coBRIM trial (cobimetinib wih vemurafenib) - updated results

I reported on this combo first back in 2014:  BRAF/MEK combo: vemurafenib with cobimetinib

Then this also in 2014:  Combination therapies for melanoma (with some cool graphs)

Here in 2015 with the FDA approval:  Two new FDA approvals for the treatment of melanoma

 

And this was out of ASCO this year: ASCO 2016: cobimetinib and vermurafenib

Here is the latest update:

Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.  Ascierto, McArthur, Dréno, Chang, Ribas, et al. Lancet Oncol. 2016 Jul 29.  

The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF^V600-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies.  In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAFV600 mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants.  Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months, the updated investigator-assessed median progression-free survival was 12·3 months for cobimetinib and vemurafenib versus 7·2 months for placebo and vemurafenib. The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months for cobimetinib and vemurafenib versus 17·4 months for placebo and vemurafenib. The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [less than 1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group.  These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF^V600-mutant melanoma.

And as one would assume....progression free survival as well as median overall survival was greater when vemurafenib was combined with cobimetinib than when it was given with a placebo.  Perhaps a little surprising was the fact that side effects were higher in those receiving the cobimetinib and vemurafenib combo, as the BRAFi/MEKi combo's are generally shown to have greater efficacy than BRAFi given alone, but also produce FEWER side effects in previous studies.

Thanks, ratties. - c

Alkaline diets and "complementary" treatments??? Be VERY careful! They may cause an increased risk of progression in melanoma!!!

While it makes complete sense that we are all searching for something...anything...to get rid of our melanoma and/or make our treatments more effective...even "benign" "natural" supplements can cause problems!!!  I published this in 2016:  Combining alternative and conventional treatments for melanoma....a risky business!

Now, there's this:

The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study. Knapen, Koornstra, Driessen, et al. Target Oncol. 2018 Apr 11. 

The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown.

To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs.

A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012-March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital. Cox regression analysis was used to estimate the risk of progression with full-dose (n = 64) versus reduced-dose vemurafenib (n = 48) and with simultaneous use of vemurafenib and ARAs (n = 35) versus vemurafenib alone (n = 77). Analyses were adjusted for age and sex.

In total, disease progression occurred in 55% of treated patients on vemurafenib, with a median progression-free survival of 6.0 months. Compared to patients on vemurafenib alone, there was no increased risk of progression among patients requiring vemurafenib at a reduced dose or among patients receiving simultaneous therapy with vemurafenib and ARAs. In addition, there was no increased risk of progression among patients who used reduced-dose vemurafenib and ARAs versus those receiving full-dose vemurafenib as sole therapy. However, a tendency for progression was observed among patients who used full-dose vemurafenib and ARAs versus full-dose vemurafenib alone, which became statistically significant in a sensitivity analysis.

There was no association between the use of vemurafenib in a reduced dose or the simultaneous use of vemurafenib and ARAs and the risk of progression. In addition, there was no association between the simultaneous use of vemurafenib in a reduced dose and ARAs and the risk of progression. However, patients tolerating  full-dose vemurafenib simultaneously with ARAs might have an increased risk of progression. This finding requires prospective validation.

While this is not the most definitive study...these data certainly point to the need for caution when adding "complementary" treatments to your melanoma therapy!!!  Stay well! - c

BRAF/MEK combo's for melanoma analyzed ~

About half of melanoma patients are BRAF positive.  A strange delineation that I tried to explain in 2014:  BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!  Only melanoma peeps who are BRAF positive will gain an effect from the BRAF/MEK combo (targeted therapy).  Since 2010, ratties have taught us much about how targeted therapy works and should be used.  Back in the day, we didn't realize that combining a BRAF inhibitor with a MEK inhibitor led to fewer side effects and greater efficacy.  Or that alternate dosing could help avoid resistance.  Or how best to handle side effects.  Now there are many combo's available for use as targeted therapy.  But, as no direct comparison studies have been made - what combo is best?  Now, there's this:

Efficacy, Safety, and Tolerability of Approved Combination BRAF and MEK Inhibitor Regimens for BRAF-Mutant Melanoma.  Hamid, Cowey, Offner, et al.  Cancers (Basel). 2019 Oct 24.

No head-to-head studies exist comparing BRAF inhibitor/MEK inhibitor (BRAFi/MEKi) combination treatments for BRAF-mutant melanoma. A side-by-side analysis of randomized phase III trials is presented that evaluated dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib. The baseline characteristics, efficacy, and safety were compared: COMBI-v (dabrafenib/trametinib versus vemurafenib); coBRIM (vemurafenib/cobimetinib versus vemurafenib); and COLUMBUS (encorafenib/binimetinib versus encorafenib and vemurafenib). Vemurafenib was the control arm in all studies. The data sources included literature databases, European public assessment reports, U.S. Food and Drug Administration review documents, and prescribing information. The baseline characteristics were similar, except for coBRIM, which had a higher proportion of patients with elevated lactate dehydrogenase (LDH) levels. The median progression-free survival (PFS) and overall response rate (ORR) were similar across the trials, although numerically higher values were observed with encorafenib/binimetinib. In contrast, the median overall survival (OS) was numerically longer with encorafenib/binimetinib (33.6 months) compared to dabrafenib/trametinib (25.6 months) and vemurafenib/cobimetinib (22.3 months). Among vemurafenib arms, PFS, ORR, and OS were similar, despite variations in the baseline LDH. Each combination displayed a unique safety profile, with higher incidences of pyrexia with dabrafenib/trametinib and photosensitivity reactions with vemurafenib/cobimetinib. This analysis of BRAFi/MEKi combinations for BRAF-mutant melanoma, while limited as not a direct head-to-head clinical trial, highlights the differences in tolerability and efficacy that may be useful for therapeutic decision making.

So, there you have Hamid's take on comparing three of the BRAF/MEK combo's.  Their conclusions were pretty similar to my own in this post from 2018:  Well, okie dokie!!! BRAFTOVI/MEKTOVI (Seriously guys??? That's the name???!!!) Encorafenib with Binimetinib approved for melanoma.

Then, there's this:

Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series.  Holbrook, Lutzky, Davies, et al. Cancer. 2019 Oct 28.

Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited.  A multicenter, retrospective case series investigation of consecutive BRAF-mutant patients with melanoma brain metastases (MBMs) treated with a combination of BRAF inhibitor encorafenib and MEK inhibitor binimetinib was conducted to evaluate the antitumor response. Assessments included the intracranial, extracranial, and global objective response rates; the clinical benefit rate; the time to response; the duration of response; and safety.

A total of 24 patients with stage IV BRAF-mutant MBMs treated with encorafenib plus binimetinib in 3 centers in the United States were included. Patients had received a median of 2.5 prior lines of treatment, and 88% had prior treatment with BRAF/MEK inhibitors. The intracranial objective response rate was 33%, and the clinical benefit rate was 63%. The median time to a response was 6 weeks, and the median duration of response was 22 weeks. Among the 21 patients with MBMs and prior BRAF/MEK inhibitor treatment, the intracranial objective response rate was 24%, and the clinical benefit rate was 57%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in patients with melanoma without brain metastases.

Combination therapy with encorafenib plus binimetinib elicited intracranial activity in patients with BRAF-mutant MBMs, including patients previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted and ongoing.

Okay.  Good.  But, I don't find these results that "new".  Small numbers were evaluated and we already knew BRAF/MEK worked in the brains of folks with BRAF positive melanoma.  To me, the best "news" of the article is that even those previously treated with BRAF/MEK were able to gain a response.  

Finally, there's this:

Extended 5-Year Follow-up Results of a Phase Ib Study (BRIM7) of Vemurafenib and Cobimetinib in BRAF-Mutant Melanoma.  Ribas, Daud, Pavlick, et al.  Clin Cancer Red. 2019 Nov 15.  To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study. This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced BRAF V600-mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve (n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy-progressive disease (PD); n = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7). Median OS was 31.8 months in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy-PD cohort, the median OS was 8.5 months (6.7-11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events. A subset of patients with advanced BRAF V600-mutated melanoma treated with a combination regimen of vemurafenib and cobimetinib achieve favorable long-term outcomes.

Again.  Nothing really new here.  As I noted at the start, we have known for years now that folks treated with a BRAF/MEK combo do better than those treated with BRAFi alone.  The best take away from this, is the fact that given targeted therapy is known to have responses that are less durable than those for responders to immunotherapy - overall survival plateaued at 39% at 4 and 5 years out.  Something amazing ratties like Dick K (aka Richard K - thanks to spam blockers) have been demonstrating for some time.  NOTE:  For additional comparison, this post includes a report on the 5 year outcomes for the Dabrafenib/Tramedtinib combo:   Melanoma patients want to know! What do I choose? Targeted or immunotherapy? What happens then?

Hang tough ratties.  You save us all! - c

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

Encorafenib plus binimetinib better than vemurafenib or encorafenib alone in melanoma! Well, duh!!! We already knew that a BRAF/MEK combo is better than a single agent!!!!

I report this again only because "they" are!  Institutions, Big Pharma, and researchers like to have their name in lights.  So, I will shine my spotlight once again!  I reported on and evaluated the results of the COLUMBUS study here, back in May of 2017:  Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS 

Now that title statement, is absolutely true and good!!!  In that report, I went to the trouble to look up these stats:

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.

So, yes...the encorafenib with vemurafenib combo has a better PFS than the combo's noted above ~ at least in this study of the 192 BRAF positive unresectable/metastatic Stage IIIB/C or Stage IV peeps  who were given it below.....

Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Dummer, Ascierto, Gogas,...Flaherty, et al.  Lancet Oncol. 2018 Mar 21. 

Combined BRAF-MEK inhibitor therapy is the standard of care for BRAF^V600-mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAF^V600-mutant melanoma.

COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAFV600E or BRAFV600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) via interactive response technology to receive either oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib. Efficacy analyses were by intention-to-treat. Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment. The results of part 2 will be published separately. This study is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38.

Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months, median progression-free survival was 14·9 months in the encorafenib plus binimetinib group and 7·3 months (5·6-8·2) in the vemurafenib group. The most common grade 3-4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased creatine phosphokinase (13 [7%]), and hypertension (11 [6%]); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and in the vemurafenib group it was arthralgia (11 [6%] of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator.

Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma.  

But...  Here are some comments I made (in red) in the prior post which provides more info about the trial and trial results than this re-run abstract just posted in the Lancet:

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, 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!]

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%.]

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.]

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

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So....yep.  Pretty good sum up, I'd say.  STILL have no OS data.  Which is possibly good...in that they are having to watch it a long time, because these ratties are still trucking!  Or, possibly not good...and Array and the researchers just haven't wanted to put it out there yet!  (Oh, yeah...I'm definitely in the pocket of Big Pharma, right?  Just a little inside MPIP humor there!!!)  Hopefully, those numbers will be good and the Encorafenib/Binimetinib BRAF/MEK combo will be an improvement over current BRAF/MEK combo's for BRAF positive melanoma peeps.  However, the problem with this trial is just as it so often is with others: 
1.  We don't compare apples to apples. 
2.  We leave out folks (brain mets, LMD, ocular, and mucosal melanoma patients) in serious need....cause WHY????  (Yeah, I actually know.  Those folks do not respond as well to most current therapies and make your products look bad don't they Array, BMS, Merck...and all the rest of you???) 
3.  We don't base trial questions on what we already KNOW!!!
4.  Results are slow in coming.
5.  We saw the same logs over and over.

Still...ratties rock and will save the day! - c

TIL with Vemurafenib in melanoma - Good showing in small Pilot trial

A Pilot Trial of the Combination of Vemurafenib with Adoptive Cell Therapy in Patients with Metastatic Melanoma.  Deniger, Kwonf, Pasetto, et al.  Clin Cancer Res. 2017 Jan 15.

This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAF^V600 mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma.

A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration. Vemurafenib was restarted at the time of TIL infusion and was continued for 2 years or until disease progression. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Metastases resected prior to and after 2 weeks of vemurafenib were compared using TCRB deep sequencing, immunohistochemistry, proliferation, and recognition of autologous tumor.

The treatment was well tolerated and had a safety profile similar to that of TIL or vemurafenib alone. Seven of 11 patients (64%) experienced an objective clinical response, and 2 patients (18%) had a complete response for 3 years (one response is ongoing at 46 months). Proliferation and viability of infusion bag TILs and peripheral blood T cells were inhibited in vitro by research-grade vemurafenib (PLX4032) when approaching the maximum serum concentration of vemurafenib. TCRB repertoire (clonotypes numbers, clonality, and frequency) did not significantly change between pre- and post-vemurafenib lesions. Recognition of autologous tumor by T cells was similar between TILs grown from pre- and post-vemurafenib metastases.

Coadministration of vemurafenib and TILs was safe and feasible and generated objective clinical responses in this small pilot clinical trial.

Granted, this requires being BRAF positive...but still....it may be a good option for those peeps. Questions I do have:  Are these folks EVER going to get to come off BRAF....even with their complete response?  One would think so...but this study comes to mind:   Stopping BRAF/MEKi after a complete response? Case study of 12 melanoma patients...     
There is also this:  How are these patients dealing with side effects if they are given only a BRAFi, rather than BRAF/MEK, since we have learned that, oddly enough, the combo causes not only less resistance, but fewer side effects as well?  Guess the ratties will teach us all.  - c

Melanoma research results to which my only response is: Are you guys for real right now?????

B keeps perusing the literature, hoping for something better for melanoma peeps to pop up.  There are some new things and combo's in the works... but some of the stuff researchers are publishing right now is just tired!  But...here you go:

Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials. Kaufman, Andtbaka, Collichio, et al.  J Immunother Cancer. 2017 Sep 19.

Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting greater or equal to 6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival.  

We evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation).

Four hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9 months, 12 months, and 18 months that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI and a higher TOI improvement rate (58.1% versus 30.0%).  

Achieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint.

The grand summary finding here is that when a durable response is achieved - it is associated with improved overall survival, and a longer treatment free interval.  Well, duh!!!  Did we really need a study to tell us that???????

Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Chapman, Robert, Larkin, et al.Ann Oncol. 2017 Oct 1.

The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3.

Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib.
Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months versus 9.7 months}, as was median OS without censoring at crossover [13.6 months versus 10.3 months]. Kaplan-Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis.

Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies.

Here...the shocking take-away is:  DACARBAZINE sucks in the treatment of melanoma when compared to immunotherapy or BRAF inhibitors.  THIS IS NOT NEWS!  Could we stop with the dacarbazine already?????  This post is from 2013!!!!!!!  Ipi, BRAF/MEK, Anti-PD1 [and NO MORE DACARBAZIN???!] - per chat with Antoni Ribas A conversation in the wake of data presented at the European Cancer Congress 2013....  Come on, Man!!!!!

Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Schachter, Ribas, Long, et al.  Lancet. 2017 Aug 16.

Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis.

In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319.

Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab. 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group.

Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. 

Finally, while this study provided essential information when we wanted to make sure that the data we were seeing in studies of nivo and pembro alone...like mine back in 2010...were valid when compared head-to-head with ipi...this study is also testament to how long it takes to get data reported out from a trial that started 4 years ago!  Additionally, though we already knew that ipi has a response rate of about 15% in melanoma patients vs. a response rate of about 40% when anti-PD-1 products are used, it does take the data one step further.  Despite an average time of follow-up of almost 23 months, median overall survival was not yet reached with pembro...while median overall survival for ipi maxed out at 16 months.  Another point was that overall 24 month survival was the same, at 55%, for pembro no matter if patients took it every 2 weeks or every 3 weeks....vs only 43% for the ipi group.  So....at least there is SOMETHING new here!!!

Thanks, ratties!!!  And researchers, "Are you guys for real right now????" - c

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

Treating melanoma by COMBINING targeted therapy AND immunotherapy!!

As usual, I've written on this topic previously:

As long ago as 2015, there was this:  BRAFi better when combined with or after immunotherapy and surgery!!!

And this in 2016:  BRAF/MEK combined with immunotherapy!!!

This from 2017:  The whole she-bang - immunotherapy WITH BRAF/MEK for melanoma...

This from ASCO 2017:  ASCO 2017: Atezo (anti-PDL1) with Cobimetinib (MEKi) and Vemurafenib (BRAFi) for BRAF V-600 melanoma

Now there are these reports (highlights = my own):

Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma.  Ribas, Lawrence, Atkinson, Agarwal, ..., Hodi, ..., Hamid.  Nat Med. 2019 Jun;25. Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab ( NCT02130466 ). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%) had an objective response, and six (40%) continued with a response at a median follow-up of 27 months (range = 10.3-38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients.  Sullivan, Hamid, Gonzalez, et al.  Nat Med. 2019 Jun;25.

Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF^V600 mutations. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAF^V600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4⁺ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8%. The estimated median duration of response was 17.4 months with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.

Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.  Hellmann, Kim, Lee, et al.  Ann Oncol. 2019 Mar 27.

Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a PD-L1 inhibitor, atezolizumab, in patients with solid tumors.

This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary endpoints included ORR, PFS and OS.

Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received greater than/= to 1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had mCRC (n = 84), melanoma (n = 22), NSCLC (n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%) and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases.

Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study.

So - small numbers.  Pretty significant toxicity.  Only effective in the roughly 1/2 of melanoma patients who are BRAF positive.  Looks like BRAF/MEK with anti-PD-1/PD-L1 is demonstrating a 70% objective response rate while anti-PD-L1 with a MEK inhibitor alone attained a 40% response rate (ie = no better than the ipi/nivo combo).  Again, no matter the result...small numbers treated (only 37 melanoma patients total were in the first and last studies reported here - and Hamid et al ain't sharing their #'s unless you buy the paper - FYI).  Still, throwing the "kitchen sink" at melanoma may be a worthwhile treatment for some.

Hang tough ratties!!! - c

All things BRAFi...latest articles

BRAF mutation status as an independent prognostic factor for resected stage IIIB and IIIC melanoma:  Implications for melanoma staging and adjuvant therapy.
Barbour, Tang, Amour, et al.  Eur J Cancer. 2014 July 25.

5 year survival for melanoma metastasis to regional lymph nodes is less than 50%.  Knowledge of outcomes following therapeutic lymphadenectomy for stage III melanoma related to BRAF status may guide adjuvant use of BRAF/MEK inhibitors along with established and future therapies.  DNA was obtained from patients with TLND who also had 2 or more positive nodes, largest node of greater than 3 cm, or extracapsular invasion.  Mutations were most commonly detected in BRAF (46%) and NRAS (21%).  Patients with BRAF mutations had higher 3-year recurrence rate of 77% vs 54% for BRAF wild-type patients.  The only prognostically significant mutations occurred in BRAF:  median recurrence-free disease and disease specific survival for BRAF mutation patients was 7 mo and 16 mo vs 19 months and not reached for BRAF wild-type patients, respectively.
CONCLUSION:  Patients with BRAF mutations experienced rapid progression of metastatic disease with locoregional recurrence rarely seen in isolation, supporting incorporation of BRAF status into melanoma staging and use of BRAF/MEK inhibitors post-TNLD.

This seems to be important data to consider to me.  Wonder if I would have progressed had I been given BRAFi after my first lymphadenectomy with a positive node.  I would not have met this criteria as it was only one microscopically positive node....but something to think about as I experienced my second primary just before making it 5 years out.


The nature and management of metastatic melanoma after progression on BRAF inhibitors:  Effects of extended BRAF inhibition.
Chan, Haydu, Menzies, et al.  Cancer. 2014 July 1.

"Dabrafenib and vemurafenib have high response rates in BRAF-mutant metastatic melanoma, however, 50% of patients progress by 7 months." 95 of 114 BRAFi treated patients (treated between July 2009 and September 2012, whose data was collected and analyzed) had disease progression.  53 of 95 patients progressed in extracranial sites alone, 18% progressed in intracranial and extracranial sites simultaneously, and 16% progressed in intracranial sites alone. 29 of the 95 patients progressed in a single site or organ, 48% progressed in existing mets only, and 18% had new mets alone.  At the time of progression, 35 of 95 patients received no subsequent systemic treatment, 20% changed systemic treatments and 39% continued BRAFi for a median of 97 days.  BRAFi continued beyond disease progression and known prognostic factors (LDH, RECIST sum of dimension of target lesions) were associated with overall survival from the time of disease progression.

Ok.  So....perhaps continued BRAFi after progression is helpful.

Features and management of pyrexia with combined dabrafenib and trametinib in metastatic melanoma.
Lee, Menzies, Haydu, et al.  Melannoma Res. 2014 July 22.

CombiDT (dabrafenib and trametinib) is an effective treatment for BRAF-mutant metastatic melanoma.  However, over 70% of patients develop drug-related pyrexia [fever].  32 patients reviewed.  14 (44%) developed pyrexia.  Fever was recurrent in 11/14.  Pyrexia was not associated with age, sex, disease burden, RECIST response, progression-free, nor overall survival.  Paracetamol, NSAIDs and/or dose reduction were ineffective secondary prophylaxis for pyrexia, whereas corticosteroids were effective in all patients.  In patients with previous dose reductions who commenced steroids, CombiDT doses were re-escalated without pyrexia. 

So....treating fevers with steroids stops the fever and allows patients to continue effective therapy!


Cost-effectiveness of treatment strategies for BRAF-mutated metastatic melanoma.
Curl, Vujic,  van't Veer, et al.  2014 September 8.

Genetically-targeted therapies are both promising and costly advances in the field of oncology.  They extend life but are more expensive than the previous standard of care - dacarbazine.

NOTE:  Don't forget what Weber said about Dacarbazine:  "...when talking about some of these trial options with Dr. Weber, he acknowledged that had ipi or anti-PD1 had been discovered first....Dacarbazine would never have attained FDA approval...yet, we continue to use it.  Incredible."
http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2012/12/new-trials-for-melanoma.html 

Vemurafenib costs $13,000 per month ($207,000 for a patient with median survival).  Patients failing vemurafenib are often given ipi at $150,000 per course.  "Present value of lifetime costs and quality-adjusted life years" were analyzed.   The incremental cost-effectiveness for vemurafenib vs dacarbazine was $353,993 per quality-adjusted life years.  For vemurafenib followed by ipi compared with vemurafenib alone was $158, 139. In sensitivity analysis, treatment cost had the largest influence on results:  the incremental cost-effectiveness for vemurafenib vs dacarbazine dropped to $100,000 per quality-adjusted life years gained with a treatment cost of $3,600 per month.  CONCLUSION:  The cost for time gained by treatments with vemurafenib alone or in combination exceeds...thresholds for cost-effectiveness.  These strategies may become cost-effective with lower drug prices or confirmation of a durable response without continued treatment.

Wow Curl and Vujic et al.  I hope you don't get melanoma.  You can't afford it!!!!


BRAF V600 mutations and pathological features in Japanese melanoma patients.
Yamazaki, Tanaka, Tsutsumida, et al.  Melanoma Res. 2014 July 19.

Primary sites of melanoma and the frequency of BRAF mutations might differ between races.  Melanoma is rare in Japan (1500-2000 cases per year compared with 132000 per year worldwide) and frequency and distribution of BRAF V600 mutations are unknown. Testing methods were defined.  BRAF V600 mutations were found in 41.8% of tested tumours.  Mutation rate = more than 60% in patients aged less than 60 years and more than 36% of patients with stage III/IV disease.  BRAF V600 mutations were detected in 18.8% of acral lentiginous melanomas. 64.7% of superficial spreading melanoma, 50% of lentigo maligna melanomas and 20% of nodular melanomas.

I'd have to do a little research to be positive, but those percentages for BRAF positive peeps seem about equivalent to folks in the states and Europe.  As far as BRAF status, perhaps the Japanese do better in avoiding the sun and other risk factors (known or unknown) that contribute to melanoma...or there are genetic factors we don't even know anything about...that are keeping their rates of melanoma lower than those for the rest of us.

Not sure what all this is worth....but there you go!  Best - c

Well, okie dokie!!! BRAFTOVI/MEKTOVI (Seriously guys??? That's the name???!!!) Encorafenib with Binimetinib approved for melanoma.

Here's a link to the nice little ad (I mean announcement!!!):  ARRAY pharma gains FDA approval for the Encorafenib/Binimetinib

Here are prior posts on the combo: 
This from May 2017:  Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS 

My review: 
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.

This from March 2018:  Encorafenib plus binimetinib better than vemurafenib or encorafenib alone in melanoma! Well, duh!!! We already knew that a BRAF/MEK combo is better than a single agent!!!

Here are some snippets from that post:
I report this again only because "they" are!  Institutions, Big Pharma, and researchers like to have their name in lights.  So, I will shine my spotlight once again!  I reported on and evaluated the results of the COLUMBUS study here, back in May of 2017:  Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS 
Now that title statement, is absolutely true and good!!!  In that report, I went to the trouble to look up these stats:

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.

So, yes...the encorafenib with vemurafenib combo has a better PFS than the combo's noted above ~ at least in this study of the 192 BRAF positive unresectable/metastatic Stage IIIB/C or Stage IV peeps  who were given it below.....

[The abstract followed (you can see it for yourself via the link above).] My synopsis:

But...  Here are some comments I made (in red) in the prior post which provides more info about the trial and trial results than this re-run abstract just posted in the Lancet:

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, 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!]

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%.]

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.]

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

---------------------------------------------------------------------------------------

So....yep.  Pretty good sum up, I'd say.  STILL have no OS data.  Which is possibly good...in that they are having to watch it a long time, because these ratties are still trucking!  Or, possibly not good...and Array and the researchers just haven't wanted to put it out there yet!  (Oh, yeah...I'm definitely in the pocket of Big Pharma, right?  Just a little inside MPIP humor there!!!)  Hopefully, those numbers will be good and the Encorafenib/Binimetinib BRAF/MEK combo will be an improvement over current BRAF/MEK combo's for BRAF positive melanoma peeps.  However, the problem with this trial is just as it so often is with others: 
1.  We don't compare apples to apples. 
2.  We leave out folks (brain mets, LMD, ocular, and mucosal melanoma patients) in serious need....cause WHY????  (Yeah, I actually know.  Those folks do not respond as well to most current therapies and make your products look bad don't they Array, BMS, Merck...and all the rest of you???) 
3.  We don't base trial questions on what we already KNOW!!!
4.  Results are slow in coming.
5.  We saw the same logs over and over.

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Now, BACK TO TODAY ~ I don't think this approval is necessarily a bad thing at all!!!  But....I do believe in truth in advertising.

Here are a few more deets from the package insert:  OOOOOPS!  Is Array inept or not providing full disclosure???!!!  Cause.....no matter how I look it up, I have not succeeded in finding a working link to the prescribing info for BRAFTOVI, only the one for MEKTOVI seems to be working.  So, I'll suffice it to say that these are basically new BRAF/MEK inhibitors that should be given together for folks with BRAF positive (V600E or V600K) melanoma which is about half of us.  They are administered orally.  They come with about the same side effect profile as all the other BRAF/MEK combo products. 

Here's hoping that many melanoma peeps benefit from the combo.  Here's hoping that someday, clinical trials will be set up in such a way that folks who MIGHT benefit are NOT excluded, that apples are compared to apples, that pharma will realize that we ratties are NOT stupid and can see very clearly when they stack the deck in their favor.

For what it's worth. - c