ASCO 2012 Report – Trametinib delays tumour growth and extends survival in certain melanoma patients

by Marybeth Burke – Median progression-free survival (PFS) was significantly greater in the trametinib group, 4.8 months, vs the chemotherapy group, 1.4 months, according to a study presented at the American Society of Oncology annual meeting in Chicago.

“This is the first in a new class of targeted drugs that could benefit patients with melanoma who have BRAF mutations.  The findings show that targeting the MEK molecular pathway is a viable strategy for treating many people with the disease,” said Caroline Robert, MD, PhD, Head of Dermatology at the Institute Gustave Roussy in Paris, France.

MEK Inhibitors

Dacarbazine and paclitaxel have been used to treat metastatic melanoma (MM) patients but with limited effect, according to the study abstract, #LBA8509.  “The MM landscape has recently changed with the approval of vemurafenib and ipilimumab in 2011, but secondary malignancies or other toxicities are of concern,” the abstract says.

Trametinib is a reversible, highly selective allosteric inhibitor of MEK 1/2 activation and kinase activity.  “Trametinib is the first MEK inhibitor to show statistically significant PFS, objective response rate (ORR) and overall survival (OS) benefit in a randomized trial compared to chemotherapy,” Dr Robert said.

“RAF inhibitors do not inhibit RAF signaling in tumours in which ERK activity is driven by RAS mutation or other upstream aberrations.  In fact, RAF inhibitors may accelerate the growth of such tumours.  For such tumours, MEK/ERK inhibitors represent the only option,” David B. Solit, MD, Memorial Sloan-Kettering Cancer Center, NY, said at the conference.

“Some BRAF mutant tumours that become resistant to RAF inhibitors may still be BRAF dependent and sensitive to MEK inhibitors,” he added.

“Discovery of BRAF inhibitors was an important breakthrough for patients with metastatic malignant melanoma.  Despite this advantage, almost all of these patients will develop resistance and many develop aggressive recurrence.  One has to ask, what is really next regarding treatment options?  Is it time for a MEK inhibitor to be available to the oncology community as part of its melanoma therapeutic armamentarium? … Absolutely,“ discussant Patricia Mucci LoRusso, D.O., Director, Experimental Therapeutics, Karmanos Cancer Institute, Detroit, MI, said at the conference.

“But we know there will be challenges especially with monotherapy approval.  We have encouragement in a tumour type with unmet need, these patients with NRAS mutant disease,” she added.

Patients were randomized 2:1 to T (2mg QD) or C (D or P).  Patients were stratified by baseline LDH level and prior C.  Patients in the C arm were allowed to crossover to receive T after confirmation of PD.  PFS and OS were compared using a stratified log-rank test.  The study was designed with ³99% power and a one-sided a=0.025 to detect 57% reduction in the risk of PD or death in patients treated with T vs C.

Between December 2011 and July 2011, 322 patients were randomized to T (n=214) or C (n=108); 273 patients were BRAFV600E mutation-positive with no prior brain mets.  HR for primary population for PFS by investigator was 0.44 (95%CI 0.31-0.64; p<0.0001) in favor of T with a median PFS of 4.8 months vs 1.4 month with C.  PFS benefit in favour of T was observed in ITT and confirmed by independent review.

The confirmed ORR was 24% with T and 7% with C.  OS benefit was consistent with ITT despite 51 patients crossing over from C to T.  The most frequent adverse events with T were skin rash, diarrhoea, oedema, hypertension, and fatigue.