Long-Term and Brain Mets Data Demonstrate Strong Dabrafenib/Trametinib Efficacy in Melanoma

Jeffrey S. Weber, MD, PhD

Favorable long-term phase II results of the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) in patients with BRAF V600-mutant melanoma were presented at the 2017 ASCO Annual Meeting, demonstrating that the regimen had 4-year and 5-year overall survival (OS) rates of 30% and 28%, respectively.¹

In the open-label trial, patients with BRAF V600-mutant melanoma were randomized 1:1:1 to receive dabrafenib plus 1 mg/day of trametinib, dabrafenib plus 2 mg/day trametinib, or dabrafenib alone (n = 54 each). Forty-five patients in the dabrafenib-alone arm crossed over to receive the combination as of October 13, 2016.

The data showed that OS with dabrafenib/trametinib continued to remain superior to dabrafenib monotherapy. The progression-free survival (PFS) curve for dabrafenib/trametinib also remained stable, with 4-year and 5-year rates both at 13%. At the 5-year landmark, 1 patient who received dabrafenib/trametinib went from a partial response to a complete response.

Additional encouraging findings presented at the meeting focused on the impact of this combination in BRAF-mutant patients with melanoma who harbor brain metastases. An analysis of the phase II COMBI-MB trial results showed that dabrafenib plus trametinib achieved an intracranial response (IR) rate of 58% in melanoma that metastasized to the brain.² The median duration of response (DOR), 6.5 months, was generally shorter than that observed in patients with melanoma who did not have brain metastases.

Patients in cohort A (n = 76) were asymptomatic for brain metastases, had an ECOG performance status of 0 or 1, and had not received prior local therapy. Cohorts B through D were considered exploratory due to their small sizes (n = 16, 16, and 17, respectively). Moreover, all patients received 150 mg of dabrafenib twice daily plus 2 mg of trametinib daily.

In cohort A, 29 of 44 patients (66%) experienced a survival event. The median DOR was 6.5 months (95% CI, 4.9-10.3), and the 6-month OS rate was 63% (95% CI, 45%-76%) in this cohort. In cohort A, 44 patients showed an overall response (95% CI, 46-69). The cohort’s overall median DOR was 6.5 months (95% CI, 4.9-10.3), and the 6-month rate was 57% (95% CI, 41-71).

The PFS in the overall study cohort was 5.6 months (95% CI, 5.3-7.4). Also, preliminary data showed that 44 patients experienced a survival event and the median OS was 10.8 months (95% CI, 8.7-19.6).

Aside from dabrafenib/trametinib, the combination regimen of nivolumab (Opdivo) plus ipilimumab (Yervoy) generated excitement in a phase II trial, in which more than 40% of patients with melanoma who had brain metastases achieved objective IRs when treated with the combination.³ The response rate increased to 50% for patients with previously untreated melanoma, and one-fifth of patients with untreated disease had IRs to treatment with nivolumab alone.

OncLive: Can you discuss the 5-year follow-up results with the dabrafenib/trametinib combination in melanoma presented at the 2017 ASCO Annual Meeting?

Jeffrey S. Weber, MD, PhD, deputy director and co-director of the Melanoma Program, Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, discussed both pivotal studies for dabrafenib/trametinib in patients with melanoma and any unanswered questions that remain after the extensive 5-year follow-up in an interview with OncLive during the 2017 ASCO Annual Meeting.Weber: The gist of the presentation that I made was that our study was the longest-term follow-up with any BRAF/MEK inhibitory combination trial done. This was a randomized phase II portion of a larger phase I/II trial, part C, in which 50 or so patients per arm were randomized to get the BRAF/MEK inhibitor combination, dabrafenib/trametinib, at the standard dose of dabrafenib 150 mg twice daily by mouth and then trametinib at either 2 mg or 1 mg once daily by mouth versus the control arm of dabrafenib alone, which was then an FDA-approved treatment at the 150-mg daily standard dose.

The long-term follow-up suggest that of the patients free of progression at 4 and 5 years, it plateaued between 10% and 15%. Some of those patients will be free of progression—which includes a handful of patients who actually stayed on treatment beyond 5 years—or patients who came off treatment for various causes, such as the investigator’s choice or the patient’s decision not to continue, or toxicity. And they never progressed.

If you look at the survival curve, there does appear to be a plateau at year 5, in that the 4-year survival was 30% and the 5-year survival was 28%. It does appear that past year 3, there is a plateau on that survival curve. This implies that it’s a tail on the curve that you traditionally see with immunotherapy, but here you are seeing it with targeted therapy.

Again, not all of these patients went on to get immunotherapy. About one-third of patients received PD-1 antibodies [and] another 20% or so received other immunotherapies, but a considerable portion of patients never did go on to immunotherapy. This suggests that the BRAF/MEK inhibitors combination alone can induce long-term survival.

Dabrafenib was also found to demonstrate promising activity in BRAF-mutant patients with melanoma who also have brain metastases. Could you provide an overview of these findings as well?

What is the prevalence of patients with melanoma who also develop brain metastases?

It puts lie to the “urban legend” that, virtually, everybody who is treated with BRAF/MEK inhibition is going to progress and die within a couple of years of starting therapy. A considerable proportion of patients will be alive and well in years 4 and 5, and that was the main message of this presentation. The main message of the presentation on brain metastases was that BRAF/MEK inhibitors can induce responses in these patients with brain metastases. Patients can have long-term survival and good PFS when they have brain metastases, but, again, most of the patients with brain metastases eventually will progress so there is certainly activity in the brain of the BRAF/MEK drugs; there can be long-term survival. It remains to be seen whether it is as good as the response rates and survival of patients who get ipilimumab with nivolumab, which was the subject of the other 2 abstracts in that particular session. Certainly, there is activity and that is the important thing. Over time, a minority of patients will develop brain metastases—maybe 30% to 50% of patients. It is probably going to happen in almost all patients who progress. With combination immunotherapy, 50% or so of patients are destined to progress.

The vast majority of these patients are going to develop brain metastases, some as the first site of presentation and some later on after progressing elsewhere—but it is extremely common. It is a medical problem that represents a major unmet medical need. It is also an unmet medical need in lung cancer and breast cancer, which are the 2 other histologies where you commonly see brain metastases. Therefore, seeing activity with both BRAF/MEK inhibitors and, of course, even more activity with ipilimumab/nivolumab is a big deal.

What unanswered questions do we still have with the dabrafenib/trametinib combination?

The ipilimumab/nivolumab data were confirmatory. There was a Bristol-Meyers Squibb study, and then there was a separate Australian/New Zealand study suggesting that there is good validity to those results. It is interesting. A lot of the action in the melanoma world—in the cancer world, in general—is immunotherapeutic. Obviously, the targeted drugs need to be combined with immunotherapy. There are a number of interesting trials; the KEYNOTE-022 trial, which is a combination of pembrolizumab (Keytruda), dabrafenib, and trametinib, [is one]. That is a very interesting study that is now in a randomized trial.

There is also a Genentech study of atezolizumab (Tecentriq), vemurafenib (Zelboraf), and cobimetinib (Cotellic) versus atezolizumab alone. The unanswered question there is, “Can you actually stop any or all of the components of the regimen?” Sometimes, you are a little hesitant to stop the targeted therapy for fear that you will have patients progress. You don’t know how quickly you can stop the PD-1 inhibitor because, then, you are only on the BRAF/MEK inhibitor and how long are you going to stay on that?

It is a little confusing. However, those are very good phase III trials, and they are probably at or near accrual. We will find out in a couple of years if those are positive studies.

From these promising, long-term findings, what should community oncologists take away to apply to clinical practice? Also, at what point should clinicians test their patients for BRAF status?

The other thing that is being pursued is BRAF/MEK inhibition with CDK 4/6 inhibition. The initial results show that this regimen can be pretty toxic, but we await the clinical efficacy data from that triple targeted combination. Most of us would agree that anybody who presents with stage IV melanoma should have BRAF testing. You can do immunohistochemistry quickly, in 2 to 3 days, just to find out if it’s V600E. If you’re waiting for your genetic testing to see if it’s V600E or V600K, it might take a couple of weeks. If you have a patient with rapidly progressing disease, you want to move on and get them treated. Therefore, you might need to do IHC to make that decision.

There are those who argue that anyone with stage III disease should be BRAF tested. There are no current ongoing trials that I know of or adjuvant trials that would require stage III patients to be treated. They can probably safely wait, if and when they metastasize, to be tested. You will save a couple of days—even 1 week or 2—if you test this stage III patient who relapsed, and then when they develop stage IV disease, you will know their BRAF status. Certainly, every stage IV patient—which is anyone who is going to receive systemic therapy as their treatment—should be tested for BRAF.

References

1. Long GV, Eroglu Z, Infante JR, et al. Five-year overall survival (OS) update from a phase II, open-label trial of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600—mutant unresectable or metastatic melanoma (MM). J Clin Oncol. 2017;35(suppl; abstr 9505).
2. Davies MA, Robert C, Long GV et al. COMBI-MB: a phase II study of combination dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600-mutant (mut) melanoma brain metastases (MBM). J Clin Oncol. 2017;35(suppl; abstr 9506).
3. Long GV, Atkinson V, Menzies AM, et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): the Anti-PD1 Brain Collaboration (ABC). J Clin Oncol. 2017;35(suppl; abstr 9508).