Blood Test Predicts Clinical Response to Immunotherapy in Metastatic NSCLC

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. 

References:

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.