'Highest Survival' With Combo Immunotherapy in Advanced Melanoma

Roxanne Nelson, RN, BSN

December 06, 2021

An updated analysis of the phase 3 CheckMate 067 trial confirms the durability of combination immunotherapy for metastatic melanoma, representing a "substantial development" in treatment, researchers say.

Nearly half the patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) were alive at 6½ years. Within this group, 77% had not received further systemic treatment after coming off the study drugs.

After a minimum follow-up of 77 months (6½ years), median overall survival was 72.1 months in patients on the combination, which was more than three times longer than the 19.9 months with ipilimumab alone (hazard ratio, 0.52; 95% CI, 0.43 - 0.64) and twice as long as the 36.9 months with nivolumab alone (HR, 0.84; 95% CI, 0.67 - 1.04).

The results represent the longest median overall survival seen in a phase 3 trial of advanced melanoma and are evidence of "a substantial development in the melanoma treatment landscape vs the standard median survival of 8 months a decade ago," researchers write in a study published online November 24 in the Journal of Clinical Oncology.

However, lead author Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, noted that the study was not designed to compare nivolumab alone with the combination. "It wasn't powered for that. [But] what we can say is that the highest survival was in the combination group," Wolchok told Medscape Medical News.

Wolchok cautioned that the combination therapy is not currently standard of care. "PD-1 blockade — either nivolumab or the combination — are both excellent options for care," he added. "I can't tell you that one of them is the standard of care because that's too complex of a decision."

For example, he explained, "for a patient who only has lung metastases, a single agent PD-1 blockade might be sufficient. But if it has spread to other organs, such as the liver or bones, which are more difficult to treat, that's when we often reach for the combination."

Other factors that weigh into the therapeutic decision are the patient's performance status and their so-called clinical reserve for tolerating side effects. "The likelihood of having a high-grade side effect with the combination is more than twice that of the single agent," Wolchok said.

Until 2011, only two therapies were approved for metastatic melanoma: chemotherapy with dacarbazine and immunotherapy with high-dose interleukin 2, neither of which was very effective at prolonging life.

But patient survival changed with the advent of targeted therapies and immunotherapy. Some patients are now living for years, and as the current study shows, many have surpassed the 5-year mark and are treatment-free.

The updated CheckMate 067 analysis included patients with previously untreated, unresectable stage III/IV melanoma who were randomly assigned to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (four doses) followed by nivolumab 3 mg/kg every 2 weeks (n = 314), nivolumab 3 mg/kg every 2 weeks (n = 316), or ipilimumab 3 mg/ kg every 3 weeks (four doses; n = 315).

The authors reported the 5-year overall survival rates from the trial, published in the New England Journal of Medicine in 2019 — 52% with the combination, 44% with nivolumab alone, and 26% with ipilimumab alone.

In the updated study, overall survival at 6½ years had dropped slightly to 49%, 42%, and 23%, respectively. Patients with BRAF-mutant tumors had overall survival rates of 57%, 43%, and 25%, vs 46%, 42%, and 22% in those with BRAF–wild-type tumors.

Overall, median investigator-assessed progression-free survival was 11.5 months with the combination, 6.9 months with nivolumab alone, and 2.9 months with ipilimumab.

The new analysis also evaluated melanoma-specific survival (MSS), which removes competing causes of deaths from the long-term follow-up. The melanoma-specific survival was not reached in the combination group, and was 58.7 months in the nivolumab group and 21.9 months for ipilimumab, with MSS rates at 6.5 years of 56%, 48%, and 27%, respectively.

No new safety signals were detected, but there was more immune-mediated toxicity in the combination group, the researchers reported.

"The patients will continue to be followed," said Wolchok, "And data are still being collected."

The trial was supported by Bristol-Myers Squibb, the National Cancer Institute, and the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

Wolchok and co-authors report relationships with Bristol-Myers Squibb and other drugmakers.

J Clin Oncol. Published online November 24, 2021. Full text

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