A higher tumor mutational burden (TMB) predicted a higher likelihood of lung cancer response to an immunotherapy combination, irrespective of PD-L1 expression status, final results of a phase II clinical trial showed.
The combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) led to an overall response rate of 41% in patients with tumor PD-L1 expression ≥1% and 15% in patients with PD-L1 expression <1%. In contrast, patients with a TMB ≥10 mut/megabase (TMB-high), and with PD-L1 positive or negative tumors, had an overall response rate of 47%-48%.
TMB <10 (TMB-low) was associated with a lower response rate and progression-free survival (PFS), reported Neal Ready, MD, PhD, of Duke University Medical Center in Durham, North Carolina, and colleagues in the Journal of Clinical Oncology.
“This study showed two important things,” Ready told MedPage Today. “One is the activity of nivolumab and ipilimumab in untreated non-small cell lung cancer (NSCLC). But probably more important, is the potential for use of total mutational burden as a biomarker.”
PD-L1 has emerged as the standard immune biomarker for immunotherapy targeting the PD-1 receptor or its ligand, he noted. Patients whose tumors test positive for PD-L1 have a higher likelihood of responding to the therapies, but some patients with PD-L1 negative tumors also respond to immunotherapeutic agents.
“We need other biomarkers to help identify patients who can benefit from immune therapy,” said Ready. “There is a lot of accumulating data to indicate there is an association between cancers that have a higher TMB and the likelihood of benefiting from immune therapy.”
The findings came from the CheckMate 568 trial, a phase II, open-label study evaluating the safety and efficacy of nivolumab and low-dose ipilimumab (1 mg/kg every 6 weeks) as first-line therapy for advanced/metastatic NSCLC. The trial had a primary endpoint of objective response rate (ORR) in patients with tumor PD-L1 expression ≥1% or <1%. Secondarily, investigators examined the efficacy of the combination on the basis of TMB, using the commercially available FoundationOne CDx assay.
The trial involved 288 patients with untreated, recurrent stage IIIB/IV NSCLC. The authors reported that 252 (88%) patients could be evaluated for PD-L1 expression and 98 patients for TMB.
The combination led to an ORR of 30% overall — 41% of the PD-L1 positive subgroup and 15% of the patients with PD-L1 negative tumors. The subgroup with both PD-L1 and TMB data consisted of 48 patients with TMB ≥10 and 50 with TMB <10. TMB ≥10 was associated with a 48% ORR in patients with PD-L1 ≥1% and an ORR of 47% in patients with PD-L1 <1%. Patients with TMB <10 had an ORR of 18% if they were PD-L1 positive versus 5% if they were TMB-low and PD-L1 negative.
Median PFS was almost three times higher in patients with TMB-high tumors (7.1 vs 2.6 months).
CheckMate 568 was one of two recent studies showing better outcomes in TMB-high advanced NSCLC treated with nivolumab and ipilimumab. In the randomized CheckMate 227 trial, the immunotherapy combination led to a 12-month PFS of 42.6% in patients with TMB-high tumors versus 13.2% with chemotherapy. The trial also showed higher response rates among patients with TMB-high tumors, irrespective of the tumors’ PD-L1 status.
Ready said therapeutic development and clinical research have increasingly focused on chemotherapy-free strategies for patients with advanced NSCLC, many of whom are older or frail and have difficulty tolerating conventional cytotoxic agents. In keeping with that trend, CheckMate 568 and 227 employed a lower dose of ipilimumab than had been used in earlier melanoma trials nivolumab-ipilimumab combination therapy, which caused substantial toxicity.
Additionally, the dosing interval for ipilimumab was extended to every 6 weeks, as compared with every 2 weeks for nivolumab. Those modifications led to much less toxicity and made the combination both feasible and tolerable for the NSCLC population, he added.
The CheckMate 568 trial was supported by Bristol-Myers Squibb (BMS).
Ready disclosed relevant relationships with BMS, Novartis, Merck, AbbVie, Celgene, Merck Serono, and AstraZeneca. Co-authors disclosed multiple relevant relationships with industry.