Dr Rodriguez on the Rationale for Testing LAG-3/PD-1 Dual Blockade in Nonsquamous NSCLC

“PD-1 is not the only way that T cells become exhausted and lose their [antitumor] response. There are other complementary mechanisms that lead to T-cell dysfunction and exhaustion, which means that if you really want to reinvigorate the immune system, you can look at other pathways that could bring more effective T cells to attack the cancer.”

Estelamari Rodriguez, MD, MPH, associate director of community outreach for thoracic oncology and assistant director of diversity, equity, and inclusion at the University of Miami Sylvester Comprehensive Cancer Center, discussed the rationale for combining LAG-3 inhibition and PD-1 blockade to overcome primary immunotherapy resistance in non–small cell lung cancer (NSCLC), including findings from the phase 2 RELATIVITY-104 trial (NCT04623775) evaluating frontline nivolumab and relatlimab-rmbw (Opdualag) plus chemotherapy.

Immunotherapy has transformed NSCLC outcomes, but not every patient responds, and the next wave of trials aims to overcome primary resistance to PD-1 blockade, according to Rodriguez. PD-1 is only one of several pathways driving T-cell exhaustion, she explained, and blocking complementary checkpoints such as LAG-3 can help reinvigorate a more effective antitumor response. This approach was first validated in melanoma, where immunotherapy was pioneered, and adding a LAG-3 inhibitor to PD-1 blockade improved outcomes, Rodriguez noted.

That rationale drove RELATIVITY-104, findings from which were presented at the 2024 ESMO Congress, which added relatlimab to frontline nivolumab plus platinum-doublet chemotherapy in stage IV or recurrent NSCLC. The combination showed encouraging, though not definitive, activity and was well tolerated, with grade 3/4 treatment-related adverse effects in 55% of patients in both arms, Rodriguez said. Benefit was concentrated in patients with PD-L1–expressing, nonsquamous tumors, where relatlimab nearly doubled the objective response rate (58% vs 40%) and extended median progression-free survival from about 7 months to nearly 12 months (HR, 0.55).

Those findings generated the hypothesis now being tested in the phase 3 RELATIVITY-1093 trial (NCT06561386), evaluating whether adding relatlimab as a costimulatory agent to frontline chemoimmunotherapy can improve outcomes vs pembrolizumab (Keytruda) plus chemotherapy in PD-L1–positive, nonsquamous NSCLC, Rodriguez said.