CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2btrial.
In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.
In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.
“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.
Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues hadin a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.