Array/Novartis’ Binimetinib Expected to Best Chemotherapy in Phase III Trial Despite Protocol Change

• Enrollment criteria expanded mid-trial to reflect shifting treatment landscape

• Inhibiting MEK elicits enthusiasm for NRAS patients considering lack of options

• Chemo comparator, PFS as primary endpoint will suffice for approvals if results positive

Array BioPharma (NASDAQ:ARRY) and Novartis (VTX:NOVN) can expect MEK inhibitor binimetinib (MEK162) to meet the primary endpoint in a Phase III trial in NRAS Q61-mutant melanoma, experts said. Yet, they noted, binimetinib will not make as big of a difference to this patient population as BRAF inhibitors did for BRAF-positive patients.

Despite protocol amendments to reflect the rapidly changing treatment landscape and include treatment-experienced patients, experts said the trial (NCT01763164) is designed well enough to meet the progression-free survival (PFS) primary endpoint compared to chemotherapy dacarbazine.

Though binimetinib’s data so far in NRAS patients does not seem to be as good as efficacy results seen with BRAF inhibitors for the BRAF population, MEK inhibition is a good enough option. NRAS-mutant melanoma patients represent less than 20% of advanced melanoma patients, as the majority harbor BRAF mutations, and this smaller population represents a significant unmet need for targeted therapy, experts agreed.

Much of the optimism for the study showing a PFS benefit is based on the response rate seen in a Phase II trial compared to the known response rates of chemotherapy in the NRAS population, experts said.

While a chemo comparator is not the best for newly diagnosed patients, it is acceptable for previously treated patients and along with PFS used as the primary endpoint, could be sufficient for approval.

The trial was initiated in July 2013, and primary outcome data will be collected December 2014, according ClinicalTrials.gov.

The company declined to comment.

Trial design valid despite protocol amendments

The global Phase III trial dubbed NEMO pits binimetinib against dacarbazine in NRAS patients with a Q61 positive mutation. This mutation can be compared to the V600 mutation among BRAF patients, in that it is the most common mutation among the NRAS group, experts said. The Q61 mutation was tested locally but confirmed with Novartis’ in-house diagnostic at a central lab, said investigator Dr Christian Blank, assistant professor, Department of Medical Oncology, Netherlands Cancer Institute.

The trial was initiated in July 2013, and the protocol was amended due to a rapidly changing regulatory landscape, noted Blank. Bristol-Myers Squibb’s (NYSE:BMY) immunotherapy Yervoy (ipilimumab), approved in the US in March 2011, is the preferred first-line treatment for many NRAS patients. While the drug was also approved in the EU in 2011 as a second-line treatment, it was expanded into the first-line setting in November 2013. The EU expansion prompted a change in NEMO’s protocol to include both treatment-naive and treatment-experienced patients, said Dr Paolo Ascierto, who is on the trial steering committee and is vice-director,Unit of Medical Oncology and Innovative Therapy, National Tumor Institute Fondazione G. Pascale, Naples, Italy.

The protocol was altered to more closely mirror clinical practice, in which binimetinib would likely be used after Yervoy failure, said Blank. Patients were randomized 2:1 to the binimetinib or dacarbazine arms and are stratified according to whether they are immunotherapy-naïve or not.

The trial is thus designed to capture differing response rates between treatment-naïve and treatment-experienced patients, experts added. Previously treated patients will likely see worse outcomes because they are further along in disease progression, said Dr Alexander Spira, oncologist, Virginia Cancer Specialists, director, VCS Research Program. However, Blank said, the response rates might not be significantly different between these two groups.

Experts were positive on the prospect of superior PFS for the treatment arm as a whole compared to the chemo arm. However, secondary endpoints including OS may be influenced by the immunotherapy patients receive after trial completion, said Blank, and Dr David Minor, associate director, melanoma research, California Pacific Melanoma Center, San Francisco.

While OS may be confounded by post-trial treatments, the US-based trial investigator noted there are few options for NRAS patients after immunotherapy or MEK inhibition, and therefore OS will still be a meaningful endpoint.

MEK inhibition for NRAS a good strategy

Based on the results of the Phase II study in 71 patients with either BRAF or NRAS mutations, the concept of using MEK inhibitor as a targeted therapy in NRAS patients is fairly promising, said Dr Ryan Sullivan, oncologist, Massachusetts General Hospital Cancer Center, Boston.

The Phase II trial demonstrated a 20% partial response rate for separate NRAS and BRAF groups at 3.3 months [Lancet Oncol. 2013 Mar ;14(3):249-56. doi: 10.1016/S1470- 2045(13)70024-X. Epub 2013 Feb 13]. None of the patients showed complete responses at the time the data was collected.

Despite the similar response rates for the two subgroups, a successful Phase III trial in 393 NRAS-only patients would be the first demonstrated effective targeted therapy for the minority group, experts agreed.

A 20% response rate is going to be fairly consistent moving into the Phase III trial, said Dr Robert Conry, associate professor, medicine, University of Alabama at Birmingham. The MEK inhibitor binimetinib in an NRAS patient does not appear to be as much of a home run as a BRAF inhibitor in a BRAF patient but still represents a promising enough level of activity to bode well for Phase III, said Minor. It is hard to predict results with certainty, but the Phase III trial is designed well enough to show similar outcomes of the approximate four-month PFS and 20% response rate that was observed in Phase II, Sullivan said.

Secondary end points in the trial include safety as well as impact on health-related quality of life and use of healthcare resources.

If you consider that, historically, PFS is 1.7 months with dacarbazine, and PFS in the Phase II trial reached about 4 months, it is likely binimetinib will yield superior PFS, Ascierto said. Based on Phase II results, of which Ascierto was the lead author, the 45mg twice-daily dose used in Phase III represents the best balance of efficacy and safety, he noted. Toxicity does not appear to be a serious concern, experts noted.

While RAS mutations are present in a number of cancers, they are the most common in melanoma, said Dr Wilson Miller, deputy director, Segal Cancer Center, McGill University, Montreal, Canada. Binimetinib is likely to show benefit for this population as the first targeted single agent, he added.

Chemo comparator, PFS will suffice for approval

When the Phase III trial was originally designed, Yervoy was a second-line treatment in Europe, so to avoid any possible treatment that might confound results after disease progression, PFS was chosen as the primary endpoint, said Ascierto. Normally, overall survival (OS) would be preferred, but PFS will be a clear indicator of efficacy, he continued. Blank agreed PFS will be a good indicator.

The inclusion of treatment-naïve and treatment-experienced patients does not negatively impact the trial’s potential to show a significant PFS benefit, experts said.

Even though recruitment might be difficult with a chemotherapy comparator arm, it is still viewed as a valid comparator in terms of regulatory approvals, noted Miller.

Enrollment has not been a problem since the protocol change, Ascierto noted. And now, considering the recent clinical development and US market entry of Merck’s (NYSE:MRK) antiPD1 immunotherapy Keytruda (pembrolizumab), there are an increasing number of patients who have received two prior immunotherapies.

Novartis has a market cap of of CHF 240.1bn (EUR 198.9bn), and Array has a market cap of USD 514.2m.

November 3, 2014

Sony Salzman

Reporter, BioPharma Insight

Sony previously worked as the Managing Editor for MedTechBoston.com, a publication covering Boston’s medical innovation landscape. She holds a master’s degree in Science Journalism from Boston University and has won awards in both narrative writing and radio journalism. Additionally, Sony worked as a reporter for MassDevice. com, a wire service covering the medical device industry, and as a research intern for NOVA, a PBS program produced by Boston’s WBUR. She also was a freelance journalist and her stories have been featured by organizations such as the Boston Globe, WBUR (Boston’s NPR news station) and TechCrunch.com.