Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS

Since it was double skirt day....I decided to go ahead and make it a double post day!!!!
To continue the subject of BRAFi -

From The coBRIM trial - August 2016 we learned - that when cobinmetinib and vemurafinib were combined, the median overall survival (OS) was 22.3 months and the median progression free survival (PFS) was 12.3 months.

From this discussion of BRAF/MEK and immunotherapy (Nov 2016)  we learned = that generally treatment that was a combination of a BRAF inhibitor and a MEK inhibitor could illicit a response rate of 48-59%, even as much as 70% with some combo's and PFS of 11-12 months.

Now there's this (I've included most of the report, you may read it yourself via the link at the bottom, my comments are in red!):

Update Confirms Benefit of Encorafenib/Binimetinib Combo in Melanoma  Jason Broderick – Thursday, May 11, 2017 From OncLive

The combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib reduced the risk of disease progression or death by 23% compared with single-agent encorafenib for patients with BRAF-mutant melanoma, according to findings from part 2 of the phase III COLUMBUS trial.  The median progression-free survival (PFS) for patients treated with the combination was 12.9 months compared with 9.2 months for patients receiving encorafenib alone.  Based on these data, along with previously reported findings from part 1 of the COLUMBUS trial, the developer of the combination, Array BioPharma, anticipates filing a new drug application with the FDA in June or July.

The COLUMBUS trial included 921 patients with locally advanced, unresectable, or metastatic BRAFV600-mutant melanoma. Prior treatment with immunotherapy was allowed. Those with untreated CNS lesions, leptomeningeal metastases, uveal melanoma, and mucosal melanoma were excluded from the trial. [Why the hell not???? You could put them in their own separate group, so as not to sully your results Array CEO person!!! And still give them access to the drug!]

In part 1 of the study, 577 patients were randomized in a 1:1:1 ratio to receive encorafenib plus binimetinib, encorafenib alone, or vemurafenib alone. In the combination arm, encorafenib was administered at 450 mg daily and binimetinib was administered at 45 mg twice daily. Single-agent encorafenib was given at 300 mg daily. Vemurafenib was administered at 960 mg twice daily.  Part 2 of the study randomized 344 patients in a 3:1 ratio to receive encorafenib plus binimetinib at 45 mg twice daily or encorafenib alone. Encorafenib was given at 300 mg daily.  “Part 2 was designed specifically to assess the contribution of binimetinib to the combination of binimetinib and encorafenib by reducing the dose of encorafenib to 300 mg in the combination arm to allow for a comparison of equal doses across arms,” Array wrote in a press release.
In Part 1 of the study, the median PFS was 14.9 months with the combination of encorafenib and binimetinib compared with 7.3 months for vemurafenib alone. The improvement in PFS represented a 46% reduction in the risk of progression or death. [That's good, but of course we have learned never to give vemurafenib, a BRAF inhibitor without a MEK inhibitor!!! So that's a bit of a false comparison!]
When single-agent encorafenib was compared with the combination arm the difference between the groups did not reach statistical significance. However, median PFS with encorafenib was statistically superior to vemurafenib. Findings for overall survival (OS) were not yet available. [hmmmmmm.....]

The objective response rate (ORR) with the combination was 63% versus 40% with vemurafenib. [Again...not comparing apples to apples...we KNOW that response rates are better with a BRAF/MEK combo!!!] With single-agent encorafenib, the ORR was 51%. [This fact can at least be compared to single agent vemurafenib response rate of 40%.]The complete response rate was 8% with the combination versus 5% and 6% with encorafenib and vemurafenib, respectively. The median duration of response was 16.6 months with the combination versus 14.9 months with encorafenib and 12.5 months with vemurafenib.

By local review, median PFS with the combination was 14.8 versus 7.3 months with vemurafenib. The ORRs by local review were 75% for the combination versus 49% and 58% for vemurafenib and encorafenib monotherapy, respectively.  In this assessment, the combination was superior to single-agent encorafenib. The median PFS with encorafenib was 9.2 months, which was also superior to single-agent vemurafenib.

All-grade AEs with the most variability between the two arms for the combination, single-agent encorafenib, and vemurafenib, respectively, were arthralgia (26%, 44%, 45%), pyrexia (18%, 15%, 28%), alopecia (14%, 56%, 37%), hyperkeratosis (14%, 38%, 29%), dry skin (14%, 30%, 23%), rash (14%, 21%, 29%), palmoplantar keratoderma (9%, 26%, 16%), and palmar-plantar erythrodysesthesia syndrome (7%, 51%, 14%). All-grade AEs of special interest with the combination included rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%), and photosensitivity (5%).

Grade 3/4 AEs were experienced by 58% of patients treated with the combination versus 66% and 63% with encorafenib and vemurafenib, respectively. [As previously demonstrated, side effects were DECREASED with a BRAF/MEK combo.]  The most common grade 3/4 AEs with the combination were gamma-glutamyltransferase, increased blood creatine phosphokinase, and hypertension. Time to first grade 3/4 AE was long with the combination, at 2.5 months versus 0.4 months for encorafenib and 1.3 months for vemurafenib.

In March, Array withdrew its FDA new drug application for single-agent binimetinib as a treatment for patients with NRAS-mutant advanced melanoma, based on feedback from the FDA during a preplanned review meeting.  [So I gather they are going to market this only for BRAF positive folks, rather than NRAS mutant.]  The application for binimetinib was based on data from the phase III NEMO study, which was presented at the 2016 ASCO Annual Meeting. In the open-label study, PFS with binimetinib was 2.8 versus 1.5 months with dacarbazine, representing a 38% reduction in the risk of progression or death; however, OS was not improved with the MEK inhibitor. [Pretty sad if you can't beat dacarbazine!]

Link to article:  http://www.onclive.com/web-exclusives/update-confirms-benefit-of-encorafenibbinimetinib-combo-in-melanoma

Okay.  My synopsis is this:  Generally, prior studies of BRAF/MEK combos demonstrate about a 12 month PFS.  This combo showed a PFS of 14.9 months.  Objective response rate was 63% with the comb0.  There was an ORR of 51% to encorafenib alone.  Objective response rates to BRAF/MEK combo's in other studies have ranged from 48-70%, depending.  OS data for encorafenib/binimetinib has not yet been reported.  OS in most other BRAF/MEK combo's is around 2 years.  The combo discussed here demonstrated fewer side effects than when the BRAFi component was used alone....which is consistent with other reports using a BRAF/MEK combo vs BRAFi alone.

PFS of 14.9 months is better than 12.  Wish they had allowed testing in a greater swath of patients. (But I say that about most all trials!!!)  We'll have to see what the OS data shows and if these current figures hold in future cohorts.  Hang tough ratties.  You will save us all. - c