An exploratory analysis from the randomized KEYNOTE-061 trial showed a strong association between tissue tumor mutational burden (tTMB) and clinical efficacy with second-line pembrolizumab but not with paclitaxel in patients with gastric/gastroesophageal junction (GEJ) adenocarcinoma, according to study results published in Annals of Oncology.

Study results suggested that tTMB is a significant and independent predictor of improved clinical benefit in response to pembrolizumab monotherapy, the authors reported.

The primary analysis of the global phase 3 KEYNOTE-061 trial ( Identifier: NCT02370498), which was conducted at 148 medical centers in 30 countries, showed no significant improvement in overall survival (OS) with second-line pembrolizumab compared with paclitaxel in patients with gastric/GEJ cancer whose tumors express programmed death-ligand 1 (PD-L1) with a combined positive score (CPS) of 1 or higher.

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Researchers sought to investigate the relationship between tTMB and clinical outcomes, including the relationship with CPS and microsatellite instability-high (MSI-H) status in the KEYNOTE-061 population receiving second-line pembrolizumab or paclitaxel.

The randomized, open-label trial enrolled 592 patients who were randomly assigned to receive pembrolizumab or paclitaxel. Whole-exome sequencing (WES) data were available for 420 (71%) patients who were included in the exploratory analysis. Among these, 218 patients received pembrolizumab and 202 patients received paclitaxel. The median follow-up was 7.9 months (interquartile range, 3.4-14.6 months).

Univariate analysis showed a strong association between WES-tTMB and clinical outcomes inclusive of overall response rate (ORR), progression-free survival (PFS), and OS (all P <.0001) among patients treated with pembrolizumab. In contrast, no significant association was found between WES-tTMB and clinical outcomes among patients treated with paclitaxel (2-sided P >.6).

Among patients treated with pembrolizumab for whom WES-tTMB data were available, the area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 (95% CI, 0.56-0.81) compared with 0.51 (95% CI, 0.39-0.63) in patients treated with paclitaxel. Little or no correlation was found between WES-tTMB and CPS in both the treatment groups (r ≤.16).

Patients with MSI-H tumors generally had high WES-tTMB values. After adjusting for CPS and excluding known MSI-H tumors (26 patients), WES-tTMB remained significantly associated with all clinical endpoints for pembrolizumab, indicating that the strong association between WES-tTMB and clinical efficacy was not driven entirely by MSI-H status.

The findings of tTMB using WES were found to be similar to FoundationOne®CDx-tTMB, which demonstrated a positive relationship with ORR, PFS, and OS in patients treated with pembrolizumab (all P ≤.003) but not PFS or OS in patients treated with paclitaxel (P >.1).

Disclosure: This research was supported by Merck Sharp & Dohme Corp, a subsidiary of

Merck & Co., Inc. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Shitara K, Özgüroğlu M, Bang Y-J, et al. Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma. Ann Oncol.  Published online May 31, 2021. doi:10.1016/j.annonc.2021.05.803