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Research Clarifies Immunotherapy, Targeted Treatment Order for BRAF-Mutant Melanoma Patients


NEW YORK – Advanced melanoma patients who receive immunotherapy before targeted therapies live longer, researchers have found.

In the Phase III DreamSeq trial, researchers set out to find the ideal treatment sequence for advanced melanoma patients, a setting crowded with immunotherapy and targeted treatment options. The full results, published in the Journal of Clinical Oncology in September, showed nearly three-quarters of advanced BRAF-mutant melanoma patients who received a first-line immunotherapy combination of Bristol Myers Squibb's Opdivo (nivolumab) and Yervoy (ipilimumab) were alive at two years. By comparison, about half of patients who first received Novartis' BRAF and MEK inhibitor combination, Tafinlar (dabrafenib) and Mekinist (trametinib), were alive at two years.

The Tafinlar-Mekinist combination is approved in the US for first-line treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Other BRAF/MEK inhibitor combinations also approved in this setting include Pfizer's Braftovi (encorafenib) plus Mektovi (binimetinib) and Genentech's three-drug combo of its checkpoint inhibitor Tecentriq (atezolizumab), MEK inhibitor Cotellic (cobimetinib), and BRAF inhibitor Zelboraf (vemurafenib).

However, oncologists' frontline treatment choice for melanoma patients is complicated by the approval of immunotherapies for all patients with unresectable or metastatic melanoma, regardless of biomarker status. Opdivo and Yervoy are approved in this setting, along with Merck's Keytruda (pembrolizumab) and BMS's newly approved immunotherapy combination Opdualag (nivolumab and relatlimab).

DreamSeq investigators hoped to gather evidence that would help physicians pick the treatment sequence most beneficial for their patients. In the trial they randomized patients to two treatment sequences: immunotherapy followed by targeted therapy and targeted therapy followed by immunotherapy. Once patients started to progress in the arm they were on, they could switch over to the other arm.

Michael Atkins, principal investigator of the DreamSeq trial and deputy director of Georgetown Lombardi Comprehensive Cancer Center, said these "practice changing" results may help resolve ongoing questions about when melanoma patients should receive targeted therapies.

"If patients are eligible to receive immunotherapy at all, then they should be receiving the immunotherapy combination," he said. "The immunotherapy tended to work better in the frontline setting than [when given] after targeted therapy, while targeted therapy seemed to work as well in the second-line setting as it did in the frontline setting. In order to get the most impact of the immunotherapy, you had to give it first."

However, the optimal treatment sequence can depend on several factors including how aggressive a patient's disease is and whether they have central nervous system (CNS) metastases, Atkins said.

In DreamSeq, survival on the immunotherapy arm was initially inferior to the Tafinlar-Mekinist arm, with 24 patients (18 percent) dying within the first 10 months on immunotherapy. The researchers noted in the paper that these patients had more aggressive disease and received less therapy than the overall study population, which may suggest that the targeted therapy has greater benefit for patients with aggressive cancers.

"It's likely that there are some patients whose disease is very aggressive where it may be more appropriate to start with targeted therapy and probably crossover to immunotherapy once the disease is a little bit better under control," he said. He also noted that a method called the "sandwich" treatment, where immunotherapy is given between two regimens of BRAF and MEK inhibitor therapy, improved survival in the Phase II SECOMBIT trial.

Meanwhile, Atkins suggested that patients with CNS metastases are likely to benefit more from first-line immunotherapy followed by the targeted therapies, due to immunotherapy typically being more effective in CNS, though he noted that most patients in the DreamSeq study had no history of CNS metastases.

"The majority of patients who relapsed after responding to targeted therapy later progressed in the central nervous system," he said. "That is a bad site of progression, which probably contributed to those patients doing less well."

The researchers will continue following these patients and report survival, progression-free survival, and response rate data with longer follow-up. They also recently published a quality of life and toxicity sub-analysis from DreamSeq showing that patients receiving the Tafinlar/Mekinist combination had better function and fewer side effects than those receiving Opdivo and Yervoy. Atkins said that toxicity shouldn't dissuade physicians from using these drugs, however, noting that the sites participating in the DreamSeq study were able to manage toxicity and still see benefit from the immunotherapies.

Atkins said his team will continue to analyze the data from DreamSeq, including biomarker analysis of blood and tissue samples, to further refine the patient group that should receive immunotherapy first or targeted therapy first.

"There are a lot of correlative studies that we're looking at using blood and tumor tissue to see if we can best identify the patients who might do better with one approach versus another and isolate the group of patients who might need a targeted therapy," he said

There is also an opportunity to conduct a similar study in the adjuvant melanoma setting where oncologists face similar challenges in choosing between approved immunotherapies and targeted therapies. Atkins said although he is not involved in a potential second study in this area, colleagues have discussed follow-on explorations to clarify the optimal adjuvant treatment.