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Tumor Mutational Burden Disappoints as Biomarker for Treatment Response in Exploratory Analyses of Nonsquamous NSCLC


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Tumor mutational burden failed to prove effective as a biomarker for response to chemotherapy plus checkpoint inhibitor or chemotherapy alone as first-line treatment for nonsquamous non–small cell lung cancer (NSCLC) in two different exploratory analyses of KEYNOTE trials.1,2 In both analyses, which were presented at the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer (WCLC) in Barcelona, tumor mutational burden was not associated with response rates, progression-free survival, or overall survival. KEYNOTE-189 was presented by Marina Garassino, MD, of Fondazione IRCC Istituto Nazionale dei Tumori in Milan, Italy, and KEYNOTE-021 was presented by lead author Corey J. Langer, MD, of Abramson Cancer Center of the University of Pennsylvania, Philadelphia.

Marina Garassino, MD

Marina Garassino, MD

Corey J. Langer, MD

Corey J. Langer, MD

The identification of biomarkers that consistently signal a response to immune checkpoint inhibitor therapy continues to be elusive. Programmed cell death ligand 1 (PD-L1) expression—currently used as a biomarker to select patients more likely to respond to immunotherapy—is associated with inconsistent results, and some patients with very low expression of PD-L1 nevertheless respond to immunotherapy. Studies have suggested that tumor mutational burden, either alone or in combination with PD-L1 expression levels, might separate responders from nonresponders to immunotherapy.

Little is known about the potential role of tumor mutational burden in patients treated with immunotherapy plus chemotherapy or chemotherapy alone. Both KEYNOTE studies looked at tumor mutational burden as a biomarker in this setting. Results of these analyses have dampened enthusiasm for the clinical utility of tumor mutational burden in selecting patients for immune checkpoint inhibitor plus chemotherapy vs chemotherapy alone as first-line treatment for nonsquamous NSCLC.

KEYNOTE-189

“The First interim analysis of KEYNOTE-189 showed that there is already a benefit of pembrolizumab plus pemetrexed and platinum vs placebo plus pemetrexed and platinum for overall survival, progression-free survival, and response rate irrespective of PD-L1 status. Some data suggest that tumor mutational burden may be a biomarker for immunotherapy or the combination of immunotherapy plus chemotherapy,” said Dr. Garassino. “Until now, we had no data for tumor mutational burden on patients taking chemotherapy and immunotherapy.”

She continued, “In an analysis of KEYNOTE-189, pembrolizu­mab plus chemotherapy performed similarly in tumor mutational burden–high and tumor mutational burden–low subgroups. Tissue tumor mutational burden may not help select patients for first-line immunotherapy plus chemotherapy,” she stated.

In the randomized, double-blind phase III KEYNOTE-189 study, 616 patients with metastatic nonsquamous NSCLC with no targetable EGFR or ALK genetic aberrations irrespective of PD-L1 expression were randomly assigned 2:1 to pembrolizumab plus chemotherapy vs placebo plus chemotherapy. Dr. Garassino reported the results of an exploratory analysis of clinical benefit associated with tumor mutational burden in 293 evaluable patients. Almost 50% of enrolled patients did not have sufficient tissue samples for the evaluation of tumor mutational burden, which was done by whole-­exome sequencing of tumor and matched normal DNA.

“Overall survival, progression-free survival, and response rates were similar in the tumor mutational burden–evaluable population and the overall study population,” she said.

Similar to other studies, no association was found between tumor mutational burden and PD-L1–expression level. Using a prespecified cutoff for tumor mutational burden–high of  175 mutations per exome (n = 134) and tumor mutational burden–low of < 175  mutations per exome (n = 159), no difference was observed in the reduction in risk of death for immunotherapy combined with chemotherapy.

“Combination pembrolizumab plus chemotherapy performed the same way in both tumor mutational burden–high and tumor mutational burden–low subgroups,” Dr. Garassino stated. 

KEYNOTE-021

Similar to the previous study, an exploratory analysis from KEYNOTE-021 found no significant association between tumor mutational burden and the efficacy of pembrolizumab plus chemotherapy or chemotherapy alone as first-line therapy for advanced nonsquamous NSCLC. “In this exploratory analysis, tumor mutational burden was not significantly associated with the efficacy of pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone as first-line therapy for metastatic nonsquamous NSCLC,” said Dr. Langer.

KEYNOTE-021 was an open-label, phase I/II multicohort study conducted at 26 medical centers in the United States and Taiwan. Cohort C assessed combination pemetrexed and carboplatin with pembrolizumab in 24 patients with metastatic nonsquamous NSCLC. Cohort G of the study enrolled 123 patients with untreated stage IIIB or IV nonsquamous NSCLC with no targetable EGFR or ALK genetic aberrations irrespective of PD-L1 expression and randomly assigned these patients 1:1 to chemotherapy alone or to chemotherapy combined with pembrolizumab.

Based on tumor response and progression-free survival in KEYNOTE-021, pembrolizumab was granted accelerated approval by the U.S. Food and Drug Administration in combination with pemetrexed/carboplatin as first-line treatment for metastatic NSCLC.

TUMOR MUTATIONAL BURDEN AND NSCLC

  • Two different exploratory analysis of studies of pembrolizumab plus chemotherapy or chemotherapy alone as first-line therapy for nonsquamous non–small cell lung cancer (NSCLC) found no association between tumor mutational burden and outcomes.
  • Immunotherapy plus chemotherapy produced better outcomes compared with chemotherapy alone, but tumor mutational burden failed to identify responders.
  • Patients with high tumor mutational burden and low tumor mutational burden had response rates, progression-free survival, and overall survival similar to the overall study populations.
  • At this time, tumor mutational burden should not be used for patient selection for first-line treatment with checkpoint inhibitor plus chemotherapy in patients with nonsquamous NSCLC.

Study Methods

For the exploratory analysis of the association of tumor mutational burden with response, tumor mutational burden was determined by whole-exome sequencing of tumor and matched normal DNA. The prespecified cutoff point was a tumor mutational burden of 175 mutations per exome.

Tumor mutational burden data were evaluable for 70 patients: 12 of 20 in cohort C, 32 of 60 in the cohort G arm receiving pembrolizumab plus chemotherapy, and 26 of 63 in the cohort G chemotherapy-alone arm. Approximately 50% of all enrolled patients were not evaluable for tumor mutational burden because they did not provide consent or they did not have sufficient tissue available for testing. In the tumor mutational burden–evaluable group, response rates were 66% for pembrolizumab plus chemotherapy vs 38% for chemotherapy alone. In the total population, response rates were 63% vs 31%, respectively.

First, the researchers analyzed tissue tumor mutational burden as a continuous variable and found no association with outcomes for pembrolizumab plus chemotherapy and chemotherapy alone. 

“We found no association for tumor mutational burden with overall response rate, progression-free survival, or overall survival for pembrolizumab plus chemotherapy or chemotherapy alone, and there was no association between tumor mutational burden and PD-L1 expression,” Dr. Langer said.

Using a prespecified cutoff for tumor mutational burden–high of ≥ 175 mutations per exome and for tumor mutational burden–low of < 175 mutations per exome, response rates to pembrolizumab plus chemotherapy were high in both subgroups. Response rates were 71% among patients with tumor mutational burden–high status and 61% among those with tumor mutational burden–low status.

“We need larger data sets such as KEYNOTE-189 to assess whether the clinical benefit of pembrolizumab plus chemotherapy relative to chemotherapy alone differs between tumor mutational burden–high and tumor mutational burden–low,” Dr. Langer stated.

‘Not Ready for Prime Time’

At a press conference held during the WCLC meeting, both Drs. Garassino and Langer agreed that tumor mutational burden is not ready for routine use in clinical practice.

“My own view is that there are two groups: tumor mutational burden cultists and tumor mutational burden skeptics. I’m in the latter group. We have to figure it out, but tumor mutational burden should not be used for clinical decision-making regarding pembrolizumab vs chemotherapy. Given the difficulty of obtaining tumor tissue, we may do better with liquid biopsies. Regardless, we have to distinguish between blood tumor mutational burden and tissue tumor mutational burden. Blood tumor mutational burden may yield better results,” Dr. Langer said.

“Tumor mutational burden is not ready for prime time. We must personalize treatment in clinical practice,” Dr. Garassino said. 

DISCLOSURE: Dr. Garassino reported financial relationships with AstraZeneca, Roche, Bristol-Myers Squibb, and Merck Sharp & Dohme. Dr. Langer has received research funding from Merck Sharp & Dohme and is on advisory boards for AbbVie, AstraZeneca, Celgene, Lilly, Merck, Pfizer, Roche/Genentech, and Takeda.

REFERENCES

1. Garassino M, et al: 2019 World Conference on Lung Cancer. Abstract OA04.06. Presented September 8, 2019.

2. Langer C, et al: 2019 World Conference on Lung Cancer. Abstract OA04.05. Presented September 8, 2019.

 


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