BARCELONA, Spain – One in two patients with metastatic melanoma treated with the combination of ipilimumab ( Yervoy Bristol-Myers Squibb) and nivolumab ( Opdivo Bristol-Squ. still alive after 5 years, updated results from the longest dual immunotherapy trial show.
"This is a significant improvement on what we have seen historically," says Principal Investigator James Larkin, Ph.D., FRCP
"Ten years ago, the 5-year melanoma survival rate was about 5%. With ipilimumab monotherapy, which has been in use for about 10 years, about 20% of patients are long-term survivors, and the rest live only 6 to 9 months, "he added.
Larkin presented the new survival data coming from the CheckMate 067 study, here at the annual meeting of the European Society of Medical Oncology, and the results were published simultaneously in New England Journal of Medicine .
Melanoma expert Michael Postow, MD, of the Kettering Sloan Memorial Cancer Center in New York, agreed that the data is history.
"This study provides the longest follow-up ̵
He added that the combination has a well-established place in clinical practice not only for patients with melanoma, but also for patients with renal cell carcinoma and certain types of colon cancer.
A change in the healing landscape of advanced melanoma
Postow explained that the appearance of ipilimumab introduced the field of oncology's incredible immunity capabilities. Then the blockade of the Nivolumab and pembrolizumab checkpoints showed that the results could be even better – and with fewer side effects than with ipilimumab.
"Now the combination of levelumab and ipilimumab has ushered in a new era of combination immunotherapy, further enhancing its beneficial results," he said, adding that the combination was "fantastic progress" for patients with melanoma and other cancers.  "Now we have to find ways to identify fy which patients benefit most, and if new ways of delivering levelumab and ipilimumab retain antitumor efficacy with fewer side effects," explained Postow.
"The combination is not for everyone patient with melanoma, t her patients should be appropriately selected for the potential for side effects, "said Postow. But he added that the combination of levelumab and ipilimumab is more potent than levelumab or pembrolizumab ( Keytruda Merk), with only a higher response rate and more side effects.
"If patients are suitable for both the combination of levelumab and ipilimumab, as well as levelumab or pembrolizumab alone, both approaches should be discussed with patients and the decision between them should be weighed carefully," he said.
Larkin agreed, noting that there is currently no method of predicting which patients are most likely to benefit from combination immunotherapy. "Deciding which treatment to administer is a matter for doctors to discuss with individual patients and their families," he says.
"Both drugs together definitely play a role in the treatment of metastatic melanoma and will be the choice for some patients. For others, the solution may be to administer the drugs in sequence," says Larkin.
CheckMate 067 results
CheckMate 067 randomly assigned 945 patients receiving the combination of ipilimumab and levelumab (n = 314), levelumab (n = 316), or ipilimumab (n = 315).
The 5-year overall survival was 52% for the combination of levelumab and ipilimumab, 44% for levelumab and 26% for ipilimumab.
Progression – Free survival at 5 years of mirrored OS data: 36% for combination, 29% for levelumab only, and 8% for ipilimumab.
Larkin reports that objective response rates (ORRs) were observed in 58% of patients receiving the combination, 45% of patients receiving self-levelumab and 19% of ipilimumab alone. "As long as the ORR remains stable, the frequency of complete responses improves over the 3-year, 4-year and 5-year analyzes," he says.
Fewer patients in the combination received follow-up therapies (46% for the combination, 59% for levelumab alone and 75% for ipilimumab)
"Interval without treatment (TFI) is an important outcome for patients," says Larkin . In patients discontinuing therapy, TFI was the longest in patients receiving the combination (18.1 months versus 1.9 months with levelumab alone and 1.8 months with ipilimumab alone).
Three-quarters of patients (74%) who received the combination were alive and untreated at the end of 5 years, significantly higher than 58% of patients receiving alone levelumab and 45% of patients receiving ipilimumab alone
After 5 years, no new treatment-related safety or death signals have been reported, Larkin reported.
Activity against brain metastases
Postow commented that the combination of levelumab and ipilimumab is the preferred therapy for many patients with advanced melanoma, especially those with brain metastases.
On this subject, Georgina V. Long, MD, of the Melanoma Institute of Australia in Sydney, reported in another presentation that patients receiving this combination had the best intracranial response (51% for the combination and 20% only for levelumab), as well as better survival rates.
Long's data are from an independent ABC (Anti-PD-1 Brain Collaboration) study group comparing the combination of ipilimumab and levelumab with levelumab alone in patients with brain metastases (summary 1311O).
ABC patients from Australia and New Zealand enrolled 60 patients who were not treated for asymptomatic brain metastases to receive the combination of ipilimumab and levelumab (n = 35) or single levelumab (n = 25).
The trial also included a separate group of 18 patients who had previously been treated or had symptomatic brain metastases. These patients received self-levelumab alone and these results will not be discussed further.
The full (CR) and partial (PR) response rates are also higher in patients receiving the combination. CR and PR were 26% and 26% respectively for patients receiving the combination with 16% and 4% respectively for patients receiving levelumab.
The best extracranial responses were also higher in patients receiving the combination (57% versus 29% for levelumab alone)
The three-year intracranial PFS was 43% for patients in combination and 15% for patients only on levelbl. The three-year OS was 49% for patients receiving the combination and 42% for patients receiving self-levelumab.
Long reports that there are no unexpected toxic substances and that quality of life is maintained in the study groups.
Larkin announces receipt of consultancy fees, fees and / or research grants from Achilles Therapeutics, AstraZeneca, Boston Biomedicals, Bristol-Myers Squibb, Eisai, EUSA Pharma, Imugen, IOnctym, Ipsen, Merpsen, Merpsen Serono, MSD, Nectar Novartis, Pierre Fabre, Pfizer, Roche / Genentech, Secarna and Vitaccess. Consultations with Aduro, Amgen, Massive, Bristol-Myers Skib, Merck MSD, Novartis, Roche and Pierre Fabre have long been reported. Postow received institutional support from BMS, Merck, RGenix, Infinity, AstraZeneca, Novartis, and Array BioPharma . He also receives consulting fees / fees from BMS, Merck, Array BioPharma, Novartis, Aduro, Incyte, and NewLink Genetics .
European Society of Medical Oncology (ESMO) 2019 Annual Meeting: Summary LBA 68_PR (CheckMate 067), Summary 1311O. Accessed September 28, 2019
New England Journal of Medicine . Published online September 28, 2019. Abstract
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