Growing Therapy Approaches for BRAF-Mutant Advanced Melanoma

Michael A. Postow, MD

With both targeted and immunotherapy options, the armory against BRAF-mutant melanoma is well-equipped. As more research is shared, oncologists are continuing to re-shape their practices to achieve the longest possible survival for their patients.

During the Physician’s Education Resource® 18th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®, Michael A. Postow, MD, presented data around the available targeted agents for BRAF-mutant melanoma and ongoing clinical questions about treating the disease.

“We need that obviously to be higher than it is currently so that everyone can have this long-term survival but be rapid and patients have multiple treatment options that can work for them,” Postow, chief, Melanoma Service, Memorial Sloan Kettering Cancer Center, told Targeted Oncology™, during an interview.

Two recent advances include the FDA-approved combination of atezolizumab (Tecentriq), and vemurafenib (Zelboraf), cobimetinib (Cotellic) as frontline treatment for patients with unresectable advanced BRAF V600 mutation-positive melanoma, and adjuvant dabrafenib plus trametinib in stage III melanoma with BRAF V600E or V600K mutations.

The combination of atezolizumab, vemurafenib, and cobimetinib was investigated in the phase 3 IMspire150 clinical trial (NCT02908672). The combination showed a significant improvement in progression-free survival (PFS) compared with placebo. The PFS was 16.1 months (95% CI, 11.3-18.5) with the experimental combination compared with 12.3 months (95% CI, 10.8-14.) in the control arm (HR, 0.85; 95% CI, 0.67-1.07; log-rank P =0.16).¹

Treatment with atezolizumab/vemurafenib/cobimetinib was also safe and well-tolerated in the study.

The adjuvant combination of dabrafenib plus trametinib, as investigated in COMBI-AD (NCT01682083) also demonstrated survival improvement. When administered for 12 months, adjuvant dabrafenib/trametinib achieved a longer duration of relapse-free survival (RFS) and distant metastasis-free survival.²

According to the 5-year survival analysis, the median RFS was not reached (NR) in the combination therapy group (95% CI, 47.9 to NR) compared with16.6 months (95% CI, 12.7-22.1) in the placebo group (HR, 0.51; 95% CI, 0.42-0.615). The percentage of patients living without distant metastasis at 5 years was 65% (95% CI, 61%-71%) in the dabrafenib plus trametinib arm versus 54% (95% CI, 49%-60%) with placebo (HR, 0.55; 95% CI, 0.44-0.70). Investigators found no significant differences between the study arms in terms of adverse events.

During the interview, Postow summarized the treatment landscape, provided takeaways from the most recent additions, and discussed other targets for metastatic melanoma.

TARGTED ONCOLOGY: What do survival outcomes currently look like for BRAF-mutant metastatic melanoma?

Postow: Survival outcomes look great for patients with BRAF-mutant melanoma. With both targeted therapy and immunotherapy, there can be a proportion of patients who have really excellent long-term survival. We need that obviously to be higher than it is currently so that everyone can have this long-term survival but be rapid and patients have multiple treatment options that can work for them.

Can you discuss the IMspie150 regimen and how it has impacted the field since it’s FDA approval in 2020?

The combination of atezolizumab, vemurafenib, and cobimetinib was a very interesting study where we demonstrated if you add a PD-L1 agent to BRAF and MEK inhibition, which in this context was vemurafenib and cobimetinib, the investigator-assessed progression-free survival and duration of response were improved. So, I think that data really support a long-held idea that we've been trying to develop in oncology, which is combining immunotherapy and targeted therapy and I think that's the been the best demonstration of some success with that approach.

What novel therapies are showing potential to improve outcomes for these patients?

In the BRAF mutant world, there are patients with atypical BRAF mutations, so not the common BRAF V600. Mutations where we're used to targeting them with BRAF and MEK inhibitors that are currently FDA-approved right now, there are a whole host of new BRAF inhibitors that are targeting patients with less common class 2, and class 3 BRAF-mutant tumors.

I think as we are having more patients have additional next-generation sequencing panels. We're detecting more and more of these class 2 and class 3 BRAF-mutant patients. And there are a lot of drugs in development that are showing some very interesting early preliminary activity that are targeting is less common BRAF mutation.

So, the hope ultimately would be that every patient with a BRAF mutation has a benefit from targeting the BRAF protein and/or the MAP kinase pathway that's activated in the presence of these BRAF mutations. I think that will increase the proportion of patients that benefit from this approach overall, whereas in the past, we really saw the benefit mostly around patients with BRAF V600 tumors.

For example, Pfizer has a novel inhibitor in this pathway that is believed to have better central nervous system efficacy. And that's a big problem for many patients that have brain metastases. [With current therapies], their extracranial diseases are well taken care of, but then they progress in the brain. Our hope is that a novel inhibitor can show some efficacy there. There's another drug from BeiGene, who is developing another pan RAF inhibitor that will hopefully help further improve outcomes for patients with these class 2 and class 3 BRAF-mutant tumors.

COMBI-AD showed that there’s benefit to using BRAF-targeted therapy in the adjuvant setting. What are your thoughts on this study and its potential impact?

The COMBI-AD study was a really important study for field because I think now that we have 5-year data follow up for that study, we now have convincing evidence that adjuvant dabrafenib and trametinib dramatically improves recurrence-free survival for stage III patients with resected melanoma. And I think if you look at those Kaplan Meier curves for recurrence-free survival that were published in 2019, there's a big divide between the patients that had the adjuvant targeted therapy versus those that were observed only.

We only have recurrence-free survival data. So, we don't have long-term overall survival data yet, and I think that's what we really want to see. But now with 5 years of total follow up, it's incredible that that 1-year of adjuvant treatment can result in a really promising 5-year improvement in recurrence-free survival. So, the effects of the BRAF inhibition for that year of adjuvant treatment can really linger for a long period of time. And. think that's great and demonstrating the power of adjuvant targeted therapy in resected, stage III melanoma population.

What other clinical questions do you think oncologists have about treating BRAF-mutant metastatic melanoma?

The main question when you have a patient with a BRAF mutation has always been, do you start treating these patients with immunotherapy or do you start treating these patients with BRAF plus MEK inhibition given the fact that they have a pure tumor? And the DREAMM-6 study just came out which was a randomized study testing nivolumab [Opdivo] plus ipilimumab [Yervoy] immunotherapy versus to dabrafenib and trametinib demonstrating 2-year overall survival was better for the starting patients with nivolumab plus ipilimumab. So, I think that starting to answer this question of what's better frontline treatment for patients with BRAF mutation. So, we're starting to see this immune therapy preference in the frontline treatment of patients with BRAF-mutant melanoma. We've been there for a while, but I think the results of the DREAMM-6 are truly practice changing and really give a nod to starting these patients with immunotherapy particularly combination immune therapy if the patient's an appropriate candidate and then saving the BRAF and MEK inhibitors for subsequent lines of therapy.

But many questions still remain. We have data that are coming forward for encorafenib [Braftovi] and binimetinib [Mektovi] versus nivolumab and ipilimumab from the SECOMBIT study that was conducted primarily in Italy, and I think there are still sufficient areas where we need to debate what's the right treatment for what particular patient.

What are some other druggable targets of interest for advanced melanoma?

In addition to BRAF-mutant melanoma, there are other druggable mutations and other mutations that we're certainly interested in targeting. I will give the example of KIT-mutant melanoma as another success story in melanoma perhaps more limited than the BRAF successes that we've seen. But with KIT-mutant melanoma, you can use KIT inhibitors, like imatinib [Gleevec] or nilotinib [Tasigna]. KIT-mutant melanoma is not as common as BRAF-mutant melanoma, but in certain parts of the body like chronically sun-damaged skin or mucosal surfaces, when the melanoma rises from there, it's really important to check for KIT mutations when there's no BRAF mutation because those sides of the body have a relatively higher rate of KIT mutations.

In many of those contexts, those patients can be successfully treated with KIT inhibitors.

In addition to that, NRAS has long been an area of great challenge for us in melanoma because it affects a lot of patients with melanoma, about 20% of them. There haven't been very good inhibitors of oncogenic NRAS directly, but there have been varying levels of success with targeting downstream pathway elements of the pathway that's activated when NRAS is mutant. MEK inhibitors have shown some promise in NRAS-mutant melanoma. but a number of combinations are being developed now, combining MEK inhibitors with other drugs or targeting these RAF molecules with new RAF inhibitors. So, I think NRAS-mutant melanoma will hopefully be another area that we see progress in the coming years as we have with BRAF-mutant melanoma and KIT-mutant melanoma. I think that's the next frontier is to kind of how do we really forge the path with NRAS-mutant disease?

_References:

_{1. Gutzmer R, Stoyakovskiy D, Goga H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;395(10240):1835-1844. doi: 10.1016/S0140-6736(20)30934-X}

_{2. Drummer R, Hauschild A, Santinami M, et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage III melanoma. N Engl J Med. 2020; 383(12):1139-1148
doi: 10.1056/NEJMoa2005493}