectively, for pembro + chemo vs pbo + chemo. Downstaging results are shown (Table). Conclusions: In this post hoc analysis, pts with mPR had numerically improved PFS and OS with pembro + chemo vs pbo + chemo; these findings were consistent with analysis of the ITT population. Further studies in this population are warranted. Clinical trial information: NCT03221426 . [Table: see text]