Factors Influencing Response to Pembrolizumab in Various Advanced Cancers
In an analysis from the phase Ib KEYNOTE-028 trial reported in the Journal of Clinical Oncology, Ott et al found that response to pembrolizumab across different cancers was more likely in patients with higher tumor mutational burden, T-cell–inflamed gene-expression profile, and programmed cell death ligand 1 (PD-L1) expression.
The study involved data from the KEYNOTE-028 trial, which included 475 patients with PD-L1–positive advanced disease across 20 cohorts of different cancers. Patients received pembrolizumab at 10 mg/kg every 2 weeks for 2 years or until disease progression or unacceptable toxicity.
Response and Association With Biomarkers
Among 471 patients with measurable disease on independent review, the objective response rate was 14%, with rates ranging from 0% in pancreatic carcinoma to 33% in small cell lung cancer. Median progression-free survival across all tumor types was 2.2 months, ranging from 1.7 months in pancreatic cancer to 6.8 months in thyroid cancer. Median overall survival was 11.3 months, ranging from 3.8 months in vulvar cancer to 21.1 months in carcinoid tumors (median survival was not reached in thyroid cancer).
Among all 313 tumors evaluated, T-cell–inflamed gene-expression profile scores were higher in patients who achieved an objective response and had longer progression-free survival. Meta-analysis across the 14 cohorts not included in the development of the T-cell–inflamed gene-expression profile score confirmed that the score was significantly associated with response rate (P = .012, n = 203) and progression-free survival (P = .017, n = 203).
Data on PD-L1 expression were available for 198 patients in 13 cohorts. Meta-analysis confirmed significant associations between higher PD-L1 combined positive score and objective response rate (P = .018) and progression-free survival (P = .005).
Tumor mutational burden data were available for 77 patients from 16 cohorts. Higher tumor mutational burden was associated with objective response rate (P = .018) and had a near-significant association with progression-free survival (P = .051).
The correlation between gene-expression profile score and PD-L1 combined positive score was moderate but significant (r = 0.40, P < .001, n = 151). Tumor mutational burden and gene-expression profile had a low but significant correlation (r = 0.29, P = .007, n = 72). A low correlation was also observed between PD-L1 combined positive score and tumor mutational burden (r = 0.23; P = .082, n = 39).
Study Implications
As stated by the investigators, “Notably, patients with both higher [tumor mutational burden] and higher [gene-expression profile] score or PD-L1 [combined positive score] were more likely to be deemed responders. These trends indicate that the highest likelihood of clinical efficacy with pembrolizumab may be expected in tumors with both high [tumor mutational burden] and high levels of inflammation as measured by [gene-expression profile] or PD-L1, and efficacy may not be expected in tumors with low [tumor mutational burden] and low T-cell inflammation.”
The investigators concluded: “A T-cell–inflamed [gene-expression profile], PD-L1 expression, and [tumor mutational burden] predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti–PD-1 therapies across a broad spectrum of cancers.”
Patrick A. Ott, MD, of the Center for Immuno-Oncology, Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc. The study authors’ full disclosures can be found at jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
