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
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