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WCLC 2019: Two Studies Show Tumor Mutational Burden Not Associated With Pembrolizumab Efficacy in NSCLC


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At the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer (WCLC), two presentations showed that tumor mutational burden is not associated with the efficacy of pembrolizumab in combination with chemotherapy in patients with non–small cell lung cancer (NSCLC). Tumor mutational burden is a measurement of mutations carried by tumor cells and is a predictive biomarker being studied to evaluate its association with response to immunotherapy.

KEYNOTE 189

A study evaluating the role of tumor mutational burden in the KEYNOTE 189 trial found it was not significantly associated with the efficacy of pembrolizumab plus chemotherapy or placebo plus chemotherapy as first-line therapy for patients with metastatic, nonsquamous NSCLC. These findings were presented by Marina Garassino, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori in Milan (Abstract OA04.06).

Tumor mutational burden together with programmed cell death ligand 1 (PD-L1) expression has been demonstrated to be a useful biomarker across some cancer types. To test this notion, Dr. Garassino and colleagues randomly assigned 616 patients 2:1 to receive pembrolizumab plus chemotherapy or placebo plus chemotherapy. Tumor mutational burden was determined by whole-exome sequencing of tumor and matched normal DNA. The clinical utility of tumor mutational burden on outcomes was assessed using prespecified tumor mutational burden cutpoints of 175 and 150 Mut/Mb.


“Tumor mutational burden was not significantly associated with efficacy of pembrolizumab plus chemotherapy or placebo plus chemotherapy as first-line therapy for metastatic nonsquamous NSCLC.”
— Marina Garassino, MD

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Of the 616 patients enrolled, 293 (48.3%) had evaluable tumor mutational burden data: 207 for pembrolizumab plus chemotherapy and 86 for placebo plus chemotherapy. Baseline characteristics and outcomes were generally similar in the tumor mutational burden–evaluable and total populations. Tumor mutational burden as a continuous variable was not significantly associated with overall survival, progression-free survival, or objective response rate for pembrolizumab plus chemotherapy or placebo plus chemotherapy. Pembrolizumab plus chemotherapy improved overall survival, progression-free survival, and objective response rate.

“Tumor mutational burden was not significantly associated with efficacy of pembrolizumab plus chemotherapy or placebo plus chemotherapy as first-line therapy for metastatic nonsquamous NSCLC,” said Dr. Garassino. “Pembrolizumab plus chemotherapy had a similar overall survival benefit in the tumor mutational burden–high and –low subgroups.”

KEYNOTE 021

Researchers had previously reported data from the KEYNOTE 021 trial that showed antitumor activity for pembrolizumab plus platinum-based chemotherapy in patients with untreated, advanced nonsquamous NSCLC. The same research group presented new data focusing on the role of tumor mutational burden in two new groups of patients from this trial at the 2019 WCLC (Abstract OA04.05).

The researchers, led by Corey Langer, MD, of the Abramson Cancer Center of the University of Pennsylvania, created two new groups: patients in cohort C received pembrolizumab plus carboplatin/pemetrexed; and patients in cohort G were randomly assigned 1:1 to receive pembrolizumab plus carboplatin/pemetrexed or carboplatin and pemetrexed alone. Tumor mutational burden was determined by whole-exome sequencing of tumor and matched normal DNA.


“In this exploratory analysis, tumor mutational burden was not significantly associated with efficacy of pembrolizumab plus carboplatin/pemetrexed or carboplatin and pemetrexed alone as first-line therapy for metastatic, nonsquamous NSCLC.”
— Corey Langer, MD

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Researchers were able to evaluate tumor mutational burden data for 70 patients: 12 of 24 (50.0%) in cohort C, 32 of 60 (53.3%) in the cohort G pembrolizumab-plus-chemotherapy arm, and 26 of 63 (41.3%) in the cohort G chemotherapy-only arm.

Tumor mutational burden as a continuous variable was not significantly associated with objective response rate, progression-free survival, or overall survival for pembrolizumab plus chemotherapy or chemotherapy alone. There was no significant correlation between tumor mutational burden and tissue polypeptide–specific antigen in patients treated with pembrolizumab plus chemotherapy.

“In this exploratory analysis, tumor mutational burden was not significantly associated with efficacy of pembrolizumab plus carboplatin/pemetrexed or carboplatin and pemetrexed alone as first-line therapy for metastatic, nonsquamous NSCLC,” Dr. Langer reported. “Tumor mutational burden was also not significantly correlated with PD-L1 expression. Among pembrolizumab plus chemotherapy-treated patients, objective response rate was high in both the tumor mutational burden–low and -high subgroups.”

Disclosure: For full disclosures of the study authors, visit wclc2019.iaslc.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®.
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