RELATIVITY-048 Data Highlight Potential of Triplet ICI Regimen for Advanced Melanoma

Ankit Mangla, MD

The addition of ipilimumab (Yervoy) to nivolumab and relatlimab-rmbw (Opdualag) has generated high response rates and promising survival outcomes as a first-line treatment for patients with advanced melanoma in the phase 1/2 RELATIVITY-048 trial (NCT03459222), signifying the viability of triplet checkpoint blockade for this patient population, according to Ankit Mangla, MD. However, larger studies are needed to confirm the efficacy and safety of this approach for use in the frontline setting.

Preliminary data from RELATIVITY-048 were presented at the 2024 ASCO Annual Meeting. At a median follow-up of 49.4 months (range, 0.4-55.0), patients treated with the triplet (n = 46) achieved an overall response rate (ORR) of 59% (95% CI, 43%-73%) by investigator assessment and 52% (95% CI, 37%-61%) by blinded independent central review (BICR). The median duration of response (DOR) with the triplet was not reached (NR; 95% CI, NR-NR), nor was the median progression-free survival (PFS; 95% CI, 3.9-NR) or overall survival (OS; 95% CI, NR-NR). The 48-month PFS and OS rates were 52% (95% CI, 35%-66%) and 72% (95% CI, 56%-82%), respectively.

Additionally, higher response rates were observed in patients with cutaneous nonacral melanoma (64%) vs mucosal (33%) or acral (25%) melanoma, although long-term benefit was observed in 2 patients with the latter disease subtypes. Higher response rates were also observed in patients who had LAG3-positive (68%) vs -negative (33%) and PD-L1–positive (67%) vs –negative (59%) melanoma. No new safety signals were reported with the triplet, and the safety profile was generally consistent with that of other immunotherapy combinations.

“Looking at survival outcomes, PFS and OS were not reached [with the triplet],” Mangla said in an interview with OncLive®regarding research discussed at a recent State of the Science Summit™ on melanoma, which he chaired. “These [data] tell you that that this is a combination that needs to be evaluated further.”

In the interview, Mangla highlighted the current role of dual checkpoint inhibitor regimens in patients with previously untreated melanoma; discussed promising early efficacy and safety results with the nivolumab, relatlimab, and ipilimumab triplet; and emphasized the need for further studies to confirm the safety and efficacy of this combination, particularly for patients with high-risk disease features like central nervous system (CNS) metastases.

Mangla also spotlighted updated data from the phase 2/3 RELATIVITY-047 trial (NCT03470922) in a concurrent interview.

Mangla is an assistant professor in the Department of Medicine at Case Western Reserve University School of Medicine, as well as a member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center in Cleveland, Ohio.

OncLive: How could emerging triplet therapies affect the present role of doublet regimens in the upfront management of advanced melanoma?

Mangla:We have 2 different doublets [in melanoma]. One is the older combination of an anti–CTLA-4 and anti–PD-L1 agent, which is ipilimumab and nivolumab. The second combination we have is [comprised of] an anti-LAG3 and anti–PD-1 agent, which is relatlimab and nivolumab. Although there are no head-to-head comparisons between the 2 regimens, we do know that the rate of grade 3/4 adverse effects [AEs] is much lower with the relatlimab combination than the nivolumab and ipilimumab regimen.

Data from some publications in the Journal of Clinical Oncology have also shown that efficacy-wise, these drugs are not very different. However, the long-term data with nivolumab plus relatlimab are still [emerging], so we’ll see how much will come out in the next 5 years. In comparison, nivolumab plus ipilimumab already has 6.5 years of follow-up data.

There’s now a triplet combination [comprising] nivolumab, relatlimab, and ipilimumab that has just been evaluated and it has [produced] some very interesting results. The median OS, PFS, and [DOR] have not been reached even after 48 months. This combination still needs [further evaluation], but it’s an interesting space and something to watch out for.

What were some of the notable features from the patient population that was included in the RELATIVITY-048 trial?

[RELATIVITY-048] was not a huge trial, and phase 1 [data from the melanoma cohort] were presented with median follow-up of 49.4 months. These patients were previously untreated, but they were allowed to have [prior exposure to] neoadjuvant or adjuvant therapies [if they had completed treatment] more than 6 months [prior to enrollment. A total of] 72% of these patients had cutaneous melanoma, [26%] had M1B disease, [30%] had liver metastases, and 93% were naive to any immunotherapies. In general, when we see a patient with liver or brain metastases [we know that] those patients are at the highest risk of progressing on immunotherapy, so it’s very interesting to see blockade of all 3 checkpoints with an anti–CTLA-4, anti-LAG3, and anti–PD-L1 combination.

How did the triplet therapy perform in terms of ORR and clinical benefit rate (CBR), particularly for patients with traditionally immunologically resistant melanoma subtypes?

The best ORR per investigator assessment was 59%, which is almost equal to what we saw in patients treated with ipilimumab plus nivolumab [in the phase 3 CheckMate 067 trial (NCT01844505)]. Per central review the ORR was 52%. The CBR was 76% [per investigator assessment] and 72% per central review. Seventeen percent of patients achieved complete responses per investigator, 41% achieved partial responses, and 17% of patients had stable disease. These are impressive numbers.

When we look at the waterfall plot, some of these patients with acral and mucosal melanoma [also] achieved significant responses. This is important to know, because [these subtypes], especially acral melanoma are immunologically cold tumors. They [typically] don’t respond that well to checkpoint inhibition. [Additionally, patients with] acral melanoma have been underrepresented in most clinical trials in the Western Hemisphere, primarily because of the rarity of the disease. To see responses in a patient with acral melanoma and [1 with] mucosal melanoma is very heartwarming, and it’s a good area to explore [through future studies].

What should be known about the triplet’s safety profile in this trial?

Currently, the [rate of] grade 3/4 treatment-related AEs [TRAEs] was 39% [with the triplet], which is somewhat lower than in CheckMate 067. Twenty-two percent of patients discontinued treatment due to grade 3/4 AEs, there were 2 deaths, and 1 was directly related to immune-mediated myositis. Notably, ipilimumab was [administered] at 1 mg/kg every 8 weeks, which diverges from most [clinical trial] protocols where the maximum extension of ipilimumab has been 6 weeks. [Others have questioned] why [the melanoma space tends to] use [ipilimumab] so sparingly, [and this] has been a point of criticism. TRAEs need to be watched, and we will probably have to do post-correction as [the study continues]. Colitis and hepatitis were the most common immune-related AEs.

What are the next steps for evaluating this triplet therapy in advanced melanoma?

We have yet to see complete data [from this study.] More comparisons and a proper trial design [are needed] to see exactly which patients will benefit from the triplet therapy. My hunch is that one of the biggest areas of benefit may be in patients who have CNS metastases, because one of the biggest challenges in melanoma currently is the treatment of patients with symptomatic brain metastases. That challenge has not been overcome yet.

What is your main message for colleagues regarding the ongoing development of combination therapies for melanoma management?

First, it is an absolute necessity to understand what is going on in the brain for patients with metastatic disease, because that is where the melanoma can hide and grow. It can also [influence] the trajectory of treatment. Second, nivolumab and relatlimab will have an increasingly important role [in the management of melanoma going forward]. What we need to see is how second-line nivolumab performs in patients who have progressed on this combination. Lastly, the triplet combination of nivolumab, ipilimumab, and relatlimab [is in development]. That is something to watch out for. It will be exciting to see [further] trials designed [to assess this regimen] and then [see] how they turn out.

Reference

1. Ascierto PA, Dummer R, Gaudy-Marqueste C, et al. Efficacy and safety of triplet nivolumab, relatlimab, and ipilimumab (NIVO + RELA + IPI) in advanced melanoma: results from RELATIVITY-048. J Clin Oncol. 2024;42(suppl 16):9504. doi:10.1200/JCO.2024.42.16_suppl.9504