Dual Checkpoint Blockade Usurps PD-1 Monotherapy as Gold Standard in Unresectable Melanoma

Ankit Mangla, MD

Updated findings from the phase 2/3 RELATIVITY-047 trial (NCT03470922) showing sustained responses and favorable survival outcomes with nivolumab (Opdivo) plus relatlimab-rmbw (Opdualag) in previously untreated patients with metastatic or unresectable melanoma signal the diminishing role for anti–PD-1 monotherapy in the frontline setting, according to Ankit Mangla, MD.

Three-year follow-up data from RELATIVITY-047 presented at the 2024 ASCO Annual Meeting demonstrated a progression-free survival (PFS) advantage with nivolumab plus relatlimab (n = 355) vs nivolumab alone (n = 359) in this patient population (HR, 0.79; 95% CI, 0.66-0.95). Notably, a trend in favor of the combination was seen for overall survival (OS; HR, 0.80; 95% CI, 0.66-0.99), with 3-year OS rates of 55% (95% CI, 49.2%-59.6%) vs 48% (95% CI, 42.7%-53.1%), respectively.

Improvements in melanoma-specific survival (MSS) observed with the combination over nivolumab alone (HR, 0.75; 95% CI, 0.60-0.94) were also maintained; 3-year MSS rates were 63% (95% CI, 57.2%-67.7%) vs 54% (95% CI, 48.4%-59.2%), respectively. MSS, central nervous system (CNS) metastasis-free survival in specified populations, and efficacy on subsequent systemic therapy represented exploratory analyses presented from the trial. Additionally, efficacy results were consistent across most patient subgroups.

“The most important message is that the role of anti-PD-1 alone in the frontline setting is shrinking fast,” Mangla emphasized in an interview with OncLive^® regarding the clinical significance of RELATIVITY-047, as discussed in a State of the Science Summit™ on melanoma. “When we look at the forest plots, everything is favoring nivolumab plus relatlimab [vs nivolumab alone.”

Mangla, who chaired the event, highlighted updated survival data from the RELATIVITY-047 trial and discussed factors influencing the selection of nivolumab plus ipilimumab (Yervoy) vs nivolumab plus relatlimab in his own clinical practice.

Mangla is an assistant professor in the Department of Medicine at the 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: What findings were previously reported from RELATIVITY-047?

Mangla: RELATIVITY-047 was a phase 2/3 trial evaluating patients who were previously untreated and had unresectable metastatic melanoma. Patients were [randomly assigned to receive] 480 mg of nivolumab and 160 mg of relatlimab vs 480 mg of nivolumab [alone]. The primary end point of this trial was PFS, and secondary end points included OS and overall response rate [ORR]. [Primary findings showed that] the combination of nivolumab and relatlimab [produced superior PFS outcomes] vs nivolumab.

What did updated findings from RELATIVITY-047 reveal about the PFS and OS benefits with nivolumab plus relatlimab vs nivolumab alone?

At the 2024 ASCO Annual Meeting an exploratory analysis of the trial was presented. Before we delve into the results, it is important to understand that exploratory analyses are merely follow-ups of patients enrolled in the trial. The trials are not powered to follow patients for 4 years or beyond, so [data from an] exploratory analysis must be taken with a grain of salt.

There was a continued statistically significant PFS benefit [with nivolumab plus relatlimab vs nivolumab]. The HR stayed at 0.79 (95% CI, 0.66-0.95), once again making it statistically significant. More interestingly, there [was a trend towards median] OS benefit [with nivolumab plus relatlimab] vs nivolumab; the HR was 0.80 (95% CI, 0.66-0.99). [However,] one must remember that the trial was not powered [to evaluate] OS as the primary end point. The combination was not [shown to produce a statistically] significant [OS benefit vs] nivolumab alone in the 3-year follow up [of the study].

We have to remember that this is an exploratory analysis. Even if [data] look significant by mathematical standards, we don’t consider this to be a statistically significant result. Although, there was a difference in OS between the combination and nivolumab alone which was maintained. Eventually, if a patient is getting the combination they will have better outcomes with the combination of anti–LAG3 and anti–PD-L1 vs single agent anti–PD-1 therapy.

How did ORR compare for patients treated with nivolumab plus relatlimab vs nivolumab alone?

The ORR data presented showed that the difference [between both arms] was 9.8%, with an ORR of 44% in the combination arm and 34% in the nivolumab alone arm. Twenty-percent of patients in the combination arm achieved a complete response (CR) and 24% achieved a partial response [PR] compared with a CR rate of 19% and PR rate of 15% in the nivolumab arm. There was not much of a difference in the amount of CRs, but the rate of PRs was much higher [with the combination vs monotherapy]. The median duration of response was not reached in either arm. Responses are still ongoing, so we will see more data as [the study continues].

What is MSS, and how did this end point differ between the treatment arms in RELATIVITY-047?

One of the most important things [to discuss] is MSS. OS is the overall cause of mortality, whereas MSS is looking at the specific probability of a patient dying from the melanoma itself. Although this was an exploratory end point, [MSS] was significant from the very beginning. Even at 3 years it was significant, and it continues to be significant in the most updated data, where the HR is 0.75 (95% CI, 0.60-0.94). It is important for patients to know that the risk of death from melanoma is significantly less when you use the combination vs single agent.

Treatment related adverse effects [TRAEs] were updated again this year and essentially remain the same. The incidence of grade 3/4 TRAEs was 22% in the nivolumab combination [arm] compared with 12% in the nivolumab alone [arm]. This contrasts with the rate of grade 3/4 TRAEs we saw with ipilimumab plus nivolumab, which was a 59% [in the phase 3 CheckMate 067 trial (NCT01844505)]. There was a 31% rate of treatment discontinuation [due to grade 3/4 TRAEs with the ipilimumab combination] vs 8% in the nivolumab arm [as well]. The nivolumab arm showed [similar] data as approximately 20% [of patients experienced] grade 3/4 AEs.

In [RELATIVITY-047], 4 treatment-related deaths were reported in the nivolumab plus relatlimab arm. [The cause of these deaths] is still under investigation.

What did the 2024 data update suggest about the efficacy of nivolumab plus relatlimab in preventing CNS metastases and improving PFS2?

What was interesting to me in the 2024 data update was the [assessment of] CNS efficacy, which was numerically superior with the [combination] vs nivolumab. This trial was not designed to evaluate what was happening in the brain, but the [number of] patients who developed CNS metastases was lower with the combination than with nivolumab alone; there was a clear separation between the 2 curves. Again, these are numerical values, and they are not being statistically compared with each other, so we don’t know the exact answer. There is an ongoing trial [assessing] the efficacy of nivolumab plus relatlimab in [patients with] brain metastases, so [data from] that will probably be read out in a few years.

PFS2 data–the probability of a patient progressing on subsequent therapies after first experiencing progression with nivolumab plus relatlimab–were presented as well. Those patients who received second therapy after progression on nivolumab and relatlimab were offered [several] different treatments: nivolumab plus ipilimumab, ipilimumab or nivolumab monotherapy, [pembrolizumab monotherapy], or BRAF and MEK inhibitors in the event that the patient displayed a BRAF v600E mutation.

The 6-month PFS2 rate with nivolumab plus ipilimumab after progression on nivolumab plus relatlimab was 58%, which is numerically higher than the 31% PFS2 rate in those who only received nivolumab.

Additionally, the 12-month PFS2 rate [with nivolumab plus ipilimumab after progression on nivolumab plus relatlimab] was 50%, which was maintained at 24 months [compared with 19% in the nivolumab monotherapy arm which was also maintained]. This tells us that adding a third CTLA-4 [inhibitor] after progression on an anti-LAG3 inhibitor may be effective. Across the board, PFS2 was numerically superior with the combination compared with nivolumab.

What are the implications of these data for the use of single-agent PD-1 inhibitors in first-line unresectable melanoma?

There are very few clinical scenarios one can imagine in which single-agent anti–PD-L1 therapy should be used in the frontline setting. Unless a clinician thinks that their patient is, for whatever reason, not fit to receive ipilimumab at 3 mg/kg or if they have coexisting conditions [necessitating] anti–PD-1 therapy [alone], the use of nivolumab plus relatlimab should be considered instead. Are there patients who absolutely cannot tolerate dual checkpoint inhibition? Perhaps. However, that population is shrinking very fast.

Under what clinical circumstances would nivolumab plus ipilimumab be preferred over nivolumab plus relatlimab for patients with melanoma?

That’s a question on everybody’s mind right now. There are a couple of scenarios in which we would [use nivolumab plus ipilimumab based on] data from CheckMate 067 or the phase 2 CheckMate 204 [NCT02320058] trials. For any patient who walks into the clinic with stage IV melanoma, the first order of business is to figure out if they have brain metastases or not because that completely changes your outlook on therapies.

If there are brain metastases, then we have to figure out whether they are symptomatic or asymptomatic. [Patients with] symptomatic brain metastases did very poorly in CheckMate 204, with an [overall] survival of [36.6%]. For that patient, we would get creative. We may use radiation therapy, gamma knife radiosurgery, or stereotactic radiation with or without immunotherapy to control the disease.

However, for patients who have asymptomatic brain metastases, the answer is to use ipilimumab plus nivolumab. I don’t believe there are any good data to support the use of nivolumab plus relatlimab in such a patient at this point; trials are [ongoing], and we’ll see how it evolves.

If the patient does not have brain metastases, I personally look at their disease burden. One thing people ask me as a consultant is, ‘What if the patient has a BRAF v600E mutation and a high burden of disease?’ Even in that patient, there is good evidence to support the use of immunotherapy first, [including the] phase 3 DREAMseq trial [NCT02224781] data that have continuously shown that immunotherapy as a first approach will lead to better OS. [Accordingly, that supports] offering or at least thinking about immunotherapy first.

There will be a subset of patients who may present in visceral crisis or express the mutation. For these patients, there may be an argument to use a BRAF/MEK inhibitor first. If the patient has m1c disease, including liver or lung metastasis, I lean towards using a more aggressive approach, [namely] the CheckMate 067 regimen. However, if a patient has normal or slightly higher lactate dehydrogenase [levels], less than 3 sites of metastasis, and no brain metastases, nivolumab plus relatlimab should be the first approach.

What role does nivolumab plus relatlimab play in the treatment of patients with high disease burden, and how do the data from RELATIVITY-047 inform subsequent treatment strategies after progression on this regimen?

We can absolutely use nivolumab plus relatlimab for a patient with a high disease burden. That is one of the reasons why PFS2 data was important in [both the presentation at the] 2024 ASCO Annual Meeting, and in previous publications of RELATIVITY-047. The data demonstrated that if a patient [progresses on] nivolumab plus relatlimab, and you switch them to ipilimumab plus nivolumab, there’s a 58% chance that the patient will not progress at the end of 6 months, and approximately half of patients will not progress at the end of 12 months—those patients will sustain their responses at the end of 24 months.

In my practice, I would suggest that we still use the CheckMate 067 regimen when we see patients with high disease burden in relatively good health. Performance status also matters. If the disease burden is high but the performance status is poor, then you may want to go with nivolumab plus relatlimab, considering the risk of TRAEs with ipilimumab plus nivolumab. [Overall,] this question does not have a clear answer, and it [requires] statistical clarity, but for now these are the [data] in support of [either option].

Reference

Tawbi HA, Hodi FS, Lipson EJ, et al. Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma (RELATIVITY-047): Overall survival (OS) and melanoma-specific survival (MSS) outcomes at 3 years. J Clin Oncol. 2024;42(suppl 16):9524. doi:10.1200/JCO.2024.42.16_suppl.9524