1. Fuerst, Mark L.

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A combination of nivolumab plus ipilimumab followed by dabrafenib-trametinib leads to 20 percent higher overall survival (OS) at 2 years than the converse sequence for patients with advanced BRAF V600-mutant metastatic melanoma. Nivolumab-ipilimumab results in more durable, ongoing responses and better OS in all subgroups examined.

Melanoma. Melanoma... - Click to enlarge in new windowMelanoma. Melanoma

Marketing data show that half of all U.S. patients with metastatic BRAF-mutant melanoma receive BRAF-MEK inhibitors, and only one-quarter received nivolumab-ipilimumab as initial therapy. No Phase III prospective data exists to determine the preferable approach or sequence.


"The PFS and OS benefits of nivolumab-ipilimumab are substantial compared to nivolumab monotherapy in the subset of patients with BRAF-mutant melanoma on the CheckMate-067 study, supporting the choice of combination nivolumab-ipilimumab as a preferred immunotherapy in this population," said Michael B. Atkins, MD, Deputy Director of the Georgetown-Lombardi Comprehensive Cancer Center, during a live broadcast of the inaugural American Society of Clinical Oncology Plenary Series.


DREAMseq Study

In 2015, researchers launched the DREAMseq trial to answer the question: which approach was preferred and, given that most patients would have access to both approaches, is there an optimal sequence? Patients with treatment-naive BRAF-mutant melanoma were stratified according to ECOG performance status and LDH normal or high, and randomized to receive either nivolumab-ipilimumab induction for 12 weeks, followed by nivolumab monotherapy maintenance for up to 72 weeks (Arm A), or dabrafenib-trametinib continuously (Arm B). For step 2, if patients experienced disease progression, they crossed over to the alternative sequence. The primary endpoint was 2-year OS.


The median follow-up was 27.7 months, with 265 patients, median age 61 years, evenly split between the Arms A (133 patients) and B (132 patients), and 73 patients who enrolled in step 2, with nearly two-thirds of those on second-line nivolumab-ipilimumab.


The two initial arms were balanced for most characteristics. Slightly more patients on Arm B had unresectable Stage III disease and had received prior adjuvant therapy, almost exclusively interferon, Atkins noted.


"Response rates were slightly lower than reported in the industry-sponsored trials, as is common with cooperative group studies. Response rates were similar between Arms A and B regimens and for dabrafenib-trametinib, whether used at first or in step 2. In contrast, nivolumab-ipilimumab appeared to be less effective after progression on dabrafenib-trametinib than on first-line therapy," he said.


For patients with sufficient follow-up, duration of initial response was significantly longer for nivolumab-ipilimumab (not reached) versus dabrafenib-trametinib-12.7 months. "Of note, 37 of 42 responders to initial nivolumab-ipilimumab remain in response, and well over half of the dabrafenib-trametinib responders have exhibited disease progression," said Atkins.


In total, 100 patients have died, with 62 patients beginning with dabrafenib-trametinib. The 2-year OS was 72 percent for patients who started on nivolumab-ipilimumab and 52 percent for those who started on dabrafenib-trametinib.


The data safety monitoring committee felt that there was a clinically meaningful difference in OS and recommended that the study be closed to approval and patients on first-line dabrafenib-trametinib be given the option to switch to nivolumab-ipilimumab, without the need for disease progression.


Some 24 patients died within 10 months on first-line nivolumab-ipilimumab. "They tended to have poor prognostic features relative to the general study population, and received limited treatment either due to early progressive disease or adverse event. Interestingly, none of them successfully crossed over to dabrafenib-trametinib. 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 explained.


Data on 115 of the 145 patients who progressed show that about half did not enroll in step 2 due to early disease-related death.


The incidence of Grade 3 treatment-related adverse events was similar between Arms A and B in between the specific treatment approaches. There were two treatment-related deaths on Arm A, one each from myocarditis and GI toxicity, and one death in step 2, related to a stroke.


For all subsets, 2-year OS was better for the sequence beginning with nivolumab-ipilimumab. "Even in the group where dabrafenib-trametinib is purported to do best, those with performance status 0, normal LDH and better stage, or perhaps as a surrogate for less than three sites of disease, starting with nivolumab-ipilimumab, showed a strong trend for improved 2-year OS," said Atkins.


Dabrafenib-trametinib optimum efficacy is maintained in the second line and is a critical contributor to overall efficacy, he noted. "Nivolumab-ipilimumab could be administered safely and effectively in a cooperative group setting. PFS and OS curves were biphasic, with curves crossing at 6 and 10 months, respectively. Patients dying early on nivolumab-ipilimumab had worse prognosis and adverse events, and never received dabrafenib-trametinib. Efforts are underway to further identify and best manage this small subset of patients," said Atkins.


He concluded that "in this population with an oncogene-driven tumor and an effective targeted therapy, nivolumab-ipilimumab, followed by a BRAF/MEK inhibitor, if necessary, should be the preferred treatment sequence."


Keith Flaherty, MD, Associate Professor of Medicine at Harvard Medical School, noted that new treatment regimens have emerged. Particularly relevant to the BRAF-mutant population is a positive Phase III trial combining BRAF/MEK with a PD-L1 antibody, improving PFS, the primary endpoint of the study.


"We saw just this past year a LAG-3 antibody, relatlimab, combined with PD-1 monotherapy, nivolumab. This two-drug regimen was prospectively testing the question of PFS impact for the two-drug regimen versus monotherapy [and] was a positive result. Gratifyingly, this came at the expense of fairly modest increase in toxicity for the combination versus PD-1 monotherapy."


He added: "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."


Mark L. Fuerst is a contributing writer.