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Expert Point of View: Adil Daud, MBBS, and Georgina V. Long, MBBS, PhD


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The invited discussant of the RELATIVITY-047 trial, Adil Daud, MBBS, said the findings1 “mark a major advance for immunotherapy beyond CTLA-4 and PD-1” as upfront treatment for advanced melanoma. However, the findings trigger a host of questions for clinicians. Dr. Daud is Co-Director of the University of California San Francisco (UCSF) Melanoma Center and Director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center.

Adil Daud, MBBS

Adil Daud, MBBS

As Dr. Daud pointed out, progression-free survival remained statistically significant (hazard ratio [HR] = 0.78), and overall survival was improved (HR = 0.80) in the updated analysis. Although the overall survival endpoint did not reach statistical significance, the numerical overall survival benefit was sustained out to 36 months, he noted.

Comparing RELATIVITY-047 and CheckMate 067

Dr. Daud put RELATIVITY-047’s findings in context with the landmark CheckMate 067 trial,2 which led to the approval of ipilimumab plus nivolumab in advanced melanoma. Despite more patients with M1c and M1d disease in CheckMate 067, response rates to ipilimumab/nivolumab were higher than those seen with nivolumab/relatlimab, though toxicity was greater for ipilimumab/nivolumab (see Table 1 in related article). (Other differences in the study population are described in a perspective on the recently published initial findings in the April 10 issue of The ASCO Post.) In -RELATIVITY-047, however, patients with PD-L1–negative disease derived more benefit (HR = 0.68) from the combination, while those with PD-L1 expression of at least 1% (HR = 0.96) did not.

As for BRAF mutation status, CheckMate 067 found this to be a useful biomarker; patients with BRAF-mutant disease benefited significantly from the combination (HR = 0.59) vs those with wild-type disease (HR = 0.89). In RELATIVITY-047, however, risk reduction was similar for mutant and wild-type tumors (HR = 0.77 and 0.78).

Dr. Daud briefly noted the advantages and disadvantages of the first-line treatment options:

Single-Agent Nivolumab or Pembrolizumab: Low efficacy but also low toxicity, with response rates of 30% to 40%, median progression-free survival of 4 to 8 months, median overall survival of 30 to 40 months, and grade 3 or 4 toxicity of 10% to 15%.

Nivolumab Plus Ipilimumab: High efficacy but also high toxicity, with response rates of 50% to 60%, median progression-free survival of 10 to 12 months, median overall survival of 72 months, and proven activity in patients with brain metastases and with BRAF mutations.

Nivolumab Plus Relatlimab: High efficacy and potentially lower toxicity, with a response rate of 43%, median progression-free survival of 10 months, and median overall survival not reached, though long-term efficacy and activity in brain metastases are unknown, as are relevant biomarkers.

Questions Remain

During the discussion, RELATIVITY-047 lead investigator, Georgina V. Long, MBBS, PhD, and Dr. Daud agreed that the emergence of a potential first-line competitor for nivolumab plus ipilimumab (pending approval of relatlimab) raises questions and will require clinicians to individualize therapy.

Georgina V. Long, MBBS, PhD

Georgina V. Long, MBBS, PhD

“As we get used to using these treatments, we now have to delve into the data to determine the best sequencing,” Dr. Long said. “Will nivolumab/relatlimab become the new first-line regimen? It does appear a lot less toxic than nivolumab/ipilimumab.” However, she reminded listeners, in metastatic melanoma, efficacy often trumps toxicity for patients, especially young adults. “In melanoma, we are going for long-term durable control, for cure, and patients are willing to accept a bit more toxicity,” she added. “However, we do have to keep in mind those patients whose quality of life is completely obliterated with rare but difficult immune toxicities.” Dr. Daud agreed that in an otherwise healthy young patient desiring aggressive treatment, he might give nivolumab/ipilimumab and reserve nivolumab/relatlimab as salvage therapy.

So, what is the optimal sequencing of regimens (their relative activity in the second-line setting), their activity in certain subsets (brain metastases, BRAF-mutant), and the role of monotherapy, now that a more tolerable first-line option has emerged? Without an established, optimal first choice, treatment decisions, for now, might be made based on certain patient characteristics, the speakers agreed.

Choosing Among First-Line Treatments

Meanwhile, Dr. Long and Dr. Daud shared how they might choose among three potential first-line options. For patients with BRAF mutations or brain metastases, nivolumab/ipilimumab would likely remain their first choice. For patients with PD-L1–negative disease, the choice is less clear, as both combination regimens had benefit in that subset, they said.

“It will be very difficult to replace nivolumab/ipilimumab for these specific populations,” Dr. Long commented. “It’s difficult to break old habits when you have confidence about the activity of nivolumab/ipilimumab.”

For patients in whom toxicity is an issue, nivolumab/relatlimab may have the upper hand and, according to Dr. Daud, may even be an acceptable alternative to monotherapy, considering its safety profile. He might opt for PD-1 monotherapy in patients with high PD-L1 expression and limited disease, older patients, and patients with desmoplastic melanoma (for whom PD-L1 is known to be a good marker for response), he said.

Answers to these remaining questions are likely not to come from a head-to-head trial of the two nivolumab-containing regimens, according to Dr. Long, but from retrospective studies. 

DISCLOSURE: Dr. Daud disclosed financial relationships with Trex Bio, Xencor, Neuvogen, Iovance, Nektar, Chemocentryx, Oncosec, Merck, and Pfizer. See the full text for Dr. Long’s disclosures.

REFERENCES

1. Long GV, Hodi S, Lipson EJ, et al: Relatlimab and nivolumab versus nivolumab in previously untreated metastatic or unresectable melanoma: Overall survival and response rates from RELATIVITY-047 (CA224-047). 2022 ASCO Plenary Series. Abstract 360385. Presented March 15, 2022.

2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23-34, 2015.


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