Relatlimab Plus Nivolumab and Chemo Improves Clinical Benefit in Stage IV NSCLC

Nicolas Girard, MD, PhD

Adding relatlimab to nivolumab (a combination known as Opdualag) plus platinum-doublet chemotherapy demonstrated improved clinical benefit compared with nivolumab (Opdivo) plus chemotherapy in patients with stage IV or recurrent non–small cell lung cancer (NSCLC), according to findings from the phase 2 RELATIVITY-104 study (NCT04623775) presented at the 2024 ESMO Congress.

These findings were shown in patients with PD-L1 of at least 1%, and further enriched in patients with nonsquamous histology.

“RELATIVITY-104 is the first proof-of-concept, randomized phase 2 study in metastatic NSCLC that demonstrated improved clinical benefit from the addition of LAG3 inhibition to anti–PD-1 [inhibition] plus chemotherapy in the PD-L1–positive stratified and prespecified patient subgroup, which was further enriched with nonsquamous cell histology,” Nicolas Girard, MD, PhD, head of the Curie-Montsouris Thorax Institute and professor of respiratory medicine at Versailles Saint Quentin University Paris Saclay Campus in Paris, France, said during the presentation.

After a median follow-up of 10.7 months, 24% of patients in the relatlimab plus nivolumab and chemotherapy group (n = 38) and 30% of those in the nivolumab plus platinum-doublet chemotherapy group (n = 44) were still receiving study treatment. Safety was comparable between both arms, with grade 3 or 4 treatment-related adverse effects (TRAEs) occurring in 54% (n = 86) of patients in the relatlimab-based therapy arm vs 55% (n = 82) in the nivolumab plus chemotherapy arm. Any-grade TRAEs leading to discontinuation occurred in 13% (n = 21) in the relatlimab group compared with 14% (n = 21) in the nivolumab plus chemotherapy group. Grade 3 or higher treatment-related neutropenic AEs were observed in 6% of patients in the relatlimab arm vs 14% in the nivolumab plus chemotherapy group.

“The safety profile of nivolumab plus relatlimab 360 mg plus platinum-doublet chemotherapy was consistent with the known profile of the individual components of the combination and showed no increase in adverse effects rates vs nivolumab plus chemotherapy,” Girard said.

Six patients in the relatlimab group died from TRAEs including neutropenic sepsis (n = 2), febrile neutropenia (n = 1), pneumonitis (n = 2), and pneumonia (n = 1). Five patients died in the nivolumab plus chemotherapy group due to febrile neutropenia, sepsis, septic shock, asthenia, and lung disorder, occurring in 1 patient each.

The most common TRAEs, occurring in at least 20% of patients treated with the relatlimab-based treatment included nausea, anemia, neutropenia, fatigue, and thrombocytopenia.

Efficacy Findings

Efficacy was assessed in all patients in the trial randomized to either relatlimab plus nivolumab and chemotherapy (n = 158) or nivolumab plus chemotherapy (n = 151). The HR for progression-free survival (PFS) was 0.88 (90% CI, 0.71-1.11), slightly favoring treatment with relatlimab plus nivolumab plus chemotherapy compared with nivolumab plus chemotherapy. The median PFS for each group was 6.7 months (90% CI, 5.6-8.4) and 6.0 months (90% CI, 5.5-6.9), respectively.

There was also a moderate improvement in overall response rate (ORR) with relatlimab plus nivolumab and chemotherapy compared with nivolumab plus chemotherapy (51.3% vs 43.7%, respectively; difference = 7.6%). The median duration of response was 10.1 months in the relatlimab plus nivolumab and chemotherapy group vs 9.1 months in the nivolumab plus chemotherapy group.

Girard noted that data on overall survival were not yet mature at this follow-up.

In stratified patient subgroups, patients with a PD-L1 expression of 1% or higher had improved PFS and response rates with the relatlimab-based treatment. The median PFS was 9.8 months (90% CI, 5.9-13.8) in the relatlimab group vs 6.1 (90% CI, 4.2-7.0) in the nivolumab plus chemotherapy group (HR, 0.63; 90% CI, 0.45-0.88). The ORR was 53.2% (90% CI, 43.3%-62.8%) and 40.8% (90% CI, 31.0%-51.3%), respectively.

“We do not see this trend in PD-L1–negative tumors,” Girard said.

When assessed by histology, the benefit derived from relatlimab plus nivolumab and chemotherapy compared with nivolumab plus chemotherapy was further enhanced in patients with nonsquamous cell histology, with a median PFS of 8.3 months (90% CI, 5.6-9.8) vs 6.0 months (90% CI, 4.6-7.0), respectively (HR, 0.86; 90% CI, 0.64-1.13).

In patients with squamous cell histology, response rate and PFS were "somewhat similar,” Girard added.

Researchers then took into consideration the individual trends seen by PD-L1 expression and histology. “We see that the addition of relatlimab to nivolumab plus chemotherapy clearly favor,” Girard said.

In this analysis, PFS is improved with the addition of relatlimab to nivolumab plus chemotherapy vs nivolumab plus chemotherapy, with a median PFS of 11.6 months (90% CI, 6.9-NR) and 6.9 months (90% CI, 4.2-7.1), respectively (HR, 0.55; 90% CI, 0.36-0.85).

Similar improvements were seen in responses to treatment, with a 58.0% response rate in the relatlimab-based treatment and 39.6% in the nivolumab plus chemotherapy group (difference = 18.4%). The median duration of response was 13.8 months vs 12.6 months, respectively.

“These data provide the rationale for further investigation in a phase 3 study,” Girard said.

Patients also benefitted from treatment with the relatlimab-based therapy in PD-L1 expressions between 1% and 49% and nonsquamous cell histology in terms of PFS (HR, 0.45; 90% CI, 0.25-0.81). The response rate for each group was 60.7% and 30.0%, respectively (difference = 30.7%).

Patients with a PD-L1 expression of 50% and higher, in addition to nonsquamous cell histology also demonstrated an improved median PFS with the relatlimab-based treatment vs the nivolumab plus chemotherapy treatment (13.8 months vs 7.1 months; HR, 0.60; 90% CI, 0.31-1.15).

“The difference in overall response rate was more moderate than in the 1% to 49% PD-L1 expression cases, but still, with [nivolumab] plus [relatlimab] plus platinum-doublet chemotherapy, we see a 55% response rate in the subgroup of patients,” Girard said.

Background and Design

Relatlimab is a human LAG3-blocking antibody that restores effector T-cell function, Girard explained.

He added, “The inhibition of PD-1 and LAG3 with nivolumab plus relatlimab further improves anti-tumor immune response with an effect that is greater than that of either antibody alone. This combination was approved for the treatment of advanced melanoma.”

Part 2 of the RELATIVITY-104 study, which was reported during this presentation, aimed to identify patient populations with metastatic NSCLC who might benefit from the addition of relatlimab. In particular, 309 patients with treatment-naive stage IV/recurrent NSCLC, no driver alterations, and an ECOG performance status of 0 or 1. Patients were randomized 1:1 to receive 360 mg of nivolumab, 360 mg of relatlimab, and platinum-doublet chemotherapy every 3 weeks, or 360 mg of nivolumab plus chemotherapy. Patients in the trial were stratified by tumor PD-L1, histology, and ECOG performance score.

The primary end point of the study was ORR by blinded independent committee review. Secondary end points included PFS, efficacy by PD-L1 status, and safety.

Girard mentioned RELATIVITY-1093 (NCT06561386), an open-label, randomized phase 3 study that will evaluate nivolumab plus relatlimab and platinum-doublet chemotherapy compared with standard-of-care pembrolizumab (Keytruda) plus chemotherapy as first-line treatment of patients with metastatic NSCLC with a PD-L1 expression between 1% and 49% and nonsquamous cell histology.

Reference

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.