RELATIVITY-1093 Trial Aims to Advance Nivolumab Plus Relatlimab and Chemo in Nonsquamous NSCLC

Adding the LAG-3–blocking antibody relatlimab to nivolumab (Opdualag) and chemotherapy may help address primary immunotherapy resistance up front in patients with PD-L1–expressing, nonsquamous non–small cell lung cancer (NSCLC), according to Estelamari Rodriguez, MD, MPH.¹

The phase 3 RELATIVITY-1093 trial (NCT06561386) is evaluating a fixed-dose combination of nivolumab and relatlimab plus platinum-pemetrexed chemotherapy vs pembrolizumab (Keytruda) plus the same chemotherapy as first-line treatment for patients with stage IV or recurrent nonsquamous NSCLC with PD-L1 expression of at least 1%, building on findings from the phase 2 RELATIVITY-104 trial (NCT04623775).^1,2

"We know that PD-1 is not the only way that T cells become exhausted and [that] you lose your response of the immune system," Rodriguez said in an interview with OncLive®. "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."

In the interview, Rodriguez discussed the rationale for LAG-3/PD-1 dual blockade in NSCLC, detailed the RELATIVITY-104 data that led to the phase 3 trial, and outlined what RELATIVITY-1093 may mean for the first-line treatment paradigm.

Rodriguez is co-lead of the Thoracic Site Disease Group and associate director of community outreach for thoracic oncology at Sylvester Comprehensive Cancer Center, University of Miami Health System, in Florida.

What is the rationale for LAG-3/PD-1 dual blockade in NSCLC?

Chemoimmunotherapy has become the first-line standard for patients with metastatic nonsquamous NSCLC without actionable alterations. In the phase 3 KEYNOTE-189 trial, pembrolizumab plus pemetrexed and platinum chemotherapy produced a median overall survival (OS) of 22.0 months vs 10.6 months with placebo plus chemotherapy (HR, 0.60; 95% CI, 0.50-0.72), with 5-year OS rates of 19.4% vs 11.3%, respectively.³

"Immunotherapy has really changed the landscape of treatment for [NSCLC]," Rodriguez said. "The next line of trials is really looking at ways to overcome primary immunotherapy resistance, because as much as these therapies can work for some patients, they don't work for every patient."

PD-1 and LAG-3 are immune checkpoints upregulated in NSCLC that inhibit effector T-cell function and promote T-cell dysfunction.² In advanced melanoma, nivolumab plus relatlimab significantly improved progression-free survival (PFS) vs nivolumab alone, leading to regulatory approval of the combination.²

"[In] a tumor that is very sensitive to immunotherapy, you can augment that response by adding a LAG-3 inhibitor," Rodriguez noted.

She also explained that the field has learned hard lessons from earlier dual checkpoint strategies. Initial combinations of CTLA-4 and PD-1 inhibitors produced high rates of colitis, she said, and the benefit was undermined by toxicity, leaving clinicians to use that approach selectively. The goal with LAG-3/PD-1 blockade is a combination that is both well tolerated and improves survival.

What did the phase 2 RELATIVITY-104 trial show?

RELATIVITY-104 enrolled adult patients with previously untreated stage IV or recurrent NSCLC, an ECOG performance status of 1 or lower, and no targetable mutations were eligible.² In part 2 of the study, 309 patients were randomly assigned 1:1 to nivolumab 360 mg plus relatlimab 360 mg plus platinum-doublet chemotherapy or nivolumab 360 mg plus chemotherapy every 3 weeks, stratified by PD-L1 expression, histology, and ECOG performance status. The primary end point was objective response rate (ORR) per blinded independent central review (BICR).²

At a median follow-up of 10.7 months, the ORR was 51.3% with the relatlimab regimen vs 43.7% with nivolumab plus chemotherapy; the median duration of response was 10.1 months (90% CI, 7.4-not reached) vs 9.1 months (90% CI, 6.7-13.4), respectively, and the PFS HR was 0.88 (90% CI, 0.71-1.11).²

The benefit concentrated in prespecified subgroups. In patients with PD-L1 expression of at least 1% and nonsquamous histology (n = 98), the ORR was 58.0% (90% CI, 45.4%-69.9%) with relatlimab vs 39.6% (90% CI, 27.7%-52.5%) without it, and the median PFS was 11.6 months (90% CI, 6.9-not reached) vs 6.9 months (90% CI, 4.2-7.1; HR, 0.55; 90% CI, 0.36-0.85).² Among patients with nonsquamous disease and PD-L1 expression of 1% to 49%, the ORR was 60.7% vs 30.0% and the PFS HR was 0.45 (90% CI, 0.25-0.81), according to data presented at the 2024 ESMO Congress.⁴ An exploratory analysis showed a potential OS improvement with the relatlimab regimen in the PD-L1 ≥1% nonsquamous subgroup (HR, 0.60; 90% CI, 0.38-0.94).⁵

Grade 3/4 treatment-related adverse effects (TRAEs) occurred in 54% of patients in the relatlimab arm vs 55% in the control arm, and TRAEs leading to death occurred in 3.8% vs 3.4%, respectively.²

"[RELATIVITY-104] showed an encouraging but not definite activity of this combination of PD-1 and LAG-3," Rodriguez said. "What was really important [was] that it was well tolerated. When they looked at this data set, they found that…it was actually patients that had some PD-L1 expression and had nonsquamous NSCLC where they saw the biggest response. So it really generated an important hypothesis."

How is the phase 3 RELATIVITY-1093 trial designed?

RELATIVITY-1093 is a randomized, open-label, global phase 3 study that plans to enroll approximately 1000 patients.¹ Patients in arm A receive a fixed-dose combination of nivolumab and relatlimab plus pemetrexed and cisplatin or carboplatin; those in arm B receive pembrolizumab plus pemetrexed and cisplatin or carboplatin.

Eligible patients must have histologically confirmed stage IV or recurrent nonsquamous NSCLC with no prior systemic therapy for advanced or metastatic disease, PD-L1 tumor cell expression of at least 1% by the VENTANA PD-L1 (SP263) assay as assessed by a central laboratory, measurable disease per RECIST 1.1 criteria, an ECOG performance status of 1 or lower, and a life expectancy of at least 3 months. Patients with sensitizing EGFR, ALK, or ROS1 alterations—or unknown status for those genes—are excluded, as are those with known BRAF V600E mutations, RET alterations, or NTRK fusions; untreated central nervous system metastases; active autoimmune disease; a history of pneumonitis requiring steroids or of myocarditis; or prior checkpoint inhibitor therapy.

The primary end point is OS in patients with PD-L1 expression of 1% to 49%. Secondary end points include OS in all randomly assigned patients with PD-L1 expression of at least 1%, PFS per BICR, ORR, duration of response, safety, immune-mediated adverse effects, and time to definitive deterioration on the NSCLC–Symptom Assessment Questionnaire.

"The current standard for patients [who] don't have actionable mutations…is to use chemotherapy and immunotherapy, and the most commonly used immunotherapy in that combination has been pembrolizumab," Rodriguez said. “[The trial] needs to go against the standard of care…but it needs to go further and try to really find those patients that are more likely to respond."

She added that the PD-L1 1% to 49% population represents a key gap. "The high PD-L1 expressors, more than 50%, already have several single-agent immunotherapy options that can work really well," Rodriguez said. "The 1% to 49% [group] is a big range of patients….It's really a big area of need to push forward in this group of patients that can respond, but we lose responses faster because they don't have that high sensitivity to immunotherapy."

What could a positive result mean for first-line treatment of nonsquamous NSCLC?

Rodriguez emphasized that statistical significance alone will not be enough to shift practice. "To have a win, you don't only need a statistically significant hazard ratio, because that just means that it's marginally better than the standard," she said. "We really want to see a clinically meaningful improvement in overall survival…. That has to be supported by a good PFS improvement, a durable response, and more importantly, good quality-of-life data that shows that adding another potential agent is not going to add more toxicity, because obviously we want our patients to live longer but also live better."

If positive, the regimen would apply to a defined population: patients with nonsquamous histology, PD-L1 expression of 1% to 49%, no actionable alterations, and a performance status that allows combination therapy, Rodriguez said. She also highlighted the potential impact during maintenance. "Sometimes patients don't tolerate all of the chemo, and we're relying on one immunotherapy to kind of carry them over in the maintenance period," she explained. "Having another mechanism to stimulate the immune system in that maintenance period may make a big difference for patients living longer without chemotherapy."

She added that the safety profile of relatlimab should feel familiar. "It's not like we have to deal with new immune-related [adverse] effects," Rodriguez said. "We are dealing with the same endocrinopathies and potentially immune-related reactions that we have all learned to manage."

References

1. A study to compare the efficacy of nivolumab and relatlimab plus chemotherapy vs pembrolizumab plus chemotherapy for stage IV/recurrent non-squamous non-small cell lung cancer with PD-L1 expression ≥ 1%. ClinicalTrials.gov. Updated October 23, 2026. Accessed October 30, 2026. https://clinicaltrials.gov/study/NCT06561386
2. Girard N, Burotto M, Paz-Ares LG, et al. Nivolumab (NIVO) plus relatlimab with platinum-doublet chemotherapy (PDCT) vs NIVO + PDCT as first-line (1L) treatment (tx) for stage IV or recurrent NSCLC: results from the randomized phase II RELATIVITY-104 study. Ann Oncol. 2024;35(suppl 2):S1243-S1244. doi:10.1016/j.annonc.2024.08.2295
3. Garassino MC, Gadgeel SM, Speranza G, et al. KEYNOTE-189 5-year update: first-line pembrolizumab (pembro) + pemetrexed (pem) and platinum vs placebo (pbo) + pem and platinum for metastatic nonsquamous NSCLC. Ann Oncol. 2022;33(suppl 7):S992-S993. doi:10.1016/j.annonc.2022.07.1101
4. Girard N, Burotto M, Paz-Ares LG. Nivolumab (NIVO) plus relatlimab with platinum-doublet chemotherapy (PDCT) vs NIVO + PDCT as first-line (1L) treatment (tx) for stage IV or recurrent NSCLC: Results from the randomized phase II RELATIVITY-104 study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA53.
5. Girard N, Burotto M, Paz-Ares LG, et al. Nivolumab plus relatlimab with platinum-doublet chemotherapy versus nivolumab with platinum-doublet chemotherapy in stage IV or recurrent non-small cell lung cancer: clinical, translational, and patient-reported outcomes results from the phase II RELATIVITY-104 study. Ann Oncol. Published online October 22, 2026. doi:10.1016/j.annonc.2026.10.103