ASCO 2015 - Update on coBRIM: 1st-line Cobimetinib + Vemurafenib in mutated BRAF metastatic cutaneous melanoma (in 3 slides)

coBRIM: Study design

coBRIM updated PFS at the ASCO 2015 in Chicago

The majority of significant toxicity occurs during the first few weeks of therapy

Background
1. Single-agent Vemurafenib (V) (an oral anti BRAF agent) improves survival in mutated BRAF metastatic melanoma (mMel), based on the BRIM3 trial.
2. Disease control with single-agent anti BRAF is transient.
3. Paradoxical activation of the MAPK pathway appears to be an important mechanism of resistance.
4. MEK (a downstream to BRAC MAPK element) is activated.
5. Single-agent Trimetinib (an oral anti MEK agent) improves PFS in BRAF mutated mMel.
6. coBRIM is a phase III trial comparing V to Cobimetinib (co) (an oral anti MEK agent) + V as 1st-line therapy for mBRAF mMel patients. Initial results have been published in the NEJM in 2014. The study was positive meeting the primary endpoint (see image 1).
7. The toxicity profile of the combination was slightly different to the single-agent V with less proliferative skin neoplasms, slightly more chorioretinitis, CPK and diarrhea. Co-V exhibited similar (high) rate of skin toxicity.
8. Most of the toxicity occurs the first few weeks, and resolves thereafter (see image 3).

ASCO 2015
Dr. Larkin uptdated the results of the coBRIM with a definitive PFS of 12.5 vs 7.2 months (HR: 0.58), favoring the combination of Cobimetinib + Vemurafenib vs Vemurafenib. To date, this is the first study with PFS longer than 1 year in mMel. The combination of an anti BRAF + anti MEK is highly superior to single-agent anti BRAF.

Brief editorial
At the same ASCO, the positive OS results of the COMBI-D trial were presented (see blog entry). In the COMBI-D a different anti BRAF + anti MEK combination were compared to single-agent anti BRAF. Both COMBI-D and coBRIM reinforce the same concept: dual BRAF and MEK pathway blockage appears to be more effective in mBRAF mMel patients. Other relevant trials in the field presented at ASCO 2015 include those with anti PD1 + Ipilimumab (published at the NEJM) This trial was also a positive trial with excellent results. Considering these options (when available to us in Colombia), how should we choose the optimal first line therapy for mBRAF mMel patients: targeted (anti BRAF + anti MEK agents) or immunotherapy (ie, Anti PD1 + Anti CTLA4 agents)? There is no clear-cut answer. Both strategies are very effective, so I will give a tentative answer based on a few considerations.

1. Response rate with targeted agents is extremely high, in the 70% range. Even the most active immunotherapy has less than 50% response rate.
2. Although very active, duration of disease control with targeted agents is finite. Most patients eventually progress. Whereas 1 out of 5 immunotherapy treated patients display a very long disease control akin to cure.
3. Targeted agents are highly effective in CNS metastasis. Immunotherapy is not.
4. A minority of the patients experience disease pseudoprogression with immunotherapy.
5. Both strategies are highly toxic, and are riddled with unusual side-effects, difficult to spot and treat.

So, first-line targeted therapy is my choice for patients with mBRAF mMel with high disease burden, poor PS, CNS disease, or in a patient that can not afford to experience pseudoprogression (or progression). Most mBRAF patients are in this group, since these tumors tend to be fast growing.

For those patients with low-disease burden that can withstand progression or pseudoprogression, I consider first-line immunotherapy as it can provide long-term disease control in a subgroup of patients. Moreover, targeted therapy can be administered for many of  those who do progress.