Findings from a large phase I study of 411 patients with advanced melanoma show that the PD-1 (programmed death-1 or programmed cell death-1/PCD-1) targeting antibody MK-3475 presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) held May 30, June 3, 2014 in Chicago, Ill, shows that the new trial drug yields long-term responses in a high percentage of patients.
Researchers have found that a majority of tumors are able to evade the immune-system through a mechanism that exploits the PD-1 inhibitory checkpoint protein. MK-3475, an investigational drug being developed by Merck/MSD, is highly selective anti-PD-1 immunotherapy designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein. By blocking PD-1, MK-3475 enables activation of the immune system’s T-cells that target cancer by essentially releasing a brake on the immune system.
In the study, which was supported by Merck/MSD, the one-year overall survival was 69% across all patient subgroups, and responses were ongoing in 88% of patients at analysis, after a median follow-up of 12 months. The researchers reported that responses occurred across all dose regimens and in various subgroups of patients, including patients whose disease progressed following therapy with ipilimumab (MDX-010, MDX-101, marketed asYervoy?; Bristol-Myers Squibb Company (BMS), Princeton, NJ 08543 U.S.A.), for whom there are currently no effective treatment options.
This large phase I clinical trial demonstrates continued excitement for anti PD-1 therapy… with … long-lasting clinical responses in the majority of patients, and impressive overall survival with low toxicity…
Biggest Phase I Trial
?This is probably the biggest phase I trial ever conducted in oncology. We were excited to see that MK-3475 was effective in previously untreated patients as well as in those who had multiple prior therapies, including ipilimumab,? noted lead study author Antoni Ribas, MD, PhD, a professor of medicine at the David Geffen School of Medicine at the University of California in Los Angeles, CA,and the recipient of a 2000 Conquer Cancer Foundation of ASCO Career Development Award.?These are early data, but they tell us we are on to something really important.?
Enrolled patients
The study enrolled 221 patients with prior ipilimumab treatment and 190 patients who had not previously received ipilimumab. All patients had advanced melanoma that had spread to the skin, lungs, or other major organs. Three different MK-3475 dose schedules as a single agent were tested.
Overall, 34% of patients experienced tumor response, as assessed by Independent Review, including 40% of patients not previously treated with ipilimumab and 28% of patients whose disease progressed on prior ipilimumab. Responses were durable with 88% ongoing at the time of analysis. Activity was observed across all dose levels and patient subgroups, irrespective of prior ipilimumab therapy, performance status, LDH levels, BRAF mutation status, tumor stage, and number and type of prior therapies. The estimated one-year survival rate was 69%, and median overall survival duration was not reached. The estimated one-year survival rate was 74% in patients not previously treated with ipilimumab and 65% in patients who received prior ipilimumab therapy. Overall, 8% of patients experienced serious treatment-related side effects, but only four percent discontinued treatment due to a drug-related side effect.
Breakthrough Therapy designation
The FDA had previously granted a breakthrough therapy designation to MK-3475 for unresectable, or metastatic, melanoma. In May 2014, the FDA granted MK-3475 a priority review designation under its Accelerated Approval program. Ongoing randomized controlled studies are assessing the efficacy and safety of MK-3475 in advanced melanoma patients not previously treated with ipilimumab and those who progressed on or after ipilimumab. Studies in an adjuvant setting are planned.
Impressive OS and Low Toxicity
“We?re seeing that MK-3475 results in long-lasting clinical responses in the majority of patients, and impressive overall survival with low toxicity,? noted Steven O?Day, MD, ASCO Expert and a clinical associate professor of medicine at the University of Southern California, Keck School of Medicine. ?Importantly, it?s effective regardless of prior ipilimumab treatment. Anti PD-1 as a single agent is a major breakthrough and improves on the initial success of ipilimumab in metastatic melanoma.?
An expanded access program for MK-3475 is now available for eligible patients with advanced melanoma who have been previously treated with ipilimumab and, if indicated, a BRAF inhibitor.
For more information:
Ribas A, Hodi FS, Kefford R, Hamid O, Daud A, Wolchok JD, Hwu WJ. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). Oral Abstract Session. ASCO 2014 Annual Meeting. Monday June 2, 3:00 PM to 6:00 PM. Abstract No: LBA9000^ Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr LBA9000^) [Abstract]
Photo: Antoni Ribas at the American Society of Clinical Oncology Annual Meeting, Monday June 2, 2014. Photo Courtesy: ? ASCO/Zach Boyden-Holmes 2014.
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