Researchers suggested that patients with non-small cell lung cancer (NSCLC) who have higher measures of tumor mutations that appear in a blood test generally have a better clinical response to PD-1-based immunotherapy than those with a lower measure of mutations.
According to a study published in Clinical Cancer Research, patients with non-small cell lung cancer (NSCLC) who have higher measures of tumor mutations that show up in a blood test generally have a improved clinical response to PD-1-based immunotherapy compared to those with a lower measure of mutations.1
Researchers found that in circumstances where the liquid biopsy of patients with NSCLC detects higher volumes of mutations, patients with metastatic disease are more likely to see a clinical benefit at 6 months, as well as to survive longer without seeing their disease progress.
Traditionally, doctors have used a tissue sample to look for PD-L1 in order to try an predict patient response. However, the researchers suggested that it is an imperfect biomarker and requires the availability of tissue; therefore, they decided to focus on biomarkers located in more easily obtained blood samples.
“While some people see a benefit from these therapies, unfortunately not everyone does,” lead study author Charu Aggarwal, MD, MPH, the Leslye M. Heisler Assistant Professor for Lung Cancer Excellence at Penn, said in a press release. “There is an important clinical need to identify new, non-invasive 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.”
Using a 500-gene next-generation sequencing panel to measure the plasma-based tumor mutational burden (pTMB), researchers assessed 52 evaluable patients with newly diagnosed metastatic NSCLC starting first-line pembrolizumab (Keytruda)-based therapy, either alone or combination with chemotherapy.2 Their responses were evaluated using RECIST 1.1 and associations were made for patient characteristics, 6-month durable clinical benefit, progression-free survival (PFS), and overall survival (OS).
Median pTMB was 16.8 mutations per megabase (mut/Mb; range 1.9-52.5) and was significantly higher for patients achieving durable clinical benefit compared to no durable benefit (21.3 mut/Mb vs 12.4 mut/Mb; P = 0.003). For patients who had pTMB ≥16 mut/Mb, the median PFS was 14.1 vs 4.7 months for patients who had pTMB < 16 mut/Mb (HR 0.30 [0.16-0.60]; P < 0.001). Moreover, the median OS for patients with pTMB ≥ 16 was not reached, compared to 8.8 months OS observed for patients with pTMB < 16 mut/Mb (HR 0.48 [0.22-1.03]; P = 0.061).
Mutations found in ERBB2 exon 20, STK11, KEAP1, or PTEN were more common in patients with no durable clinical benefit. Additionally, a combination of pTMB ≥ 16 and absence of negative predictor mutations was correlated with PFS (HR, 0.24; 0.11-0.49; P < 0.001) and OS (HR, 0.31; 0.13-0.74; P = 0.009).
“We believe this is the largest study to show correlation between blood-based tumor mutational burden and clinical outcomes after first-line PD-1-based treatment, including combination chemo-immunotherapy, for NSCLC,” senior study author Erica L. Carpenter, MBA, PhD, director of the Liquid Biopsy Laboratory and a research assistant professor of Medicine at Penn, said in a press release.
The researchers indicated that further research is necessary to validate the study findings, including pTMB cutoff, in a larger dataset.
“Nevertheless, our results do argue for larger-scale validation of plasma-based TMB 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,” the authors wrote.
1. Blood test can predict clinical response to immunotherapy in metastatic NSCLC [news release]. Philadelphia, Pennsylvania. Published February 26, 2020. eurekalert.org/pub_releases/2020-02/uops-btc022420.php. Accessed February 26, 2020.
2. Baseline plasma tumor mutation burden predicts response to pembrolizumab-based therapy in patients with metastatic non-small cell lung cancer. Clinical Cancer Research. doi:10.1158/1078-0432.CCR-19-3663.