1. Keller, Daniel M. PhD

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PHILADELPHIA-When treated in a Phase IB clinical trial with the anti-PD-1 monoclonal antibody MK-3475 (now known as lambrolizumab, made by Merck), patients with advanced and unresectable melanoma showed a 41 percent objective response rate and a nine percent complete response (CR) rate, with manageable toxicities. The overall survival rate at 12 months was 81 percent.

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Reporting for the first time these survival data here at the 10th International Meeting of the Society for Melanoma Research, Caroline Robert, MD, PhD, Chief of the Dermatology Service at Institut Gustave-Roussy in France, updated results presented at the 2013 American Society of Clinical Oncology Annual Meeting and published in the New England Journal of Medicine (2013;369:134-144).


The latest results show that median overall survival and the median duration of response had not yet been reached for any dose evaluated in this 135-patient study, with a median of 14.5 months of follow up for duration of response among the responders. The new results provide about five additional months of follow up for objective response rates beyond the results at the ASCO meeting.


Robert explained that PD-1 is a receptor molecule on T cells to which PD-L1 on tumor cells binds and blocks T cell function. MK-3475 blocks this interaction and allows cytotoxic T cells to lyse tumor cells. The drug has shown activity in multiple tumor types.


In this single-arm, multicenter, open-label trial, patients were treated intravenously with the drug at a dose of 10 mg/kg every two weeks or 10 or 2 mg/kg every three weeks for 12 weeks, at which time response was assessed by a blinded central review committee using RECIST (Response Evaluation Criteria in Solid Tumors) 1.1.


Patients with complete or partial responses or stable disease continued treatment. Those with progressive disease or unacceptable toxicity left the study. For entry into the study, prior ipilimumab treatment was allowed, and patients who did not receive ipilimumab were allowed to have up to two prior systemic therapies.


At baseline, participants had a mean age of 60.5 years, 22 percent had mutant-type BRAF, 30 percent had no previous regimens, 56 percent had one or two, and 14 percent had three or more prior regimens. Previous regimens included ipilimumab (36% of patients), chemotherapy (38%), a BRAF inhibitor (10%), and other immunotherapies (27%).


MK-3475 treatment was associated with a reduction in tumor size in 74 percent of evaluable patients. Among all three doses, which included 116 evaluable patients, the durable control rate was 61 percent. (Durable control was defined as confirmed responses plus stable disease.)


The response duration ranged from eight-plus weeks to 65-plus weeks, with 88 percent of patients having ongoing control. At the time of analysis, the median progression-free survival was 36 weeks.


Among the 49 patients with a partial or complete response, 43 continue to respond, Robert reported. Most responses occurred by week 12, including one complete response. Some partial responses occurred as late as 48 weeks and complete responses as late as 70 weeks.


Kaplan-Meier estimates of overall survival were similar among the three doses of MK-3475 and were also similar whether patients had or had not received ipilimumab previously.


Almost all the patients (82%) had treatment-related adverse effects, but only 13 percent had Grade 3/4 drug-related toxicities, and any single grade 3/4 adverse effects affected no more than one percent of patients. The most common adverse events were fatigue, pruritus, rash, diarrhea, arthralgia, vitiligo, headache, and nausea.


Robert said most of the adverse events were able to be successfully managed with treatment discontinuation, supportive care, and occasionally with glucocorticoids.


Potentially immune-related adverse events were pneumonitis (7% of patients), hypothyroidism (8%), and transaminase elevations, renal insufficiency, and colitis (each 1% or less). One 96-year-old man with pneumonia died from complications after bronchoscopy and biopsies.


Robert mentioned that a global, Phase III study is now comparing MK-3475 at 10 mg/kg every two weeks or every three weeks with ipilimumab at 3 mg/kg every three weeks as first- or second-line therapy for patients with unresectable or advanced melanoma.


The primary endpoints of that trial are progression-free and overall survival, with a secondary endpoint of overall response. Clinical development is also ongoing, she noted, for use of the drug in non-small-cell lung cancer, cancers of the breast, head and neck, stomach, and bladder, as well as for myeloma, myelodysplastic syndromes, and lymphoma.


In a news release, Merck said it plans to initiate combination therapy trials with the drug in melanoma and other cancers.