Research Efforts Abound in Rapidly Evolving BRAF-Mutant Melanoma Paradigm

Efforts are being made to address remaining questions in the realm of BRAF-mutant melanoma, according to Charles L. Sawyers, MD. Areas of interest include determining the effectiveness of adding immunotherapy to targeted therapy and whether intermittent dosing of BRAF/MEK inhibitor combinations might yield more benefit than continuous dosage.

The phase 3 IMspire150 trial enrolled treatment-naïve patients with BRAF V600–mutant advanced melanoma. Patients were treated with atezolizumab (Tecentriq) in combination with vemurafenib (Zelboraf) and cobimetinib (Cotellic). Results presented at the 2020 AACR Annual Virtual Meeting I showed that the triplet regimen significantly improved progression-free survival (PFS) and produced durable responses versus vemurafenib and cobimetinib alone.¹ The investigator-assessed median PFS with the triplet regimen was 16.1 months (95% CI, 11.3-18.5) versus 12.3 months (95% CI, 10.8-14.7) with vemurafenib/cobimetinib alone (log-rank, P = .1607); the benefit was observed across all prognostic subgroups.

Although this trial was positive, and the comparison that was made was very intriguing at the time that the trial was in development, the field has rapidly evolved. Now, the standard treatment for this patient population has become immunotherapy alone, either in the form of a CTLA-4 inhibitor or PD-L1 or PD-1 antibodies. “[Data reported on this approach showed that] 40% of the patients had PFS out to 5 years,” said Sawyers. “It would be hard to beat that with the data we saw presented at the [2020 AACR Virtual Meeting I] from the combination trial.”

Appropriate dosing of BRAF/MEK inhibitors is another topic of interest in the space. To this end, the SWOG S1320 trial enrolled patients with BRAF mutation–positive advanced melanoma. All patients received continuous dabrafenib (Tafinlar) and trametinib (Mekinist) for 8 weeks; at that time, those not experiencing disease progression were randomized to receive either continuous treatment or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. Results presented at the 2020 AACR Virtual Meeting I showed that continuous dosing improved PFS compared with intermittent dosing. The median PFS was 9.0 months in the continuous dosing arm versus 5.5 months in the intermittent dosing arm (HR, 1.36; 80% CI, 1.10-1.66; P = .063).²

These results sharply contrasted with what had been observed in animal models. Preclinical research suggested that intermittent dosing could delay acquired resistance by selecting tumor cells that grow in the presence of these agents.

“One criticism [of this study] is that in order for the withdrawal to work, you need to ‘pull the rug out’ from under the tumor by having the drugs that you are withdrawing rapidly cleared out of the patient,” noted Sawyers. “One of the drugs that was used, a MEK inhibitor, has a very long half-life; it hangs around in the patient for about 4 or 5 days. In a sense, that may have been a bit of a bad decision. I was not involved in any of the early planning stages [of that trial], but choosing an inhibitor with a shorter half-life might have yielded a different result. We will never know, unless that trial gets redone.”

In an interview with OncLive, Sawyers, a 2013 OncLive® Giant of Cancer Care® in Prostate Cancer; internist and hematologic oncologist; chair of the Human Oncology and Pathogenesis Program; and Marie-Josee and Henry R. Kravis Chair at Memorial Sloan Kettering Cancer Center, provided additional insight into the IMspire150 and SWOG S1320 trials presented at the 2020 AACR Annual Virtual Meeting I and underscored the need for additional research in this space.

OncLive: You were a discussant during the opening clinical plenary at AACR. What were some of the notable presentations delivered during that forum?

Sawyers: I served as the discussant for 2 phase 3 clinical trials in BRAF-mutant melanoma. One of them asked a question that has been lingering in the field for 10 years or more. That question is, “What happens if you combine immunotherapy with kinase inhibitor therapy?” Both of these regimens [are effective] in patients with BRAF-mutant melanoma. Immunotherapy has activity in a small percentage of patients, but their responses can be quite durable. Kinase inhibitors work in a larger fraction of patients, but their responses are complicated by acquired resistance. The answer to that question is that [the combination of the two] is better than the kinase inhibitor alone.

The second trial asked a different question: “Kinase inhibitors are effective, but do we have to give them continuously or can we give them in an intermittent fashion?” You might ask why we would want to give them intermittently and the answer is that there are some fascinating data generated in laboratories and confirmed in animal models that [show that] you could get a better result if you give the drug intermittently. There are some scientific details to support that rationale, so it made sense to move forward with the clinical trial. Unfortunately, however, that trial was negative. In fact, results showed that continuous therapy was better than intermittent therapy.

As you alluded to, results from the phase 3 IMspire150 trial were presented. Could you discuss that research?

In this trial, immunotherapy plus kinase inhibitor therapy was effective; this is great, but the field has moved forward at an incredibly rapid pace. The comparison that was set up, while very compelling at the time the trial was designed, is a bit troubling because now the standard treatment for patients with BRAF-mutant melanoma is immunotherapy alone but given as 2 drugs: ipilimumab (Yervoy), or a CTLA-4 inhibitor, and the other, PD-L1 or PD-1 antibodies. Those data, which were released in an early form a few years ago, and then a 5-year follow-up reported last year, is really impressive.

The field has moved ahead as well and comparisons of the 2 types of regimens are moving forward, so we will know more. It is exciting to be in a time where progress is happening so quickly all the way to the clinical level. However, my background is more on the laboratory and translational side of things. The most interesting thing about the trial was to address the question of whether by killing tumor cells with a kinase inhibitor therapy and then coming in with immunotherapy could improve or enhance the immune response. We cannot really answer that question based on the data that were shown because we do not have enough of what we often refer to as the correlative science data from the patients. [Acquiring that data would involve] tracking very carefully the status of the immune response to the tumor before the trial, before the patient received the drugs; the immune response after the kinase inhibitors; and how that response changes once immunotherapy has been added. The tools to do that have really come of age in the past year. As such, it will be exciting to address those questions going forward.

The SWOG S1320 trial examined continuous versus intermittent dosing with dabrafenib and trametinib in patients with BRAF-mutant melanoma. What were your thoughts on those data? Do you think intermittent dosing will still be examined in the future?

My takeaways from the second presentation on melanoma were that continuous therapy was superior to intermittent therapy; however, this does not mean that we are done with intermittent therapy. Unfortunately, [this approach] gets a bad name because of this trial, and some other trials done in other contexts, that have not panned out in terms of the promise that seemed to be coming from the laboratory. The reason could be that it just does not work when you move from the laboratory to patients and we should just forget about it and continue with continuous dosing. However, I hope we do not take that path because there were some problems with the trial.

One problem is that the hypothesis was based on a subset of patients who developed resistance to kinase inhibitor therapy by amplifying the target gene BRAF; that happens in about one-third of patients, but the investigators on this trial enrolled every patient. Maybe the third [of patients] who should have benefited, did benefit, but you could not see the result because that was not tracked in the trial. It is not a trivial criticism because it is very hard to monitor these things; however, there are tools, such as plasma DNA, in which this could be looked at further.

References:

1. McArthur GA, Stroyakovskiy D, Gogas H, et al. Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAF^V600 mutation-positive advanced melanoma: primary results from the phase 3 IMspire150 trial. Paper presented at: the 2020 AACR Annual Virtual Meeting I; April 27-28, 2020; Virtual. Abstract CT012. bit.ly/2Y88drw.
2. Algazi A, Othus M, Daud A, et al. SWOG S1320: Improved progression-free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma. Paper presented at: 2020 virtual annual meeting of the American Association for Cancer Research; April 27-28, 2020; Virtual. Abstract CT013. bit.ly/2M6Eg3X.