Mixed Reviews for A2AR Inhibitor in NSCLC

Researchers have hypothesized that drugs that block the immunosuppressive adenosine 2A receptor (A2AR) might increase the potency of checkpoint inhibitors. One of the first trials to test this strategy in non–small cell lung cancer (NSCLC) suggests that the combination of an A2AR inhibitor and an investigational PD-1 inhibitor is safe and induces responses in some patients with advanced disease. Researchers reported the findings this month at the 30th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland.

Monotherapy with an immune checkpoint inhibitor typically produces a response in about 20% of patients with NSCLC. Targeting A2ARs might improve these results because tumor cells often release large amounts of adenosine, which can inhibit T cells, natural killer cells, and other immune cells that carry the receptor. This inhibition may contribute to resistance to checkpoint inhibitors, preclinical research suggests. Clinical trials are now testing several combinations of A2ARs and immune checkpoint inhibitors in a variety of cancers.

At the conference, Alberto Chiappori, MD, of the Moffitt Cancer Center in Tampa, FL, presented results from a phase I/II trial of the investigational A2AR blocker NIR178 (Novartis) combined with the PD-1 inhibitor spartalizumab (Novartis). He and his colleagues enrolled 25 patients with advanced NSCLC, 11 of whom had previously received anti–PD-1 or anti–PD-L1 therapy.

Some patients appeared to benefit from the drug combination. One person had a complete response and one had a partial response. Neither had previously received anti–PD-1 or anti–PD-L1 therapy. Five treatment-naïve patients had stable disease, as did eight previously treated patients.

The most common side effect from the drugs was nausea, reported by 25% of patients. Grade 3 adverse events included increased blood levels of aspartate aminotransferase, which can indicate liver damage, and pneumonitis, a common side effect of checkpoint inhibitors in patients with NSCLC. These side effects occurred in 12% and 8% of patients, respectively. No patients developed grade 4 side effects.

The researchers plan to enroll more patients in the trial, and a second phase II trial testing the combination in several types of cancer, including NSCLC, has begun.

The safety data are reassuring, but the effectiveness data don't support launching a phase III study, says Justin Gainor, MD, of Massachusetts General Hospital in Boston, who wasn't connected to the trial. “I'd want to see more convincing evidence that the addition of the adenosine antagonist improves the efficacy of PD-1 inhibition,” he says.

Edward Garon, MD, of David Geffen School of Medicine at the University of California, Los Angeles, agrees that “so far, there's nothing to disprove the null hypothesis that the combination is no better than PD-1 or PD-L1 inhibition alone.” He also agrees that a phase III trial is premature, but says that the larger phase II trial that has already started could provide stronger evidence of the combination's effectiveness. –Mitch Leslie