Conference Coverage

Tissue TMB disappoints as treatment response biomarker in NSCLC


 

REPORTING FROM WCLC 2019

– Tissue tumor mutational burden (TMB) was not significantly associated with treatment efficacy in patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) in the phase 3 KEYNOTE-189 study and the phase 2 KEYNOTE-021 study.

Marina C. Garassino, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Dr. Marina C. Garassino

In 293 patients with evaluable TMB data in KEYNOTE-189, including 207 who were treated with pembrolizumab plus chemotherapy and 86 who received placebo plus chemotherapy, TMB as a continuous variable showed no significant association with either overall survival (OS), progression-free survival (PFS), or objective response rate (ORR), Marina C. Garassino, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, reported at the World Conference on Lung Cancer.

Pembrolizumab plus chemotherapy improved OS both in patients with TMB of 175 mutations/exome and greater and in those with TMB of fewer than 175 mutations/exome (hazard ratio for OS, 0.64 for both), and similar results were seen for PFS and ORR, Dr. Garassino said at the conference, which is sponsored by the International Association for the Study of Lung Cancer. Similar results were also seen for those with tissue TMB of 150 mutations/exome or greater and those with fewer than 150 mutations/exome, she noted.

The double-blind KEYNOTE-189 study compared first-line pembrolizumab plus chemotherapy with placebo plus chemotherapy in 616 patients who were randomized 2:1 to the treatment arms, respectively, and showed that adding pembrolizumab to pemetrexed and platinum significantly improved OS (HR, 0.49), PFS (HR, 0.52), and ORR (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) Tissue Polypeptide-specific (TPS) antigen of less than 1%, 1-49%, and 50% or greater, she noted.

In the current analysis, performed to assess the effect of tissue TMB on response rates, a similar benefit was seen in both TMB-high and -low subgroups.

“Our data suggest that tissue TMB may not help select patients who would have better outcomes with pembrolizumab plus pemetrexed and a platinum given as first-line therapy for metastatic nonsquamous NSCLC,” she concluded.

Corey J. Langer, MD, professor of medicine and director of thoracic surgery at the Hospital of the University of Pennsylvania, Philadelphia.

Dr. Corey J. Langer

Similarly, an exploratory analysis of data from the open-label, phase 2 KEYNOTE-021 trial – the first trial to show the efficacy and safety of the anti–PD-1 immune checkpoint inhibitor pembrolizumab given with chemotherapy – showed no association between tissue TMB and OS, PFS, or ORR in 70 patients with metastatic nonsquamous NSCLC who were treated with either pembrolizumab plus carboplatin and pemetrexed or with carboplatin and pemetrexed alone, Corey Langer, MD, reported at the conference.

“As you’re well aware,TMB has been widely evaluated as a biomarker for immunotherapy in advanced [NSCLC] and may identify patients who are more likely to respond to immune checkpoint inhibitors,” said Dr. Langer, professor of medicine and director of thoracic surgery at the Hospital of the University of Pennsylvania, Philadelphia. “But we have very limited data on whether TMB is of any value as a biomarker for chemo, either alone or given with an immune checkpoint inhibitor.”

In this analysis, pembrolizumab plus chemotherapy was associated with a high response rate, regardless of tissue TMB status; in those with tissue TMB of 175 mutations/exome or greater and fewer than 175 mutations/exome, the response rates were 71% and 61%, respectively.

“So, tissue TMB assessed by whole-exome sequencing was not significantly associated with efficacy for pembro and combination pem-carbo, or for chemotherapy alone, for first-line treatment of patients with metastatic nonsquamous [NSCLC], nor was there any significant association with PD-L1 expression,” he said. “Obviously an analysis of much larger datasets is needed to assess whether the benefit of pembro plus chemo relative to chemo alone differs in patients with TMB-high or TMB-low tumors,” he said.

For now, tissue TMB should not be used – “at least not yet” – in therapeutic decision making, he said, adding that it is important to distinguish between blood TMB and tissue TMB because the latter “may be more reflective of the entire tumor.”

Dr. Langer noted that he still thinks TMB has a potential role.

“We just haven’t figured it out yet,” he said.

Both KEYNOTE-189 and KEYNOTE-021 were supported by Merck. Dr. Garassino and Dr. Langer reported relationships with several pharmaceutical companies.

SOURCES: Garassino MC et al. WCLC 2019, Abstract OA04.06; Langer C et al. WCLC 2019, Abstract OA04.05.


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