IASLC World Conference on Lung Cancer
IASLC World Conference on Lung Cancer
September 23, 2019
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Tumor mutational burden an ineffective biomarker for response to pembrolizumab plus chemotherapy

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BARCELONA — Tumor mutational burden showed limited utility as a biomarker for response to pembrolizumab plus chemotherapy or placebo plus chemotherapy as first-line treatment for metastatic, nonsquamous non-small cell lung cancer, according to results from an exploratory analysis of the phase 3 KEYNOTE-189 trial presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer.

The findings mirror those of an exploratory analysis of KEYNOTE-021, results of which also were presented at the conference.

“From the first interim analysis, KEYNOTE-189 has demonstrated benefits [of pembrolizumab plus chemotherapy] in terms of OS, PFS and response rate, and this benefit was irrespective of PD-L1 status,” Marina Chiara Garassino, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, said during a press conference. “There are data suggesting that tumor mutational burden (TMB) is a good biomarker to select patients for single-agent treatment or for the combination of anti-PD-1, anti-PD-L1 and anti-CTLA-4 [therapy], but no data were available until now for patients treated with the combination of chemotherapy and immunotherapy.

The randomized, double-blind phase 3 KEYNOTE-189 trial is evaluating pembrolizumab (Keytruda, Merck) plus pemetrexed and platinum-based chemotherapy vs. placebo plus the same chemotherapy regimen among patients with metastatic, nonsquamous NSCLC. Garassino and colleagues sought to determine whether TMB as a continuous variable was associated with outcomes in the trial.

“The objective of this analysis is to evaluate the clinical benefit of the tissue TMB, determined by whole-exome sequencing, in the population of KEYNOTE-189,” Garassino said.

The researchers randomly assigned 616 patients with untreated, stage IV nonsquamous NSCLC at a 2:1 ratio to undergo treatment with either pembrolizumab plus chemotherapy or placebo plus chemotherapy.

The researchers used whole-exome sequencing of tumor and matched normal DNA to determine TMB. Prespecified TMB cut points of 175 mutations/exome and 150 mutations/exome were used to evaluate the clinical value of TMB as a biomarker. TMB of 175 mutations/exome or higher was categorized as tissue TMB-high, whereas fewer than 175 mutations/exome was considered tissue TMB-low.

Among all patients, 293 (48.3%) were evaluable for tissue TMB, including 207 in the pembrolizumab group and 86 in the placebo group. Patients in the overall and tissue TMB-evaluable populations had similar baseline characteristics and outcomes.

The researchers observed no significant association between TMB as a continuous variable and OS, PFS or objective response rate for pembrolizumab plus chemotherapy or placebo plus chemotherapy. They also found no association between tissue TMB and PD-L1 expression.

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Pembrolizumab plus chemotherapy improved OS compared with placebo and chemotherapy among tissue TMB-high patients (n = 134; 23.5 months vs. 13.5 months; HR = 0.64; 95% CI, 0.38-1.07) and tissue TMB-low patients (n = 159; 20.2 months vs. 9.9 months; HR = 0.64; 95% CI, 0.42-0.97).

“Tissue TMB, as assessed by whole-exome sequencing, is not significantly associated with the efficacy of pembrolizumab plus pemetrexed plus carboplatin and is not significantly correlated with PD-L1 expression,” Garassino said. “Pembrolizumab and chemotherapy had similar OS, PFS and response rate benefits in both tissue TMB-high patients and -low patients. Our data suggests that tissue TMB may not help in selecting patients who would have better outcomes with the combination of pembrolizumab and chemotherapy given as first-line therapy for metastatic, nonsquamous cell carcinoma.” – by Jennifer Byrne

Reference:

Garassino MC, et al. Abstract OA04.06. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.

Disclosures: Garassino reports contract/research support grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Clovis, Eli Lilly, GlaxoSmithKline, Incyte, Merck Serono, Merck Sharp & Dohme, Novartis, Otsuka, Pfizer, Roche-Genentech, Takeda and Tiziana Life Sciences. Please see the abstract for all other authors’ relevant financial disclosures.