Justin F. Gainor, MD, Director of the Center for Thoracic Cancers Program at Massachusetts General Hospital, Boston, was invited to discuss IMpower151 and ILLUMINATE at the 2023 World Conference on Lung Cancer.
IMpower151 vs IMpower150
Dr. Gainor examined why IMpower151 was negative for both patients with EGFR-mutated and wild-type disease, although IMpower1501 had been a positive study in which progression-free survival and overall survival were improved in patients receiving carboplatin or paclitaxel plus atezolizumab. As he pointed out, the studies were different in terms of chemotherapy backbone, geographic population, sample size, and proportion of patients with EGFR mutations, though these factors may not have been issues. IMpower150 employed paclitaxel as the backbone, whereas IMpower151 used mostly pemetrexed, but this was probably not impactful, noted Dr. Gainor, since numerous studies with different backbones have shown consistent benefits to adding anti–PD-1 agents. Potentially more important was the fact that IMpower150 was global with a large sample size, whereas IMpower151 was conducted in China and was half the size, he added.
Justin F. Gainor, MD
However, the most plausible explanation, according to Dr. Gainor, is the molecular composition, specifically the preponderance of patients with EGFR-mutated disease in IMpower151 vs IMpower150 (52% vs 11%). “I think this is the primary driver as to why IMpower151 was a negative study,” he maintained.
Rationale Behind ILLUMINATE
Regarding ILLUMINATE, Dr. Gainor first noted the rationale for combining a CTLA-4 inhibitor with an anti–PD-1/L1 antibody. “Translational studies have shown that EGFR-mutant lung cancers are generally less inflamed than wild-type tumors, even when they have high levels of PD-L1 expression. This is then translated into low response rates to PD-1 pathway monotherapy in EGFR-mutant lung cancer. Efforts to add chemotherapy to PD-1 inhibitors have shown fairly limited clinical benefit, with recent negative phase III studies. Other studies adding anti-VEGF [vascular endothelial growth factor] agents on top of anti–PD-1 plus chemotherapy have shown modest improvements in progression-free survival but not overall survival. The rationale for CTLA-4 inhibition is that it operates more proximal in the immune response and is involved in more priming of T cells—the hope being to drive more of them into the tumor microenvironment.”
This concept was behind the design of ILLUMINATE; however, response rates were just 20% to 30% in patients with EGFR-mutant lung cancer. “This is fairly comparable to what we would expect with platinum doublets alone,” Dr. Gainor noted. “By subgroups, there does not appear to be an obvious signal as to who is deriving benefit from the addition of anti–PD-1 and anti–CTLA-4 [drugs]. The main question is whether there really is a future for immunotherapy strategies in EGFR-mutant lung cancer, or are we just trying to pound a square peg into a round hole?” Additional research is needed, he said, to better define this phenotype and find effective ways to intensify therapy.
DISCLOSURE: Dr. Gainor has served as a consultant to or received honoraria from Bristol Myers Squibb, Genentech/Roche, Takeda, Loxo/Lilly, Blueprint Medicine, Gilead, Moderna, AstraZeneca, Mariana Therapeutics, Mirati, Jounce, Merus Pharmacueticals, Nuvalent, Pfizer, Novocure, AI Proteins, Novartis, Merck, iTeos, Karyopharm, and Silverback Therapeutics; has received research support from Novartis, Genentech/Roche, and Takeda; received institutional research support from Bristol Myers Squibb, AstraZeneca, Palleon, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; serves on the advisory board and has equity in AI Proteins; and has an immediate family member who is an employee with equity at Ironwood Pharmaceuticals.
REFERENCE
1. Socinski MA, Jotte RM, Cappuzzo F, et al: Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378:2288-2301, 2018.
