David Gandara, MD

“MYSTIC is the second phase III trial to compare a first-line immune checkpoint inhibitor with platinum that failed to meet the primary endpoint. However, both MYSTIC and CheckMate 026 identified patients who benefited from an immune checkpoint inhibitor based on tumor mutational burden,” explained formal discussant David Gandara, MD, of the UC Davis Health Comprehensive Cancer Center, Sacramento.

“Does identifying tumor mutational burden in these two well-conducted studies help us understand immune response, and does this move the field forward?” asked Dr. Gandara.

Threshold Is Key?

“There are a variety of tests to measure tumor mutational burden. All studies in non–small cell lung cancer show that tumor mutational burden and programmed cell death ligand 1 (PD-L1) expression identify nonoverlapping patient populations,” he continued. “Several studies have validated high tumor mutational burden as a biomarker in lung cancer, but these prior results were in tissue tumor mutational burden.” MYSTIC evaluated this same biomarker in blood.

Blood tumor mutational burden > 16 mut/Mb was found to identify patients who could benefit from an immune checkpoint inhibitor, “but the threshold is a continuous variable. The higher the threshold, the smaller the number of patients,” he explained.

Dr. Peters reported results using a higher threshold of blood tumor mutational burden, ≥ 20 mut/Mb. “The concern [with a higher threshold] is that if implemented, we would be restricting use of a treatment to a very select population,” Dr. Gandara stated.

Questions Remain

“We need to know more about tumor mutational burden as a predictive biomarker in MYSTIC and more about the methods of the assays and analysis used in this trial. We also want to know more about the association between PD-L1 and tumor mutational burden. We need harmonization efforts to compare assays. Currently, more than 2,000 trials of checkpoint inhibitors are ongoing, requiring about 380,000 patients, and we are seeing ‘accrual fatigue.’ In the long run, we will need to use biomarkers to select patients appropriately,” he stated.

As for looking at other biomarkers, Dr. Peters commented, “We need to validate the tumor mutational burden story first. Looking at neoantigens may be the next step down the road.”

“The INSIGNIA trial will begin soon, comparing checkpoint inhibitor monotherapy to the combination with chemotherapy; this study has a significant biomarker component with an embedded study of immune signatures, which will include the microenvironment. Hopefully, this study will provide important new information,” Dr. Gandara said. ■

DISCLOSURE: Dr. Gandara is a consultant/advisor for Celgene, AstraZeneca, Genentech, Lilly, Guardant Health, and Liquid Genomics; and has received institutional research funding from Genentech and AstraZeneca/MedImmune.