Is Tumor Mutational Burden a Useful Predictor of NSCLC Therapy Efficacy?

Tumor mutational burden (TMB) was not significantly associated with the efficacy of pembrolizumab plus chemotherapy or placebo plus chemotherapy when used as a first-line treatment for metastatic nonsquamous non–small-cell lung cancer (NSCLC). The findings were presented at the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer (WCLC) held in Barcelona.

“Our data suggest that tissue TMB may not help select patients who would have better outcomes with the combination of pembrolizumab plus pemetrexed and a platinum given as first-line therapy for metastatic nonsquamous NSCLC,” said first author Marina C. Garassino, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan. “Pembrolizumab plus chemotherapy had a similar overall survival benefit in the TMB-high and TMB-low subgroups.”

A total of 616 patients were randomized 2:1 to either pembrolizumab plus chemotherapy or placebo plus chemotherapy. The researchers used whole-exome sequencing of tumor and matched normal DNA to assess TMB. Prespecified TMB cutoffs were used to determine the clinical utility of TMB.

Only 293 of 616 patients (48.3%) could be evaluated with TMB data (207 in the pembrolizumab plus chemotherapy group vs 86 in the placebo with chemotherapy group). When compared with the total population, baseline characteristics and outcomes were generally similar in the TMB population.

The researchers concluded that, when tested as a continuous variable, TMB was not related to overall survival, progression-free survival, or objective response rate for either chemotherapy group. However, the trial did find that pembrolizumab plus chemotherapy lengthened progression-free survival, overall survival, and objective response rate.

Corey J. Langer, MD, director of thoracic oncology at the University of Pennsylvania Abramson Cancer Center, presented similar research on TMB and pembrolizumab at IASLC 2019. He provided insight on the results of this study as well as his own findings.

“I think it’s still an investigational marker,” said Langer. “From my own perspective as a clinical researcher, the approach to TMB can be divided into two groups: the TMB cultists and the TMB skeptics. I would group myself in the latter. Although I still think it has a potential role, we haven’t figured it out. It would not be used, at least not yet, in therapeutic decision making,” he said.

Langer is curious whether TMB may have other uses, although no supportive data yet exists. For example, he said he is interested to see whether patients with high TMB and programmed death ligand 1 levels do well on an immunotherapy and chemotherapy combination or on multiple immunotherapy agents. Langer also wonders whether blood samples may better reflect TMB levels compared with a single tissue sample.

Garrassino agreed with Langer’s assessment that TMB as a predictive biomarker is not yet proven. Nevertheless, she sees its potential and advocates for personalized and precision treatment. “Analysis of larger datasets is needed to assess whether the benefit of pembrolizumab plus chemotherapy relative to chemotherapy alone differs in patients with TMB-high and TMB-low tumors,” she concluded.