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Tumor mutational burden does not predict efficacy of pembrolizumab, chemotherapy for advanced NSCLC
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BARCELONA — Tumor mutational burden did not appear significantly correlated with the effectiveness of chemotherapy alone or with pembrolizumab as first-line treatment for metastatic nonsquamous non-small cell lung cancer, according to results from an exploratory analysis of KEYNOTE-021 presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer.
“Tumor mutational burden has been widely evaluated as a biomarker for immunotherapy in advanced NSCLC to identify patients who are more likely to respond to immune checkpoint inhibitors,” Corey J. Langer, MD, director of thoracic oncology at University of Pennsylvania’s Abramson Cancer Center and professor of medicine at the Hospital of the University of Pennsylvania, said during a press conference. “We have very limited data on whether tumor mutational burden has value as a biomarker for chemotherapy, whether given alone or with an immune checkpoint inhibitor.
“The phase 1/phase 2 KEYNOTE-021 study was the first study to show the efficacy and safety of the anti-PD-1 immune checkpoint inhibitor pembrolizumab given in combination with chemotherapy,” Langer added. “We performed an exploratory analysis of KEYNOTE-021 to determine if tumor mutational burden might have value as a biomarker for pemetrexed and carboplatin, given either alone or with pembrolizumab.”
Langer and colleagues evaluated 145 patients from cohorts C and G of KEYNOTE-021. All patients in cohort C received pembrolizumab (Keytruda, Merck) plus carboplatin and pemetrexed. Researchers had randomly assigned patients in cohort G 1:1 to pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone.
Seventy patients (median age, 65 years; interquartile range, 57-70; 61% women) — including 12 from cohort C and, from cohort G, 32 assigned pembrolizumab plus chemotherapy and 26 assigned chemotherapy alone — were evaluable for tumor mutational burden, which researchers assessed using whole-exon sequencing of tumor tissue and matched normal DNA.
Researchers conducted an initial analysis to determine whether tissue tumor mutational burden as a continuous variable was associated with outcomes of pembrolizumab plus chemotherapy or with chemotherapy alone. A second analysis evaluated whether the response to the three-drug combination differed in participants with tumor mutational burden-high vs. -low tumors.
The researchers found no association between tissue tumor mutational burden and efficacy in terms of overall response rate, PFS or OS for treatment with chemotherapy alone or with pembrolizumab.
Also, tissue tumor mutational burden did not appear to correlate with PD-L1 status (r = 12).
Researchers defined tissue tumor mutational burden-high tumors as those with 175 or more mutations/exome. Forty-eight percent of patients met this threshold.
ORR appeared comparable among patients with high- vs. low-mutational burden tumors (71% vs. 61%).
Langer said although tumor mutational burden may ultimately prove useful as a biomarker for response to chemotherapy, it is not yet ready for prime time.
“Tissue tumor mutational burden assessed by molecular sequencing was not significantly associated with the efficacy of pembrolizumab plus chemotherapy or chemotherapy alone as first-line therapy for patients with metastatic nonsquamous NSCLC, whether we look at ORR, PFS or OS, nor was there any association between tumor mutational burden and PD-L1,” Langer said. “The response rate was high in both the tumor mutational burden-low and -high subgroups.
“Obviously, analyses of much larger data sets are needed to assess whether the benefits of chemotherapy and pembrolizumab relative to chemotherapy alone differ in patients with tumor mutational burden-high and those with tumor mutational burden-low tumors,” he added. – by Jennifer Byrne
Reference:
Langer C, et al. Abstract OA04.05. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.
Disclosures: Langer reports research grants from ADVANTAgene, Celgene, Inovio Pharmaceuticals, Takeda and Stemcentrx. Please see the abstract for all other authors’ relevant financial disclosures.