The findings from RATIONALE-315 were discussed at the ESMO (European Society for Medical Oncology) Virtual Plenary by Luis Paz-Ares, MD, PhD, Head of the Medical Oncology Service at the Hospital Universitario 12 de Octubre, Madrid. He noted that inhibitors of PD-1 and its ligand PD-L1, as monotherapy or paired with chemotherapy, have become key components of systemic treatment in early-stage, resectable non–small cell lung cancer (NSCLC). There is evidence of benefit with pembrolizumab and atezolizumab in the adjuvant setting; for nivolumab (plus chemotherapy) in the neoadjuvant setting; and for pembrolizumab, nivolumab, durvalumab, and toripalimab-tpzi (plus chemotherapy) in the perioperative setting.

“However, there are a number of challenges that have not been fully satisfied yet,” Dr. Paz-Ares said, listing among them the need for more anti–PD-1/PD-L1 agents. “This is an issue with ­RATIONALE-315,” he said. Treatment with tislelizumab led to “quite an increase” in pathologic response rates, not only in patients with high PD-L1 expression but, to a lesser extent, in PD-L1–negative tumors. There was also a clear improvement in event-free survival, which was consistent across subgroups, and overall survival (immature) trending in the right direction.

Luis Paz-Ares, MD, PhD

Words of Caution

“The real issue is: how relevant are these data?” said Dr. Paz-Ares. Describing outcomes with other checkpoint inhibitors in other large trials, he noted the similarities in hazard ratios. “I will say the data are very consistent, and they reinforce the efficacy of PD-1/PD-L1 inhibitors, even in patients with negative PD-L1 expression.” Additionally, he would have liked to see how pathologic response affected event-free survival and overall survival. Because the outcomes appear to be similar to what has been reported with other agents, he concluded: “I don’t think we need to develop more PD-1/PD-L1 inhibitors in this context.” Instead, he would advise that further research focus on novel immunotherapy strategies with alternative mechanisms of action. He recognized, however, that the cost of these agents could decrease as more of them enter the marketplace.

Dr. Paz-Ares highlighted some peculiarities of RATIONALE-315: The study was restricted to Chinese patients, only 10% were female, only 20% had squamous histology, and none had stage IIIB disease. Considering the scarcity of non-Asian patients in this trial, and concerning potential approval by regulatory agencies, a phase II trial in a Western population, with pathologic complete response as an endpoint, could be informative. Dr. Paz-Ares further suggested comparing novel drugs with established PD-1/PD-L1 inhibitor regimens in this scenario, rather than with chemotherapy alone. 

DISCLOSURE: Dr. Paz-Ares reported financial relationships with Altum Sequencing & Stab Therapeutics, AstraZeneca, AstraZeneca Spain, Bristol Myers Squibb, Eli Lilly, MSD, Pfizer, Roche, Amgen, BeiGene, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Merck Serono, Mirati, Novartis, Pfizer, PharmaMar, and Roche/Genentech.