NGS Sequencing

Tumor Mutation Burden by Targeted Next Generation Sequencing Predicts Benefit to Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

Introduction of immune checkpoint inhibitors has revolutionized the treatment of non-small cell lung cancer (NSCLC), but only subset of patients responds to these agents and there remains a high unmet need for effective biomarkers that can accurately predict which patients may benefit from immunotherapy. Currently, high levels of microsatellite instability and expression of PD-L1 are the only approved biomarkers used to select patients who are more likely to respond to PD-1 or PD-L1 inhibitors. High tumor mutation burden (TMB), as assessed by whole exome sequencing (WES), has recently emerged as a potential predictive marker across multiple tumor types, including NSCLC. However, WES is not routinely used in clinical practice while next generation sequencing (NGS) tumor profiling is currently recommended for personalization of therapy in NSCLC.

In an exploratory analysis of 240 patients with advanced NSCLC treated with either PD-1 or PD-L1 inhibitors at Memorial Sloan Kettering Cancer Center, the targeted NGS assay, MSK-IMPACT, was used to evaluate association of TMB with response to immune checkpoint blockade. Patients who experienced a durable clinical benefit (DCB) on immune checkpoint inhibitor therapy, defined as partial response or stable disease lasting longer than 6 months, had a significantly higher TMB than patients without a DCB (P = .006). Furthermore, response to therapy, duration of response, and progression free survival (PFS) rates improved with increasing levels of TMB. Of interest, presence of mutations in EGFR and STK11 genes was associated with lack of benefit on checkpoint inhibitors.

Importantly, in a cohort of 49 patient tumor samples, both targeted NGS and WES were performed and good correlation among both methods was found (P<.001), confirming the accuracy of NGS as a measure of tumor mutation burden. In 84 patients for whom PD-L1 expression data were available, PD-L1 expression ≥1% correlated with improved outcomes on PD-1/PD-L1 inhibitor therapy. However, there was no correlation between PD-L1 expression and TMB. Highest rates of DCB were seen in patients with both high TMB and PD-L1 expression ≥1%.

The investigators concluded that high TMB is associated with improved chance of response to immune checkpoint inhibitor therapy in patients with NSCLC, and that targeted NGS assays such as MSK-IMPACT are an accurate method for estimating TMB. While PD-L1 levels and TMB did not correlate, the use of both may be helpful in better identifying patients for whom PD-1/PD-L1 inhibitor therapy is an appropriate choice. In an accompanying editorial, the authors agreed that TMB determined by NGS may play an important role in bringing precision medicine to the field of immuno-oncology, but cautioned that many challenges lay ahead. Availability of tumor specimens, tumor heterogeneity, varying testing platforms, relatively long turnaround time for NGS, and cost are all potential roadblocks to the incorporation of this testing strategy into clinical practice.


Clinical Opinion Poll

What frontline therapy would you recommend for a 49 y/o woman diagnosed with low tumor burden metastatic ALK+ NSCLC (lung and liver metastases, normal brain MRI, PS0)?