Tumor Mutational Burden to Guide Immunotherapy in Lung Cancer

The combination of nivolumab and low-dose ipilimumab was effective and tolerable in the first-line treatment of advanced or metastatic non–small-cell lung cancer (NSCLC), according to a phase II trial. The trial also showed that tumor mutational burden (TMB) may be effective as a biomarker, since patients with higher TMB had improved response and progression-free survival (PFS).

“Combination immunotherapy and the identification of clinically meaningful biomarkers beyond PD-L1 have the potential to allow more patients to experience durable clinical benefit while deferring chemotherapy to the second line,” wrote study authors led by Neal Ready, MD, PhD, of Duke University Medical Center in Durham, North Carolina. There is a growing body of evidence that TMB might be useful as a biomarker to guide treatment decisions surrounding immunotherapy, especially as combination approaches multiply.

The CheckMate 568 study was an open-label, single-arm, phase II trial; it included 288 patients (252 with tumor tissue available for testing) with previously untreated, recurrent stage IIIB/IV NSCLC. Patients received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. Results of the study were published in the Journal of Clinical Oncology.

The median age in the trial was 65.0 years, and 50.7% of the cohort was female. Most patients were either a current (19.4%) or former (71.2%) smoker, and most patients had stage IV disease (85.4%). The median duration of nivolumab plus ipilimumab treatment was 4.0 months, and the median number of doses received was 8.5 for nivolumab and 3.0 for ipilimumab.

The objective response rate (ORR) in all treated patients was 30%; 7 patients (2%) had a complete response. The median duration of response was not reached, and the median PFS was 4.2 months; the 6-month PFS rate was 43%.

In the 138 patients with PD-L1 expression of 1% or greater, the ORR was 41%; in those with lower expression, the ORR was 15%. Median PFS was also longer in PD-L1–positive patients, at 6.8 months vs 2.8 months.

TMB was also associated with response rates and PFS. In patients with TMB of 10 or more mutations/megabase (mut/Mb), the ORR was 44%, compared with 12% in those with fewer than 10 mut/Mb. No additional benefit was seen as TMB rose higher. “The association of efficacy and TMB did not depend on tumor PD-L1 expression,” the authors wrote. The median PFS was 7.1 months in those with TMB above the cutoff of 10 muts/Mb and 2.6 months in those below the cutoff.

Treatment-related adverse events (TRAEs) occurred in 80% of the cohort, and grade 3/4 TRAEs occurred in 29%. The authors wrote that most adverse events with a potential immunologic cause were grade 1 or 2; TRAEs led to study discontinuation in 16% of patients.

“This analysis supported TMB of 10 or more mut/Mb as a clinically meaningful cutoff for response and PFS with this regimen in this patient population,” the authors concluded.

Edward B. Garon, MD, of the University of California, Los Angeles, spoke recently at the American Society of Clinical Oncology (ASCO)-Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Symposium, held February 28–March 3 in San Francisco, about the use of TMB as a biomarker in lung cancer. He noted several potential problems with its use, even as evidence proliferates.

He noted that in some trials, nearly half the patients don’t have enough tissue available for TMB assessment. “Further, there are concerns about reproducibility across labs,” he said, adding that several different assays are used to assess TMB. “It’s not clear that we have yet optimized the cut point for TMB, which of course is made more difficult by the slightly different assays.”

Still, he described fairly consistent results from several trials that suggest TMB is promising. “TMB consistently predicts ORR, as well as PFS,” he said. “But I would say that despite many people being evaluated, so far we have not seen an overall survival [benefit] based on TMB … This is not coming to clinic any time soon.”