RELATIVITY-047 vs CheckMate 067 Matched Cohorts in Melanoma Show Similar Efficacy

Ahmad Tarhini, MD, PhD

Director of Cutaneous Clinical and Translational Research

Leader of the Neoadjuvant and Adjuvant Translational Science Program

Moffitt Cancer Center

Professor of Oncologic Sciences

University of South Florida Morsani College of Medicine

Tampa, FL

KEY TAKEAWAYS FROM AHMAD TARHINI, MD, PHD

• The indirect matched cohort comparison of ipilimumab (Yervoy) plus nivolumab (Opdivo) and nivolumab/relatlimab (Opdualag) matched patients in the 2 trials based on baseline characteristics and follow-up time.
• Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) showed no statistically significant differences.
• Grade 3 and 4 toxicity rates were lower with nivolumab/relatlimab.

Targeted Oncology: How can outcomes with ipilimumab plus nivolumab be compared with those of nivolumab/relatlimab in patients with metastatic melanoma?

Ahmad Tarhini, MD, PhD: An interesting comparison was done. We have 2 combinations in the clinic: ipilimumab/nivolumab and nivolumab/relatlimab, and we don't have a randomized study that compared the 2 that can tell us how comparable these are. This analysis was presented by Dirk Schadendorf, MD, [of University Hospital Essen, Germany] last year, and updated this year at the American Society of Clinical Oncology [ASCO] Annual Meeting, and then published in the Journal of Clinical Oncology.¹ …This was done in a certain way to help us better understand how these data compared with each other. The fact that it was published in the Journal of Clinical Oncology speaks for the validity of the of the procedures done, and the statistical analysis supporting this, although it's an exploratory analysis. This is not a randomized trial.

They did what was considered as a match-adjusted indirect comparison, where they would take the individual-level data available to the sponsor, and the patients would be matched to be compared with each other. To make them more compatible, they also look at the median follow-up of RELATIVITY-047 [NCT03470922] at 34 months, and therefore in CheckMate 067 [NCT01844505], they took the data cut-off in 2017 for the ipilimumab/nivolumab study to make the median follow-up there 36 months.

What did the matched-cohort indirect comparison show for these patients?

This is the outcome of this analysis: looking at PFS, the rates were not that different, 36% and 39% PFS at 36 months [for nivolumab/relatlimab vs nivolumab/ipilimumab]. The PFS HR was 1.08, meaning no significant differences [95% CI, 0.88-1.33]. Looking at OS rates at 36 months, they were 57% and 57% [respectively] with an HR of 0.94, meaning no significant differences [95% CI, 0.75-1.19].

They looked at ORR before weighting and after weighting, meaning before they applied their matching adjusted statistical model. Looking at after weighting, the confirmed responses by investigator, not by BICR, was 48% for nivolumab/relatlimab vs 50% for ipilimumab/nivolumab [showing] no significant differences [post-weighting odds ratio, 0.91; 95% CI, 0.73-1.14]. Complete response rates appeared to be slightly different, 15% [for nivolumab/relatlimab] and 20% [with ipilimumab/nivolumab], with partial response rates of 32% and 30%, respectively.

These are the toxicities…after weighting: for grade 3 or 4 adverse events [AEs], [the rate was 23% for nivolumab/relatlimab] compared with 61% [for ipilimumab/nivolumab], and the differences by category of toxicity [were shown as well]. The rates are lower, in favor of nivolumab/relatlimab.

What is the relationship between antitumor immune response and immune-mediated AEs with immunotherapy?

The level of immune activity determines whether we have cancer [immune] escape in the setting of low immune activity, and then with immunotherapy we have activation.² There is an optimal level of immune activation when we have antitumor resistance and less toxicity, and as we have more activation, this leads to immune-mediated AEs. These are related to the underlying mechanism of how these drugs work. We have toxicities, we have AEs, but then with management using management guidelines, whether it’s steroids or secondary immunosuppression, we can push it down to a level where we maintain the melanoma resistance but have less toxicities. With the experience we have and the guidelines from the Society for Immunotherapy of Cancer, ASCO, and National Comprehensive Cancer Network, I think we have developed a lot of experience over the years in managing them. These can affect any organ, whether it is cutaneous, gastrointestinal, liver, pulmonary—which is relatively rare—[and] endocrinopathy.

REFERENCES:

1. Long GV, Lipson EJ, Hodi FS, et al. First-line nivolumab plus relatlimab versus nivolumab plus ipilimumab in advanced melanoma: an indirect treatment comparison using RELATIVITY-047 and CheckMate 067 trial data. J Clin Oncol. Published online August 13, 2024. doi:10.1200/JCO.24.01125

2. Amos SM, Duong CP, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011;118(3):499-509. doi:10.1182/blood-2011-01-325266