Addition of relatlimab to nivolumab plus platinum-doublet chemo demonstrates improved clinical benefit in NSCLC

Prof Nicolas Girard - Institut Curie, Paris, France

RELATIVITY-104 is a randomised phase II study that compared to nivolumab plus chemotherapy nivolumab plus relatlimab plus chemotherapy in patients with metastatic non-small cell lung cancer in the first-line setting. Relatlimab is a LAG-3 blocking antibody. It was approved in the treatment of melanoma in addition to nivolumab. Here, we want to understand in this study what is the contribution of adding relatlimab to standard of care chemotherapy plus anti-PD-1. We are using chemo plus nivolumab in this setting because a combination of relatlimab with nivolumab plus chemotherapy is the experimental arm in this study. 309 patients, so a significant cohort of patients.

The study did not meet its primary endpoint of benefit in terms of response rate. It was improved in the nivolumab/relatlimab/chemotherapy arm versus nivolumab plus chemotherapy, but that did not reach statistical significance. Of more interest is the analysis of the patient population benefitting from the addition of relatlimab to chemotherapy and nivolumab. We looked at PD-L1, and we looked at histology, because these were prespecified stratification factors in the study. It is very clear that we have a benefit in patients with PD-L1 positive, so 1% or higher expression of PD-L1, and non-squamous cell histology with a hazard ratio for PFS of 0.55, so pretty clinically meaningful, and a response rate of 58% versus 40%. So that’s obviously clinically meaningful. This is a significant benefit in this subset of patients. The benefit is observed both in PD-L1 1% to 49%, and PD-L1 of 50% or higher, which is good.

Now we have the rationale for the phase III trial, which is RELATIVITY-1093, which will compare this combination, nivolumab plus relatlimab plus chemo, to the standard of care, which is chemotherapy plus pembrolizumab, in patients with PD-L1 expression 1% to 49% and non-squamous histology.

With regard to safety, very interesting to see that the safety was comparable between the two arms. The main risk with the combination of nivolumab/relatlimab/chemotherapy is haematological toxicity, so neutropenia, febrile neutropenia, and septic shock. It was mandatory in the trial for elderly patients above 60 years old to receive prophylactic [??] growth factors, but at the end, we see a similar rate of grade 3/4 treatment-related adverse events, same rate of treatment-related adverse event discontinuations, and similar number of patients who died during the study because of treatment-related adverse events. So safety is really not a concern with this combination.

I think it raises a question of how to move forward with the first-line treatment of patients with metastatic non-small cell lung cancer. Chemo plus IO is clearly the standard of care, but we need probably now to move to intensification or escalation with more combinations. LAG-3 blocking agents are obviously promising, as I just discussed. There are other strategies, such as a combination with ADC, so antibody-drug conjugate, and several trials are ongoing with a combination of IO plus chemo plus ADCs. Finally, there are some bispecific antibodies that will work in targeting several immune checkpoints. We have data with a bispecific CTLA-4/PD-1, TIGIT/PD-1 antibodies that are underway.