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Opdivo-Yervoy Before Tafinlar-Mekinist Provides Optimal Benefit to BRAF-Mutant Melanoma Patients

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NEW YORK – New Phase III data shows that metastatic melanoma patients harboring BRAF V600 mutations are better off receiving combination immunotherapy followed by combination targeted therapy if and when their disease progresses, rather than the other way around.  

Specifically, according to the results of a large-scale, randomized Phase III trial dubbed Doublet Randomized Evaluation in Advanced Melanoma Sequencing — or DREAMseq — patients with BRAF V600-mutated metastatic melanoma treated with the PD-1 inhibitor nivolumab (BMS's Opdivo) and the CTLA4 inhibitor ipilimumab (BMS's Yervoy) first lived longer overall than patients who received the BRAF inhibitor dabrafenib (Novartis' Tafinlar) and the MEK inhibitor trametinib (Novartis' Mekinist) first.  

Although the trial results, presented last week during the American Society of Clinical Oncology (ASCO)'s virtual plenary session, came from an interim readout of the large, National Cancer Institute-sponsored trial, the survival benefit was strong enough for an independent data monitoring committee to recommend the trial stop accruing new patients, and to give patients treated with the targeted drug combo upfront an option to switch to the immunotherapy arm if appropriate.  

The Phase III trial was designed to address a pressing clinical question that has been top –of mind for melanoma oncologists for a handful of years. Targeted therapies and checkpoint inhibitor immunotherapies have individually demonstrated benefit for this biomarker-defined patient population, and each doublet could be used as an alternative treatment method for patients with disease progression after the first doublet. But does it make a difference which combination comes first?  

"Current marketing data show that half of all patients in the US with metastatic BRAF-mutant melanoma receive BRAF-MEK inhibitors, and only one-quarter receive [nivolumab plus ipilimumab] as initial therapy," explained Michael Atkins, director of the Georgetown Lombardi Comprehensive Cancer Center and one of the DREAMseq trial's lead investigators, during a presentation of the data. "No Phase III prospective data exist [before now] as to which approach, or sequence of approaches, is preferred."  

The DREAMseq results provided a definitive answer to this sequencing question for the first time; it does make a difference which doublet comes first, the trial showed, and that doublet should be nivolumab plus ipilimumab.  

To conduct the Phase III study and reach this valuable conclusion, Atkins and colleagues randomly assigned 270 patients with unresectable stage III or IV BRAF-mutated melanoma to receive either nivolumab and ipilimumab until disease progression followed by dabrafenib-trametinib; or dabrafenib-trametinib until disease progression followed by nivolumab-ipilimumab.  

The study's primary endpoint was the percentage of patients on each treatment regimen still alive after two years, and the results clearly favored the checkpoint inhibitor combination therapy: the overall survival rates were 72 percent and 52 percent for the patients treated with the immunotherapy first versus the targeted therapy first, respectively.  

Interestingly, within the first 10 months of treatment, the opposite seemed to be true, with more patients surviving on the targeted therapy combination first. According to Atkins, this reversal had to do with a small subset of patients — 24 total — who began treatment with the immunotherapy first, but died before the 10-month mark.  

These patients, according to Atkins, had poorer prognoses than the rest of the study population, and for whatever reason, never had the chance to cross over to the dabrafenib-trametinib treatment arm when their disease progressed. 

"This suggests that in addition to bad disease biology, the study criteria for crossover eligibility might have been too strict for optimal drug exposure and efficacy," Atkins said, noting as well that his team is actively working on trying to better identify who these patients are and how best to treat them. He later shared that strategies underway to accomplish this include trying out a short course of the BRAF/MEK inhibitor combination upfront for patients with poor prognostic features; analyzing circulating tumor DNA among patients who aren't responding early on in the course of treatment to identify potential additional biomarkers; allowing patients who aren't doing well on initial immunotherapy to switch to the targeted therapy much sooner; and identifying predictive biomarkers in baseline tumor tissue to help predict whether patients won't benefit from immunotherapy versus initial dabrafenib-trametinib.  

Beyond this small subset of patients, and after the 10-month timeframe, the survival benefit for nivolumab-ipilimumab as the first course of treatment was clear.  

In presenting the data, Atkins was careful to point out that the clear superiority of treating with the immunotherapy combo upfront did not negate the important role of the targeted therapy as a second-line option. "Dabrafenib-trametinib efficacy is maintained in the second line and is a critical contributor to overall efficacy," he said, referring to nivolumab-ipilimumab followed by dabrafenib-trametinib as the new "preferred treatment sequence." 

Role of single-agent immunotherapy 

As is often the case given the rapidly advancing field of precision oncology — and, indeed, oncology at large — definitive answers about patients' best course of treatment are rarely "definitive" for long, since new questions and new therapies are quick to enter the scene. 

Such is the case with the DREAMseq data. While the field may be able to breathe a collective sigh of relief knowing that the order with which they treat their BRAF V600-mutated metastatic melanoma patients is the best for their long-term survival, several key questions remain unanswered.  

One such question is the role of anti-PD-1 monotherapy as a metastatic melanoma treatment. As Keith Flaherty of the Dana-Farber Cancer Institute pointed out in a discussion of the DREAMseq data, "the big moment in the field, which is the elephant in the room, is PD-1 monotherapy … CTLA-4 versus PD-1 has always been relatively data-poor with regard to the incremental benefit… and, in terms of toxicity, is a very, very important question not addressed in the DREAMseq trial."  

Importantly, there is a Phase III trial, the CheckMate 067 trial, which was designed to evaluate immune checkpoint inhibitors for metastatic melanoma. Rather than randomizing patients to receive anti-PD-1 monotherapy or the anti-PD-1, anti-CTLA4 combination, however, the trial randomized patients to receive either the PD-1 monotherapy or the combination versus the CTLA4 inhibitor alone.  

In other words, that trial was not technically powered to compare anti-PD-1 monotherapy to combination nivolumab-ipilimumab. That said, a retrospective subset analysis did show after –the fact that the combination immunotherapy resulted in prolonged progression-free survival versus the monotherapy specifically for patients with BRAF-mutated disease. BRAF-wildtype patients saw no benefit from the combination therapy versus the PD-1 checkpoint inhibitor monotherapy.  

In Flaherty's view, the CheckMate-067 analysis, because of its retrospective and descriptive nature, did not definitively settle the question of the PD-1 monotherapy's role. Though he was careful not to directly extrapolate, he did point out that large-scale data in earlier-stage melanoma — specifically, patients undergoing post-surgery treatment — the combination did not benefit relapse-free survival versus the monotherapy. 

"PD-1 monotherapy has a remarkable therapeutic index, and the rate of severe toxicity is markedly less than PD-1, CTLA4 combination therapy," Flaherty noted, pointing out far higher rates of drug-related deaths, high-grade toxicities, and discontinuation of treatment with the combo versus the single-agent across pooled clinical trials. Given the high stakes with regard to toxicity, he emphasized the importance of showing in a head-to-head trial whether the combination was really best in this patient population.  

"This remains a very important question in the field. And unfortunately, we have no ongoing trials that are addressing it." 

Meanwhile, in Atkins' view, the retrospective CheckMate 067 data does show that the combination is clearly preferred versus PD-1 monotherapy. Even though the comparison between those two arms was not the trial's primary aim, the benefit for both progression-free survival and overall survival after 6.5 years, in his view, supports the combination.  

"I interpret the [CheckMate 067] data as showing a 14 percent difference in both the tail of the progression-free survival and overall survival curves for nivolumab-ipilimumab versus nivolumab monotherapy," he said. "That is 14 out of 100 more patients alive at 6.5 years with nivolumab-ipilimumab versus nivolumab monotherapy." 

With regard to the added toxicity with the combination therapy, Atkins said that, in this treatment setting, the added toxicity upfront is "balanced by the ability to stop treatment and get people back to their normal lives much quicker with the combo." 

In other words, if patients experience more toxicity, it will have been worth it when they reach a state of remission shortly thereafter and remain disease-free for longer. Atkins did acknowledge that the combination doesn't add much for BRAF-wildtype melanoma patients, though. 

Role of new treatments 

Even without the lingering question of single-agent immunotherapy, there may be further uncertainty on the horizon about the best way to treat BRAF V600-mutant metastatic melanoma. Recently, for example, another clinical trial showed that BMS' investigational LAG3 antibody relatlimab plus nivolumab was superior to nivolumab alone in this patient population — though the trial enrolled patients regardless of BRAF mutation status — and in another recent study, the combination of BRAF/MEK inhibitors plus anti-PD-L1 immunotherapy improved progression-free survival versus the targeted combination alone.  

"These two new regimens … now further muddy the waters with regard to the optimal treatment approach for patients in the metastatic setting who are confronting a first-line treatment decision," Flaherty said, adding that he expects the LAG-3 antibody to become "a standard part of the melanoma armamentarium next year."