Roxanne Nelson

September 30, 2012

September 30, 2012 (Vienna, Austria) — A preliminary study found that investigational MEK inhibitor GDC-0973 (Exelixis and Genentech) and vemurafenib (Zelboraf, Hoffmann-La Roche) can be delivered safely to patients with metastatic melanoma. In addition, tumor reduction was noted in some patients.

Dr. Rene Gonzalez

The study was not designed to evaluate efficacy, commented study author Rene Gonzalez, MD, director of the Melanoma Research Clinic at the University of Colorado Cancer Center, Denver. However, he pointed out that virtually all of the vemurafenib-naïve patients had some evidence of tumor shrinkage, but further follow-up is needed to evaluate the response rates.

"GDC-0973 can be combined and delivered safely with vemurafenib, adverse events were tolerable and manageable, and the preliminary antitumor activity is encouraging," said Dr. Gonzalez, who presented the findings here at the 2012 European Society for Medical Oncology (ESMO) Congress.

BRAF inhibitors such as vemurafenib can often rapidly stop and reverse tumor growth in patients with melanomas that contain the V600E mutation in BRAF. However, the response is usually temporary in most cases, and tumor growth resumes as resistance develops to these agents.

"Once the patients on BRAF inhibitors start to progress, they progress very quickly, so the fact that any of these patients responded is really remarkable," said Dr. Gonzalez.

The BRAF V600 is the most common point mutation in melanoma; it is present in approximately 50% of cases. Previous research suggests that drug resistance to BRAF inhibitors develops because the mitogen-activated protein kinase (MAPK) pathway is reactivated via the activation of MEK.

Study Details

GDC-0973 is an orally bioavailable small-molecule inhibitor of MAP2K, which specifically binds to and inhibits the catalytic activity of MEK. This pathway mediates signaling downstream of growth factor receptors, and studies show that it is prominently activated in a wide variety of human tumors.

Preclinical models demonstrate that the combined inhibition of BRAF and MEK can delay the acquisition of resistance, as compared with BRAF inhibitor monotherapy, note the authors. The BRAFV600 Mutated Melanoma (BRIM7) phase IB trial was designed to evaluate the safety and tolerability of combination BRAF and MEK inhibition with vemurafenib plus GDC-0973.

As of July 6, 2012, 70 patients had received treatment in this trial. All participants had BRAF V600–mutated unresectable or metastatic melanoma and were either naïve to vemurafenib or had disease progression while on vemurafenib. The majority (74.3%) had stage IV M1c melanoma at the time of their enrollment, and 54.3% had disease progression following prior treatment with vemurafenib. To date, patients have undergone a median of 3 prior treatment cycles.

The study consisted of dose-escalation and expansion stages, and all participants received vemurafenib 720 mg or 960 mg twice a day continuously. In addition, GDC-0973 was administered at doses of 60 mg, 80 mg, or 100 mg every day for 14 days (on/14 days and 14 off (14/14); 21 days on/7 days off (21/7); or continuously.

The primary endpoints of the study were the maximum tolerated dose, dose-limiting toxicity, and safety.

Dr. Gonzalez explained that the dose escalation stage of the trial consisted of 10 dosing cohorts that included from 3 to 6 patients each; 3 different dosing schedules were evaluated for GDC-0973. The cohorts that met the protocol-specified criteria for safety were then expanded to include up to 20 patients.

Treatment Well Tolerated

Of the 10 cohorts, 6 have thus far met the protocol-specified criteria for safety. Grade 3 QT interval prolongation, which was dose limiting, was observed in 1 out of 6 patients in the dose escalation stage, receiving 960 mg of vemurafenib and 60 mg of GDC-0973 on a 21/7 day schedule.

Two of the cohorts receiving 60 mg of GDC-0973 on a 21/7 day schedule with vemurafenib at 720 mg and 960 mg were selected for expansion.

The most common adverse events attributed to either drug were non-acneiform rash (52.9%; 7.1% grade 3 or 4), diarrhea (51.4%; 5.7%), photosensitivity/sunburn (31.4%; 0%), fatigue (30.0%; 1.4%), and nausea (28.6%; 1.4%). Other events that were attributed to either vemurafenib or GDC-0973 included creatinine phosphokinase elevation (20.0%; 4.3%), liver function test elevation (20.0%; 4.3%), arthralgia (12.9%; 1.4%), serous choreoretinopathy (4.3%; 0%), and cutaneous squamous cell carcinoma (1.4%; 1.4%).

Temporary interruptions in vemurafenib were reported in 24.3% of patients, 21.4% for GDC-0973 and 8.6% of patients for the combination of both agents.

"It seems that the combination is less toxic than the drugs given individually," said Dr. Gonzalez. "Only 1 patient on vemurafenib permanently discontinued treatment due to adverse events, and none did using the combination."

He added that phase III trials are planned for vemurafenib and GDC-0973.

Reinhard Dummer, MD, PhD, a professor of dermatology at the University Hospital of Zürich, Switzerland, pointed out that these new drug combinations that are aimed at preventing drug resistance are a very exciting development because they are science based.

Resistance patterns are seen with kinases, but "we now know that additional receptors are able to restore the pathways," said Dr. Dummer, who was the article's discussant. "Melanoma was ignored for a very long time because we had no idea how to address it."

"I am fully convinced that resistance mechanism will vary from patient to patient, and we are not able to predict it at treatment initiation," he added, noting that molecular work-ups can be done before the start of therapy to better predict resistance.

Dr. Gonzalez has disclosed relationships with Roche, Genentech, and GlaxoSmithKline.

2012 European Society for Medical Oncology (ESMO) Congress. Presented September 29, 2012: Abstract 28LBA.

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