High volumes of mutations observed through liquid biopsies may be associated with an improvement in progression-free survival and clinical benefit after first-line standard-of-care pembrolizumab-based therapy in patients with metastatic non-small cell lung cancer, according to findings from a prospective biomarker trial conducted by investigators at the University of Pennsylvania Perelman School of Medicine and Abramson Cancer Center, which were published in Clinical Cancer Research.
Charu Aggarwal, MD, MPH
High volumes of mutations observed through liquid biopsies may be associated with an improvement in progression-free survival (PFS) and clinical benefit after first-line standard-of-care pembrolizumab (Keytruda)based therapy in patients with metastatic non–small cell lung cancer (mNSCLC), according to findings from a prospective biomarker trial conducted by investigators at the University of Pennsylvania (Penn) Perelman School of Medicine and Abramson Cancer Center, which were published inClinical Cancer Research.1
Overall, 66 patients were enrolled in the study. Pembrolizumab monotherapy was administered to 47.0% of patients (n = 31), and pembrolizumab plus platinum pemetrexed-based chemotherapy was administered to the remaining 53% of patients (n = 35). The median OS among patients in these 2 arms was 22.1 months and 21.9 months, respectively. Of the 66 patients, 52 were evaluable for plasma-based tumor mutational burden (pTMB; 78.8%). Fourteen patients could not be evaluated for pTMB due to low tumor shedding or unique molecule coverage.2
The median pTMB observed was 16.8 mut/Mb (range, 1.9-52.5), showing that having a pTMB of at least 16 mut/Mb can improve PFS and clinical benefit at 6 months. The median pTMB for the 45 patients who had a complete response (CR) or partial response (PR) at week 9 was 21.5 mut/Mb (range, 7.7-52.5) versus 13.9 mut/Mb (range, 1.9-31.6) among patients with stable disease (SD) or progressive disease (PD;P= .037). A logic regression model showed that pTMB was associated with an odds ratio of 1.09 (95% CI, 1.02-1.08; P= .18) per 1 unit increase in pTMB.
There were 21 evaluable patients who received pembrolizumab and of these patients, the median pTMB for responders was 19.3 (range, 9.6-45.9), and was 15.2 (range, 9.6- 45.9) for nonresponders. The difference between these 2 groups was not statistically significant (P= .336). Among the 24 evaluable patients who received pembrolizumab plus platinum pemetrexed-based chemotherapy, the median pTMB was 23.9 mut/Mb (range, 7.7-52.5) in responders compared with 12.8 mut/Mb (range, 1.9-31.0) in nonresponders, and the difference was P= .034. The odds ratio per 1 unit increase in pTMB in patients treated with monotherapy versus patients treated with the combination was 1.07 (P= .22) and 1.11 (P= .05), respectively.
At 6 months in the 52 evaluable patients, the median pTMB among patients who achieved a durable clinical benefit (DCB) was higher for patients with no durable benefit at 21.3 mut/Mb compared with 12.4 mut/Mb (P= .003). A significant difference in the median pTMB was observed in the 26 patients who were given pembrolizumab, with a median pTMB of 21.1 mut/Mb (range, 9.6-45.9) in those who achieved a DCB and 13.4 mut/Mb in those who did not.
“While some people see a benefit from these therapies, unfortunately not everyone does. There is an important clinical need to identify new, noninvasive biomarkers to help us guide each patient to the treatments that have the best chance of success for them, and our findings show we may now have a tool to help us do that,” said the study’s lead author Charu Aggarwal, MD, MPH, the Leslye M. Heisler assistant professor for Lung Cancer Excellence at Penn.
An exploratory analysis of circulating tumor DNA (ctDNA) included 6 patients with high pTMB who did not achieve DCB. Based on previous research showing that these patients have a lack of response and primary and acquired resistance to PD1 blockade that is associated with mutations inJAK1andJAK23-5, Aggarwal et al hypothesized that mutational profiling could improve pTMB association with response.2
They found that the 9 putative negative predictor mutations that were detected in this cohort were not significantly associated with PFS, but in a combination of the negative predictor mutations, there was a significant PFS benefit. Patients with pTMB ≥16 mut/Mb and no negative predictor mutations had a median PFS of 18 months versus 4.7 months among patients with a pTMB <16 mut/Mb or with any negative predictor mutations. This HR result was 0.24 (95% CI, 0.11-0.49;P<.001) compared with 0.30 (95 % CI, 0.16-0.60) for pTMB alone.
In patients with pTMB ≥16 mut/Mb and no negative predictor mutations, the OS was not reached compared with 8.4 months in patients with pTMB <16 mut/Mb or any negative predictor mutations. The HR result in this case was 0.31 (95% CI, 0.13-0.74;P= .009) versus 0.48 (95% CI, 0.22-1.03) with pTMB alone.
Aggarwal et al asserted from these data that havingSTK11/KEAP1/PTENandERBB2 mutations may help identify patients with high pTMB, who are unlikely to respond to treatment. The note, however, that larger prospective studies should be done to validate the results of this trial.
In the study subjects, plasma was obtained at baseline before treatment with pembrolizumab-based therapy. The assay used for sequencing was the 2.145 Mb GuardantOMNI panel. The test filtered out germline alteration and excluded driver and resistance mutation and putative clonal hematopoiesis mutations. To validate the blood-based panel, 11 de-identified retrospective plasma sampled were assessed from multiple tumors, including NSCLC, to determine reproducibility.
To assess the concordance of pTMB with WES-determined TMB from 513 MSCLC tissue samples from the Cancer Genome Atlas, an in silico analysis was conducted. An addition in silico analysis was done to compare TMB scores using a publicly available, retrospective cohort of patients with advanced NSCLC.
“We believe this is the largest study to show correlation between blood-based tumor mutational burden and clinical outcomes after first-line PD-1based treatment, including combination chemo-immunotherapy, for NSCLC,” said the study’s senior author Erica L. Carpenter, MBA, PhD, director of the Liquid Biopsy Laboratory and a research assistant professor of Medicine at Penn.