MK-3475 to be Evaluated Across Wide Range of Cancers

As part of the new collaborations, Merck will begin several clinical trials. In these phase I/II studies, MK-3475 will be explored in combination with axitinib in renal cell carcinoma, talimogene laherparepvec (T-VEC) in previously untreated advanced melanoma, the immunotherapy INCB24360 in previously treated metastatic recurrent non-small cell lung cancer (NSCLC), and PF-2566 in multiple cancer types. Separate from these collaborations, Merck announced that the safety and efficacy of MK-3475 monotherapy would be evaluated in a phase I “signal finding” study in 20 PD-L1-positive solid tumor types not previously studied.

“Merck clinical scientists intend to explore the potential of our PD-1 inhibitor across a wide range of cancers, both as monotherapy and in combination,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement. “These new collaborations with Amgen, Incyte, and Pfizer underscore our shared determination to evaluate treatment regimens with the potential to provide meaningful benefits to patients suffering from cancer.”

The development of MK-3475 (formerly lambrolizumab) has been eventful over the past year, highlighted by a Breakthrough Therapy designation for the treatment of patients with advanced melanoma in April 2013.

In October 2013, at the 15th World Conference on Lung Cancer, interim data were presented from the phase Ib expansion of the PN 001 trial. In this part of the trial, MK-3475 was administered at 10mg/kg every 3 weeks in 38 patients with refractory NSCLC.

The median overall survival (OS) was 51 weeks. Median progression-free survival (PFS) was 9.1 weeks (95% CI, 8.3-17.4) and 9.7 weeks (95% CI, 7.6-17), according to investigator assessment and independent review, respectively. Preliminary objective response rates (ORR) were observed in 24% of patients as measured using investigator-assessed immune related response criteria and 21% of patients by RECIST 1.1.

The most common drug-related adverse events were fatigue (16%), rash (16%), pruritus (16%), and diarrhea grade 1 or 2 (13%). One case of a drug-related grade 3 pulmonary edema was observed.

“Based on these preliminary data and other research, we believe that PD-L1 expression has the potential to be a useful predictor of response to MK-3475 in certain cancers,” Eric H. Rubin, MD, vice president, Oncology, Merck Research Laboratories, said in a statement at the time of the presentation of interim data. “We look forward to further data from this and other studies to help us to understand the potential role of MK-3475 in lung cancer, and of PD-L1 as a biomarker.”

Results from the melanoma portion of the PN 001 trial were presented in November 2013, at the 10th International Congress of the Society for Melanoma Research.

In this portion of the trial, 135 patients with advanced melanoma were treated with MK-3475 monotherapy at 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks. An OS rate of 81% at one year was observed.

This analysis showed an ORR of 41%, including complete responses in 9% of patients, as evaluated by a blinded central review committee using RECIST 1.1 criteria. Previously reported ORR with all doses was 38%.

All grade drug-related adverse events included fatigue (37%), pruritus (26%), rash (22%), diarrhea (21%), arthralgia (17%), vitiligo (14%), headache (13%), nausea (12%), asthenia (11%), myalgia (11%), and AST increase (10%). Grade 3/4 drug-related adverse events observed in more than one patient were AST increase, fatigue, rash, and renal failure (two reports of each).

“New agents are needed for patients with advanced melanoma,” Caroline Robert, MD, head of Dermatology at Gustave Roussy, Cancer Campus, Grand Paris, said in a statement at the time of the presentation of results. “I am excited by the results seen for MK-3475 to date as a single agent and believe these findings support further study both as a monotherapy and in combination in various solid tumors.”

MK-3475 is currently being evaluated in 13 clinical trials across more than 30 types of cancer including bladder, colorectal, gastric, head and neck, melanoma, non-small and small cell lung, renal, pancreatic, prostate, triple negative and estrogen-receptor positive HER2-negative breast, gynecologic, and hematologic malignancies.