Plasma tumor mutational burden predicts outcomes with first-line pembrolizumab for metastatic NSCLC
BARCELONA — Blood-based tumor mutational burden measured using circulating tumor DNA appeared associated with outcomes after first-line treatment with pembrolizumab-based therapy for metastatic non-small cell lung cancer, according to study results presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer.
Specifically, researchers found that loss-of-function mutations in STK11, KEAP and PTEN, and ERBB2 exon 20 insertion mutations, were negative predictors of benefit.
Pembrolizumab (Keytruda, Merck), an anti-PD-1 therapy, is the standard first-line treatment for use as monotherapy among patients with a PD-L1 tumor proportion score of 50% or higher, or in combination with platinum-based chemotherapy.
“Availability of immunotherapy has changed our standard of care completely for the management of stage IV NSCLC. However, there is a subset of patients who do not benefit from pembrolizumab monotherapy,” Charu Aggarwal, MD, MPH, Leslye M. Heisler assistant professor for lung cancer excellence at University of Pennsylvania, and a HemOnc Today Editorial Board Member, told HemOnc Today. “Additionally, not everyone benefits from chemo-immunotherapy. PD-L1 is, at best, an imperfect biomarker to select patients for response to immunotherapy. Therefore, we think that it is important to study the association between an easy-to-assess biomarker, such as plasma tumor mutational burden, and outcomes following immunotherapy.”
Aggarwal and colleagues sought specifically to evaluate the association between blood-based tumor mutational burden, measured using circulating tumor DNA (ctDNA), with outcomes — including durable clinical benefit, PFS and OS — following first-line pembrolizumab alone or with chemotherapy.
The analysis included 66 patients (median age, 67 years; range, 47-89) with metastatic NSCLC, most of whom (92%) were current or prior smokers.
Thirty-one patients (47%), all of whom had a PD-L1 tumor proportion score of 50% or higher, received pembrolizumab monotherapy. The other 35 patients received platinum-pemetrexed-based chemotherapy in addition to pembrolizumab.
Researchers collected plasma from all patients at baseline prior to initiation of therapy.
At the time of the analysis, median OS was 14.8 months for patients who received pembrolizumab and not reached for patients who received pembrolizumab with chemotherapy.
Of 52 patients with available data — which included 26 patients from each treatment group — researchers calculated a median blood-based tumor mutational burden of 16.8 mutations/Mb (range, 1.9-52.5).
Researchers observed no association between tumor mutational burden and tumor PD-L1 status.
Previous study data supported using a cutoff of 16 or greater mutations/Mb to define high mutational burden. Based on this threshold, patients with high tumor mutational burden achieved longer median PFS (13.8 months vs. 4.7 months; HR = 0.27; 95% CI, 0.13-0.55) than patients with fewer than 16 mutations/Mb. Median OS was not reached for the high tumor mutations burden group and was 8.4 months for all other patients (HR = 0.47; 95% CI, 0.2-1.1).
Further, patients who achieved durable clinical benefit — defined as complete or partial response or stable disease that lasted more than 6 months — had a higher median tumor mutational burden, at 21.3 mutations/Mb, compared with 12.4 mutations/Mb among patients without durable clinical benefit (P = .004).
Researchers noted that loss-of-function mutations in STK11, KEAP and PTEN, and ERBB2 exon 20 insertion mutations appeared enriched in patients who did not achieve clinical benefit. A combined prediction method that accounted for these mutations along with tumor mutational burden improved prediction of PFS (HR = 0.18; 95% CI, 0.08-0.41) and OS (HR = 0.27; 95% CI, 0.1-0.73).
“We demonstrated that patients with high tumor mutational burden — defined as plasma tumor mutational burden higher than 16 mutations/Mb — had a greater benefit from pembrolizumab-based therapy, both in terms of response rate and PFS,” Aggarwal told HemOnc Today. “Our data are intriguing; however, they are limited by the small numbers. The role of plasma tumor mutational burden should be validated in larger prospective studies.”
Still, this is the largest prospective clinical study to correlate plasma tumor mutational burden with outcomes after first-line pembrolizumab-based therapy in metastatic NSCLC, Aggarwal said, adding that the findings suggest incorporation of individual genomic alterations may improve prediction of outcomes.
“Given the ease of obtaining plasma-based tumor mutational burden, our results argue for large-scale validation of plasma-based tumor mutational burden in the context of prospective pembrolizumab-based therapy in metastatic NSCLC. If substantiated, this assay should be integrated into routine clinical management of patients with metastatic NSCLC,” she said. – by Alexandra Todak
Aggarwal C, et al. Abstract MA25.04. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.
Disclosures: Aggarwal reports advisory board roles with AstraZeneca, Bristol-Myers Squibb, Celgene, Merck and Roche, and research funding to her institution from AstraZeneca, Incyte, Marogenics and Merck. Please see the abstract for all other authors’ relevant financial disclosures.