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

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

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

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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.

_______________________________________________
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

Melanoma madness links!! ASCO and others....

Hey guys! Don't have the time or energy to give you my usual print out and assessment on these just now!  However, in the spirit of access and knowledge, I still wanted you to have them.

So....here you go:

Galectin's GR-MD-02 Positive in Phase Ib Study With Keytruda

Why Yervoy's Resurgence Will Gain Momentum

Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option

Lifestyle Modifications and Policy Implications for Primary and Secondary Cancer Prevention: Diet, Exercise, Sun Safety, and Alcohol Reduction

New Era in the Management of Melanoma Brain Metastases

Combination Immunotherapy Development in Melanoma Practice-Changing Developments in Stage III Melanoma: Surgery, Adjuvant Targeted Therapy, and Immunotherapy Patterns of Response and Progression to Immunotherapy Emerging Strategies in Systemic Therapy for the Treatment of Melanoma Challenging Cases: Management of Immune-Related Toxicity The Role of Completion Lymph Node Dissection for Sentinel Lymph Node-Positive Melanoma. Hieken, Kane JM, Wong.  Ann Surg Oncol. 2018 Oct 3.  Completion lymph node dissection (CLND) for sentinel lymph node (SLN)-positive melanoma patients has been guideline-concordant standard of care since adoption of lymphatic mapping and SLN biopsy for the management of clinically node-negative melanoma patients more than 20 years ago. However, a trend for omission of CLND has been observed over the past decade, and we now have randomized, controlled clinical trial data to help guide treatment recommendations. Publication of these data prompted an American Society of Clinical Oncology-Society of Surgical Oncology 2018 clinical practice guideline update for these patients. Systematic review of current evidence supports a selective, individualized approach to CLND for SLN-positive melanoma. For low-risk, low-volume micrometastatic disease, SLN biopsy may be both diagnostic and therapeutic, and close clinical follow-up with imaging or CLND are reasonable options for appropriately selected patients. For higher-risk patients, omission of CLND requires careful consideration of risks versus benefits, relevant histopathology, and individualized patient discussion. This should address patient comorbidities and life expectancy, the predicted likelihood of additional positive nodes, availability of imaging surveillance, likelihood of adherence to imaging and clinical follow-up, consequences of regional recurrence, and the prognostic value of complete nodal staging and its impact on adjuvant therapy recommendations or clinical trial participation. Data on long-term outcomes, cost, and patient-reported quality of life measures are not yet available. Prognostic Value of Low Tumor Burden in Patients With Melanoma. Poklepovic, Carvajal.  Oncology (Williston Park). 2018 Sep 15. The therapeutic landscape for cutaneous melanoma has dramatically advanced in the last several years with the development, validation, and approval by the US Food and Drug Administration of several new therapies that have proven effective in treating metastatic disease. Considerable effort has been put into identifying prognostic and predictive markers of therapeutic response to better delineate the patient populations most likely to benefit from treatment. Baseline tumor burden has been described as a common clinical factor associated with treatment response: lower tumor burden at the time of therapeutic intervention is associated with improved responses and survival outcomes on several therapies. Some therapies have shown efficacy as adjuvant interventions in patients with subclinical disease following definitive treatment, further supporting their role in patients with minimal tumor burden. The increasing evidence that patients with lower tumor burden may be the ones who derive maximal benefit from several melanoma-directed therapies points toward the critical need for risk-tailored surveillance to permit early identification of melanoma metastasis in patients at high risk for recurrence.   Predictors of Sentinel Lymph Node Positivity in Thin Melanoma Using the National Cancer Database. Conic, Ko, Damiani, et al.  J Am Acad Dermatol. 2018 Sep 18.  Following melanoma excision, patients often receive sentinel lymph node biopsy (SLNB) for further staging. Limited data regarding predictors of SLNB positivity in thin melanoma are available.  To evaluate predictors of SLNB positivity in thin melanoma.  Patients with cutaneous melanoma, Breslow thickness great than/= to 1.00 mm who received a SLNB were identified from the National Cancer Database in the period from 2004-2014 (n=9,186). Predictors of SLNB positivity were analyzed using logistic regression.  In a multivariate analysis, patients with age less than 60 and Breslow thickness greater than 0.8mm were at increased risk for positive SLN. Moreover, on multivariate analysis, presence dermal mitoses increased odds of SLN positivity by 95%, ulceration by 63% and Clark level IV-V by 48%. Patients without ulceration but with dermal mitoses had 92% increased SLN positivity.  Limited survival data available.  Younger age, Breslow thickness greater than 0.8 mm, presence of dermal mitoses, ulceration and Clark level IV-V are positive predictors of positive SLN. While the new AJCC system has removed dermal mitotic rate from staging, continued evaluation of dermal mitotic rate could be valuable for guiding surgical decision making about SLNB.   Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. Wang, Salem, Cohen, et al.  JAMA Oncol. 2018 Sep 13. Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data.  To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.  We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally. Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab). Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects. Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4). In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

Systematic Review and Meta-analysis of the Prognostic Significance of miRNAs in Melanoma Patients.

Sabarimurugan, Madurantakam Royam, Das, et al.  Mol Diagn Ther. 2018 Sep 27. 

Melanoma is the most aggressive and deadly form of skin cancer. The molecular variability involving microRNA (miRNA) expression plays a significant role in melanogenesis, which leads to poor prognostic effects in melanoma. Since there is a scarcity of comprehensive data on the prognostic role of miRNAs in melanoma patients, this study focuses on filling this knowledge gap through a systematic review and meta-analysis.

The included studies were extracted from several bibliographic databases between 2012 and 2018 using multiple keywords according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The hazard ratios (HRs) and 95% confidence intervals (CIs) for different survival endpoints were compared to the high and low expression levels of miRNAs. The mean effect size of HR values was estimated using a random-effects model of meta-analysis. Inverted funnel plot symmetry was used to assess publication bias. Subgroup analysis was carried out individually for multiple miRNAs across different studies.

A total of 24 studies across eight countries were included, of which 16 studies were eligible for meta-analysis. Twenty-five miRNA expression levels were studied from 2669 melanoma patients to estimate the association between the prognostic role of miRNAs and survival outcome in these 16 studies. The overall pooled effect size (HR) for up- and downregulated miRNAs was 1.043, indicating that the miRNA expression increased the likelihood of death in melanoma patients by 4.3%. Subgroup analysis for miRNA10b, miRNA16 and miRNA21 showed a poor prognosis. The quality assessment revealed that 16 studies were good quality and eight studies were of fair quality. 

This is one of the first pooled meta-analysis studies on the role of miRNAs in the prognosis of melanoma. Our findings are inconclusive but suggest that miRNA expression could predict poor survival in melanoma patients. Therefore, miRNA expression could act as promising prognostic marker for melanoma.  

Induced Vitiligo due to Talimogene Laherparepvec Injection for Metastatic Melanoma Associated with Long-term Complete Response.

Iglesias, Ribert, Barreiro,   Acta Derm Venereol. 2018 Oct 3. 

Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma.

Huber, Vallacchi, Fleming  et al.  J Clin Invest. 2018 Sep 27.

The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and with resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs are increased in circulating CD14+ monocytes, plasma and tumor samples, where they correlate with the myeloid cell infiltrate. In plasma, their baseline level clusters with the clinical efficacy of CTLA-4 or PD-1 blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.  

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037).

Mitchell, Hamid Smith, et al.  J Clin Oncol. 2018 Sep 28.

Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported.

Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks.

Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in greater than/ = to 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non-small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies.

Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

Predictive Biomarkers for Checkpoint Immunotherapy: Current Status and Challenges for Clinical Application.

Tray, Weber, Adams.  Cancer Immunol Res. 2018 Oct;6.

Immune-checkpoint blockade (ICB), in particular PD-1 inhibition, has rapidly changed the treatment landscape and altered therapeutic paradigms across many tumor types, with unprecedented rates of durable clinical responses in a number of cancers. Despite this success, only a subset of patients responds to ICB and, as a result, predictive biomarkers would be useful to guide the selection of patients for these therapies. This article highlights currently used biomarkers, as well as several promising novel candidates, and also discusses the challenges involved in establishing their analytic validity and clinical utility. Progress is being evaluated in melanoma and non-small cell lung cancer, for which PD-1 ± CTLA-4 inhibitors have become standard therapy, to other malignancies for which PD-L1 inhibitors remain investigational. Although single biomarkers have substantial limitations, a combination of biomarkers that reflect the interaction of host and tumor will likely be needed to provide a reproducible surrogate for the benefit of checkpoint modulation.

And because y'all know I've been yelling about biomarkers for years, here are links to my prior posts on the subject:  

Better melanoma outcomes with a lower NLR, neutrophil-to-lymphocyte ratio! (Again...)  

MHC proteins and how they work if you are taking anti-CTLA4 (ipi) or anti-PD-1 (Opdivo or Keytruda) in melanoma  

Simple blood tests that tells us where we are with our melanoma....AGAIN (and again, and again, and again)!!!

And here is an update on the Columbus Trial....with my prior notes:

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!!!!

Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Dummer, Ascierto, Gogas, et al.  Lancet Oncol. 2018 Sep 12.

Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF^V600-mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival.

COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF^V600E or BRAF^V600Kmutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive 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). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and 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 receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (35·9-37·5). Median overall survival was 33·6 months (24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib. The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment.

The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF^V600-mutant melanoma.

The ASCO Educational Book looks like it might be helpful to melanoma peeps...so you might keep that in mind as an additional resource in the future.  Remember to read critically.  Use your common horse sense.  Don't fall for everything everybody is selling.  Take good care and remember I love you.  - C

Encorafenib/Binimetinib ~ BRAF/MEK inhibitor combo in patients with V600E/K mutant tumors

I've provided reports on this BRAF/MEK inhibitor combo before.  Here's a link to some of the posts:  Encorafenib/Binimetinib  Here's a link to reports on the COLUMBUS study in particular:  COLUMBUS

For this study, inclusion criteria on the Clinicaltrial.gov website notes:  "Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation"

A phase 1b/2 study of the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with BRAF V600E/K-mutant solid tumors.  Sullivan, Weber, Patel, et al.  Clin Cancer Res. 2020 Jul 15.

This open-label, dose-finding phase 1b/2 study reports the safety and activity of the first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK inhibitor (MEKi) binimetinib in patients with BRAF V600E-mutant solid tumors. (NCT01543698). 

In phase 1, the recommended phase 2 doses (RP2D) were established (primary objective). In phase 2, the clinical activity of the combination at the RP2D was assessed (primary objective) in patients with BRAF-mutant metastatic colorectal cancer (mCRC), BRAFi-treated BRAF-mutant melanoma, and BRAFi-naïve BRAF-mutant melanoma. Results 126 patients with BRAF mutant solid tumors were enrolled (phase 1: 47 patients; phase 2: 79 patients). The RP2D was encorafenib 450 mg QD plus binimetinib 45 mg BID and pharmacokinetic (PK) data suggest that drug-exposures of each agent were similar in combination compared with single-agent studies. In the phase 2 cohorts, confirmed responses were seen in 2 of 11 (18%) evaluable mCRC patients, 11 of 26 (42%) evaluable BRAFi-pretreated melanoma patients, and 28 of 42 (67%) BRAFi-naïve melanoma patients. The most common grade 3/4 adverse event in phase 2 was increased alanine aminotransferase. 

The combination of encorafenib (450 mg) plus binimetinib (45 mg) showed acceptable tolerability and encouraging activity in patients with BRAF V600-mutant tumors, which led to the dose selection for the melanoma COLUMBUS study. The safety profile of the combination was consistent with other approved BRAFi plus MEKi regimens, with several differences, including lower rates of dose-limiting pyrexia, arthralgia, and photosensitivity.  

For what it's worth.  - c