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2 results on '"Fuchs, C.S"'

1. KEYNOTE-585 : Phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer

Author

Bang, Yung-Jue, Van Cutsem, E., Fuchs, C.S., Ohtsu, A., Tabernero, Josep, Ilson, D.H., Hyung, W.J., Strong, V.E., Goetze, T.O., Yoshikawa, T., Tang, L.H., Hwang, P.M.T., Webb, N., Adelberg, D., Shitara, K., and Universitat Autònoma de Barcelona

Subjects
Neoadjuvant therapy, Chemotherapy, Surgery, Immunotherapy, Gastric cancer, Gastroesophageal junction cancer, Adjuvant therapy, Pembrolizumab
Abstract

Medical writing and/or editorial assistance was provided by M Sweetlove, and SS Shaevitz, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Background: Surgical resection is the only curative treatment option for gastric cancer. Despite widespread adoption of multimodality perioperative treatment strategies, 5-year overall survival rates remain low. In patients with advanced gastric or gastroesophageal junction adenocarcinoma, pembrolizumab has demonstrated promising efficacy and manageable safety as monotherapy in previously treated patients and as first-line therapy in combination with cisplatin and 5-fluorouracil. Combining chemotherapy with pembrolizumab in the neoadjuvant/adjuvant setting may benefit patients with locally advanced, resectable disease. Aim: To describe the design and rationale for the global, multicenter, randomized, double-blind, Phase III KEYNOTE-585 study to evaluate the efficacy and safety of pembrolizumab plus chemotherapy compared with placebo plus chemotherapy as neoadjuvant/adjuvant treatment for localized gastric or gastroesophageal junction adenocarcinoma. ClinicalTrials.gov: NCT0322142.

Published
2019

2. Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma.

Author

Shitara, K., Özgüroğlu, M., Bang, Y.-J., Di Bartolomeo, M., Mandalà, M., Ryu, M.-H., Caglevic, C., Chung, H.C., Muro, K., Van Cutsem, E., Kobie, J., Cristescu, R., Aurora-Garg, D., Lu, J., Shih, C.-S., Adelberg, D., Cao, Z.A., and Fuchs, C.S.

Subjects
*PEMBROLIZUMAB, *ADENOCARCINOMA, *ESOPHAGOGASTRIC junction, *GENETIC mutation, *TUMOR treatment, *PACLITAXEL
Abstract

In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status. • Second-line pembrolizumab showed a strong association between tTMB and efficacy in gastric and gastroesophageal cancer. • There was low correlation between WES-tTMB and PD-L1 CPS. • WES-tTMB was associated significantly with pembrolizumab PFS and OS after excluding known MSI-H tumors. • Findings with FoundationOne®CDx-tTMB were similar to those with WES-tTMB. [ABSTRACT FROM AUTHOR]

Published
2021
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