While programmed death ligand 1 (PD-L1)−directed immunotherapy grows more common, the biomarker itself comes with limitations. “PDL-1 has been contentious as a biomarker, as responses are still seen in PD-L1 negative patients,” said Greg Delgoffe, PhD, assistant professor in the department of immunology at the University of Pittsburgh, Pennsylvania.

Given this constraint, researchers are turning toward new biomarkers to help guide cancer treatment with immune checkpoint inhibitors.

At the end of February 2019, investigators reported findings of PD-L1 expression as well as an emerging biomarker known as tumor mutational burden (TMB) and their association with the efficacy of immunotherapy response in non-small cell lung cancer (NSCLC).

In addition to testing these biomarkers, the treatment approach they chose was novel for first-line therapy in advanced/metastatic NSCLC — dual therapy with nivolumab plus low-dose ipilimumab, which are thought to have complementary mechanisms of action.

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In this phase 2, open-label, single-cohort study — CheckMate 568 — 288 patients with confirmed stage IV or recurrent stage IIIB NSCLC, who had not yet been treated, received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks.  Enrollment occurred between February 2016 and November 2016.

Entry criteria included the availability of tumor tissue for central PD-L1 testing. In addition, patients could have received prior chemoradiation for locally advanced NSCLC or adjuvant or neoadjuvant chemotherapy for early-stage disease, but both of these treatments had to have been completed at least 6 months before the study.

Researchers used PD-L1 tumor expression, with a cutoff point of at least 1% and less than 1%, to measure the primary end point of objective response rate (ORR), which was defined as “the proportion of patients who achieved a best response of complete response (CR) or partial response between the dates of first treatment and documented disease progression or subsequent anticancer therapy, whichever occurred first,” the authors noted.1 They also measured the effectiveness of treatment by analyzing TMB using the FoundationOne CDx assay[.1

Of the 288 patients that were treated, 252 patients (88%) had tumor biopsies evaluable for PD-L1 expression (55% with tumor PD-L1 expression ≥1%; 45% with <1%).1 After testing for tumor PD-L1 expression, 42% of the 288 patients had enough tumor sample left to evaluate TMB — 98 of which had a successful result. Of these 98 patients, 51% had TMB of less than 10 mutations/megabase (mut/Mb), and 49% had a TMB of 10 mut/Mb or higher.1