Study discussant Michele Teng, PhD, of QIMR Berghofer Medical Research Institute, Brisbane, Australia, commented: “Cancer immunotherapy is a new pillar of cancer treatment. The aim is to improve the overall survival of patients with cancer, but there is room for improvement, and various combinations are being studied with these checkpoint inhibitors. The safety profile and clinical activity of anti–PD-1 and anti–PD-L1 make them the backbone of new approaches. One pathway of interest is combining anti–PD-1 or anti–PD-L1 with a TIGIT inhibitor, since TIGIT can be expressed on a variety of immune cell subsets.”

The phase I study assessed the safety and tolerability of tiragolumab alone and with atezolizumab. No dose-limiting toxicities were observed at all dose levels in both study phases over a 21-day window.

Michele Teng, PhD

Questions Remain

Dr. Teng questioned the choice of 600 mg every 3 weeks as the dose for phase II and III studies. “Of 24 patients in phase Ia, 12 crossed over to the combination in phase Ib at disease progression. But why allow crossover to define the efficacy of a new drug?” she asked.

Next, Dr. Teng raised some questions on PD-L1 expression. How was it assessed: centrally or locally? What was the threshold? What percentage were tumor cell/immunohistochemistry 0?

“The strongest signal for the combination was in the non–small cell lung cancer expansion cohort, and the combination seems to be more effective in smokers,” Dr. Teng continued. “Preliminary findings from the ongoing phase II CITYSCAPE trial suggest the combination is most effective as first-line therapy in patients with PD-L1–high disease,” she noted.

Dr. Teng explained that CD155 expression is associated with a poor prognosis in patients with cancer, yet the level of CD155 expression was not assessed in this trial. “Clinically, CD155 expression is associated with resistance to PD-L1 in metastatic melanoma, and CD155-low tumors have a better response to anti–PD-L1 checkpoint inhibitors,” she continued. “Another important question is the expression of DNAM-1 (CD226) in tumors.”

After Dr. Teng’s discussion, Dr. Bendell responded to the questions about dose level and crossover. “We saw such limited toxicity at 400 mg that we decided to expand the recommended dose to 600 mg. We allowed crossover because we presumed single-agent activity would be low,” she noted.

DISCLOSURE: Dr. Teng has received honoraria from Arcus Biosciences, ­Boehringer Ingelheim, Bristol Myers Squibb, and Merck Sharp & Dohme and has received research funding from Bristol Myers Squibb and Tizona Therapeutics.