BRAF/MEK combo ~ vemurafenib with cobimetinib

Combination of vemurafenib and cobimetinib in patients with advanced BRAF (V600)-mutated melanoma: a phase 1b study.
Ribas, et al.  Lacet Oncol 2014, July 15 [epub ahead of print]

My synopsis:
The addition of a MEK inhibitor to a BRAF inhibitor has been found to enhance effects on tumors, delay resistance, and provide fewer side effects in patients. (As demonstrated in the CombiDT studies where the BRAFi dabrafinib was combined with the MEK inhibitor trametinib.)  Here researchers combined the BRAFi vemurafenib with the MEK inhibitor cobimetinib, the roche/genentech MEKi.

Patients had advanced melanoma, were positive for the BRAF (V600) mutation, and had either recently progressed on vermurafenib (n=66) or had never been given a BRAF inhibitor (n=63).  They were given vemurafenib 720mg or 960mg twice daily and cobimetinib 60, 80, or 100mg once a day for either 14 days on and 14 days off, 21 days on and 7 days off, or continuously.  Trial number:  NCT01271803.

129 patients were treated at ten dosing regimens. Dose limiting effects arose in 4 patients.  All were on a 960mg bid dose with differing cobimetinib doses. AEs = Grade 3 fatigue, Grade 3 prolonged QT (a heart problem), Grade 3 stomatitis, arthralgia and myalgia.  Maximum tolerated dose turned out to be:  vemurafenib 960mg twice a day with cobimetinib 60mg (21/7)  Across all doses side effects = diarrhea (64%), acne like rash (60%), liver enzyme abnormalities (50%), fatigue (48%), nausea (45%), photosensitivity (40%).  The most common Grade 3 reactions were:  squamous cell carcinoma (9%), increased alkaline phosphatase (9%), and anemia (7%).

Confirmed objective responses were recorded in 10 (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2.8 months.  Confirmed objective responses were recorded in 55 (87%) of 63 patients who had never received BRAFi, including 6 (10%) who had a complete response, median progression free survival was 13.7 months.

My thoughts:

• The combination of vemurafenib with cobimetinib did better than results of prior studies in which vemurafenib was given alone.
• Patients who were naive to vemurafenib responded better than those who had failed on it.
• Both of these facts are being demonstrated with other meds (like the immunmodulators) in other studies.
• Meaning, studies are showing that treatment naive patients respond better than patients who have already taken the drug...though some patients can still get a response.   And, when meds are combined (like in the ipi/nivo trials) there is a greater response, but also greater side effects.
• It seems to me the researcher in my LAG3 post is really onto something when he talks about the issues surrounding getting the immune system to "RE-fire" once it has already mounted a response.
• Also...though this may be premature....according to this data, the vemurafenib/cobimetinib combo did better, with a median progression free survival of 13.7 months, when compared to the dabrafenib/trametinib combo, with a progression free survival of only 9.3 months.  Perhaps they did not have as many BRAF naive patients, I'm not sure.  See slide and prior posts below:

Jan 2014 dabrafenib/trametinib combo FDA approved

Feb 2014 BRAF info and results from CombiDT

June 2014 BRAF studies from ASCO

Good luck to all my ratties!!! - c