By: Alexander M. Castellino, PhD
One out of two patients with metastatic melanoma treated with the combination of ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb) are still alive after 5 years, updated results from the longest running trial of the dual immunotherapy indicate.
“This is a major improvement on what we have seen historically,” said principal investigator James Larkin, FRCP, PhD, of the Royal Marsden NHS Foundation Trust, London, UK.
“Ten years ago, the 5-year survival for melanoma was around 5%. With ipilimumab monotherapy, which has been used for around 10 years, around 20% of patients are long-term survivors and the remainder live for just 6 to 9 months,” he added.
Larkin presented the new survival data, which come from the CheckMate 067 trial, here at the European Society for Medical Oncology annual meeting, and the results were also published simultaneously in the New England Journal of Medicine.
Melanoma expert Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York City, agreed that these data are making history.
“This study provides the longest follow-up data we have for patients treated with the nivolumab and ipilimumab combination. It is remarkable that over 50% of patients with advanced melanoma now have long-term survival,” he told Medscape Medical News.
Change in the Treatment Landscape of Advanced Melanoma
Postow explained that the advent of ipilimumab introduced the field of oncology to the incredible possibilities of immune checkpoint blockade. Nivolumab and pembrolizumab then showed that outcomes can be even better — and with fewer side effects — than with ipilimumab.
“Now the combination of nivolumab and ipilimumab has ushered in a new era of combination immunotherapy, further increasing beneficial outcomes,” he said, adding that the combination is “a fantastic advance” for patients with melanoma and other cancers.
“We now need to find ways to identify which patients benefit most and if new ways of delivering nivolumab and ipilimumab preserve anti-tumor efficacy with fewer side effects,” Postow explained.
“The combination is not for every patient with melanoma, as patients need to be selected appropriately given the potential for side effects,” Postow said. But he added the combination of nivolumab and ipilimumab is more powerful than nivolumab or pembrolizumab (Keytruda, Merck) alone, with higher response rates and more side effects.
“If patients are appropriate for both the combination of nivolumab and ipilimumab, and for either nivolumab or pembrolizumab alone, both approaches should be discussed with patients and the decision between them weighed carefully,” he said.
Larkin agreed, noting that there is currently no method to predict which patients are most likely to benefit from combination immunotherapy. “The decision on which treatments to give is a matter for doctors to discuss with individual patients and their families,” he said.
“The two drugs together definitely have a role in treating metastatic melanoma and will be the choice for some patients. For others, the decision may be to give the drugs in sequence,” Larkin said.
CheckMate 067 Results
CheckMate 067 randomly assigned 945 patients to receive the combination of ipilimumab and nivolumab (n = 314), nivolumab (n = 316), or ipilimumab (n = 315).
The 5-year overall survival rates were 52% for the combination of nivolumab and ipilimumab, 44% for nivolumab, and 26% for ipilimumab.
Progression-free survival at 5 years mirrored OS data: 36% for the combination, 29% for nivolumab alone, and 8% for ipilimumab alone.
Larkin reported that objective response rates (ORR) were seen in 58% of patients receiving the combination, 45% of patients receiving nivolumab alone, and 19% receiving ipilimumab alone. “While ORR has remained stable, rates of complete responses have improved over the 3-year, 4-year, and 5-year analyses,” he said.
Fewer patients on the combination received subsequent therapies (46% for the combination, 59% for nivolumab alone, and 75% for ipilimumab alone).
“The treatment-free interval (TFI) is an important outcome for patients,” Larkin said. For patients who discontinued therapy, the TFI was longest for patients who received the combination (18.1 months compared with 1.9 months on nivolumab alone and 1.8 months for ipilimumab alone).
Three quarters of patients (74%) who received the combination were alive and treatment-free free at the end of 5 years, significantly higher than the 58% of patients who received nivolumab alone and 45% of patients who received ipilimumab alone.
No new safety signals or treatment-related deaths were reported after 5 years, Larkin reported.
Activity Against Brain Metastases
Postow commented that the combination of nivolumab and ipilimumab is the preferred go-to therapy for many patients with advanced melanoma, particularly those with brain metastases.
On that topic, Georgina V. Long, MD, of the Melanoma Institute Australia in Sydney, reported in another presentation that patients receiving this combination had the best intracranial response (51% for the combination and 20% for nivolumab alone) and also better survival rates.
Long’s data were from an independent, investigator-driven ABC (Anti-PD-1 Brain Collaboration) trial, which compared the combination of ipilimumab and nivolumab with nivolumab alone in patients with brain metastases (abstract 1311O).
The ABC trialists from Australia and New Zealand enrolled 60 patients who received no treatment for asymptomatic brain metastases to receive the combination of ipilimumab and nivolumab (n = 35) or nivolumab alone (n = 25).
The trial also included a separate cohort of 18 patients who were previously treated or had symptomatic brain metastases. These patients received nivolumab alone and these results will not be discussed further.
Rates of complete (CR) and partial (PR) responses were also higher for patients receiving the combination. CR and PR were 26% and 26%, respectively, for patients who received the combination compared with 16% and 4%, respectively for patients who received nivolumab.
Best extracranial responses were also higher for patients receiving the combination (57% vs 29% for nivolumab alone).
Three-year intracranial PFS was 43% for patients on the combination and 15% for patients on nivolumab alone. Three-year OS was 49% for patients receiving the combination and 42% for patients receiving nivolumab alone.
Long reported that there were no unexpected toxicities and that the quality of life was maintained across the study groups.
Larkin reports receiving consultancy fees, honoraria, and/or research grants from Achilles Therapeutics, AstraZeneca, Boston Biomedicals, Bristol-Myers Squibb, Eisai, EUSA Pharma, Imugen, IOnctura, Ipsen, Kymab, Merck Serono, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Secarna, and Vitaccess. Long reported consulting with Aduro, Amgen, Array, Bristol-Meyers Squibb, Merck MSD, Novartis, Roche, and Pierre Fabre. Postow receives institutional support from BMS, Merck, RGenix, Infinity, AstraZeneca, Novartis, and Array BioPharma . He also receives consulting fees/honoraria from BMS, Merck, Array BioPharma, Novartis, Aduro, Incyte, and NewLink Genetics .
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.