Nivolumab/Ipilimumab +/- Dabrafenib and Trametinib Improved Survival for BRAF+ Metastatic Melanoma

Phase 3 data indicated that the combination of nivolumab and ipilimumab followed by treatment with dabrafenib and trametinib, if necessary, resulted in greater overall survival at 2 years for patients with treatment-naïve BRAF-mutant metastatic melanoma.

Treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) followed by dabrafenib (Tafinlar) and trametinib (Mekinist) if needed was associated with a greater 2-year overall survival (OS) rate than the converse sequence of regimens for patients with treatment-naïve BRAF-mutant metastatic melanoma, according to results from the phase 3 DREAMseq trial (NCT02224781) presented during the American Society of Clinical Oncology (ASCO) Plenary Series.

At 2 years, OS rates were 72% (95% CI, 62%-79%) for patients who started treatment with the nivolumab/ipilimumab combination compared with 52% (95% CI, 42%-60%) for patients who started with the dabrafenib plus trametinib combination (P = .0095).

“Nivolumab plus ipilimumab results in more durable and ongoing responses,” Michael Atkins, MD, deputy director of the Georgetown Lombardi Comprehensive Cancer Center, said in his presentation of the data. “The OS benefit for the nivolumab plus ipilimumab initial sequence was seen in all subgroups examined.”

Patients with treatment-naïve BRAF-mutant metastatic melanoma were randomized to 1 of 2 arms: They received either nivolumab plus ipilimumab induction for 12 weeks followed by nivolumab maintenance therapy for up to 72 weeks (Step 1) plus continuous dabrafenib/trametinib following progression (Step 2), or dabrafenib plus trametinib continuously (Step 1) followed by induction ipilimumab and nivolumab with subsequent maintenance nivolumab upon progression (Step 2).

The primary objective of the DREAMseq trial was 2-year landmark OS. Secondary end points addressed in the initial report included overall response rate (ORR), progression-free survival (PFS), and safety of the nivolumab plus ipilimumab combination, the feasibility of crossover, and the activity of dabrafenib plus trametinib after nivolumab plus ipilimumab compared with dabrafenib plus trametinib up front, and vice versa.

As of the July 16, 2021, data cutoff date, 133 patients had enrolled in the nivolumab plus ipilimumab arm and 132 were in the dabrafenib plus trametinib arm. The median follow-up was 27.7 months.

The median age for the patient population was 61 years. Sixty-one percent of patients in the nivolumab plus ipilimumab arm were male compared with 65% of patients in the dabrafenib plus trametinib arm. ECOG performance statuses of 0 were observed in 68% and 67% of patients in the nivolumab plus ipilimumab and dabrafenib plus trametinib arms, respectively. Seven percent and 13% of patients in the respective arms had stage III unresectable disease.

Grade 3 treatment-related adverse effects (TRAEs) were observed in 60% (95% CI, 51%-69%) of patients in the nivolumab plus ipilimumab arm compared with 52% (95% CI, 43%-61%) of patients in the dabrafenib plus trametinib arm. Grade 5 AEs were observed in 11 and 10 patients, with deaths from any cause seen in 2 and 0 patients in the nivolumab plus ipilimumab and dabrafenib plus trametinib arms, respectively.

A total of 27 and 41 patients crossed over to the alternative treatments. Grade 3 TRAEs were seen in 54% (95% CI, 33%-73%) of patients who crossed over to dabrafenib plus trametinib and 50% (95% CI, 34%-66%) of patients to nivolumab plus ipilimumab. Grade 5 AEs were seen in 3 patients from each group with 1 death among patients who went to the dabrafenib plus trametinib arm.

ORR in step 1 was 46% in the nivolumab plus ipilimumab arm compared with 43% in the dabrafenib plus trametinib arm. Step 2 yielded ORRs of 48% and 30% for patients crossing over to the dabrafenib plus trametinib and nivolumab plus ipilimumab arms, respectively (P = .136). The median duration of response was not reached in the nivolumab/ipilimumab arms vs 12.7 months in the dabrafenib/trametinib arm (P <.001).

“Response rates were similar between step 1 regimens and for dabrafenib plus trametinib whether used in step 1 or step 2,” Atkins explained. “In contrast, nivolumab plus ipilimumab appeared to be less effective after progression on dabrafenib plus trametinib than on first line therapy.”

The median PFS among step 1 patients in the nivolumab plus ipilimumab arm was 11.8 months (95% CI, 5.9-33.5) compared with 8.5 months (95% CI, 6.5-11.3) for the dabrafenib plus trametinib arm. The nivolumab plus ipilimumab arm showed significant benefit at the 2-year time point compared with the dabrafenib plus trametinib arm (P = .054). The 1-year PFS rates were 49% and 36% and the 2-year rates were 42% and 19% in the nivolumab/ipilimumab and dabrafenib/trametinib cohorts, respectively.

“Patients dying early on nivolumab plus ipilimumab had worse prognosis, adverse [effects], and never received dabrafenib plus trametinib,” Atkins explained. “Efforts are underway to further identify and best manage this small subset of patients.”

Reference

Atkins MB, Lee SJ, Chmielowski B, et al. DREAMseq (doublet, randomized evaluation in advanced melanoma sequencing): a phase III trial—ECOG-ACRIN EA6134. Presented at 2021 American Society of Clinical Oncology Plenary Series. November 16, 2021; virtual. Accessed November 17, 2021. https://bit.ly/3qKpoOn