Adjuvant Dabrafenib/Trametinib RFS Benefit Persists Across Melanoma Subgroups

Georgina Long, BSc, PhD, MBBS

A doubling in 3-year relapse-free survival (RFS) rates remained consistent across patient subgroups treated with dabrafenib (Tafinlar) and trametinib (Mekinist), when compared with placebo, for patients with BRAF-mutant stage III melanoma, according to findings from the phase III COMBI-AD study presented at the 2017 World Congress of Melanoma (WCM).

At the primary analysis, which was conducted after a median follow-up of 2.8 years, the 3-year RFS rate with dabrafenib and trametinib was 58% compared with 39% for placebo (HR, 0.47; 95% CI, 0.39-0.58; P <.001). The 3-year overall survival (OS) rate was 86% in the combination arm versus 77% with placebo (HR, 0.57; 95% CI, 0.42-0.79; P = .0006), although this did not yet cross the boundary for statistical significance due to short follow up.

The benefits seen with the combination were consistent in those with BRAF V600K and V600E alterations, by gender, stage of disease, micro/macro metastases, and by disease characteristics. The presentation at WCM focused on differences in RFS across stage of disease, different metastatic groups, and those with or without tumor ulceration.

"Dabrafenib plus trametinib represents a significant advance for adjuvant treatment of stage III BRAF V600-mutant melanoma," said study co-investigator Georgina V. Long, BSc, PhD, MBBS, clinical researcher at the Melanoma Institute Australia and Westmead Hospital in Sydney. "The results were statistically significant and clinically meaningful. This RFS benefit was observed in all patient subgroups."

In the COMBI-AD study, 870 patients with BRAF-mutant stage III melanoma were evenly randomized to receive dabrafenib plus trametinib (n = 438) or placebo (n = 432). All patients were within 12 weeks of complete surgical resection and had melanoma that was stage IIIa (n = 154), IIIb (n = 356), and IIIc (n = 347). Patients received dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily for 12 months.

The baseline characteristics were similar between treatment arms. In the combination group, the median age of patients was 50 years. Most patients (92%) had an ECOG performance status of 0. Overall, 12% of patients in the combination group had in-transit metastases versus 8% with the placebo. Seventeen percent of patients had ≥4 positive lymph nodes involved, with the remainder having <4.

In those with stage IIIa disease, the 3-year RFS rate was 79.3% with the combination versus 62.9% with placebo (HR, 0.44; 95% CI, 0.23-0.84). In the stage IIIb group, the 3-year RFS rates were 57.3% and 38.5% for the combination and placebo groups, respectively (HR, 0.50; 95% CI, 0.37-0.67). In the stage IIIc group, the 3-year RFS rate with the combination was 50.2% versus 30.0% with placebo (HR, 0.45; 95% CI, 0.33-0.60).

Median RFS had not yet been reached for patients with stage IIIa/c disease but was available for those with stage IIIc melanoma. In this group, the median RFS with dabrafenib and trametinib was 39.5 months (95% CI, 27.4-not reached) compared with 7.4 months with placebo (95% CI, 5.6-11.5).

In those with micrometastatic disease in the lymph nodes (n = 309), the 3-year RFS rate was 70.3% with dabrafenib/trametinib versus 49.5% with placebo (HR, 0.44; 95% CI, 0.30-0.64). In those with macrometastases (n = 319), the 3-year RFS with the targeted therapies was 58.1% compared with 35.4% for placebo (HR, 0.43; 95% CI, 0.31-0.58).

The 3-year RFS rate in those without primary tumor ulceration (n = 502) was 63.3% with the combination of dabrafenib and trametinib versus 44.2% with placebo (HR, 0.49; 95% CI, 0.37-0.64). In those with ulcerated tumors (n = 356), the 3-year RFS rate with the combination was 52.2% versus 32.3% for the placebo arm (HR, 0.46; 95% CI, 0.34-0.61).

Adverse events (AEs) were experienced by 97% of those treated with dabrafenib and trametinib versus 88% with placebo. AEs related to study drug were seen in 91% and 63% of those in the combination and placebo groups, respectively. The rates of grade 3/4 treatment-related AEs were 31% and 5% for the combination and placebo, respectively.

Overall, AEs led to discontinuation for 26% of those in the combination arm versus 3% with placebo. Dose interruptions were needed for 66% of patients in the combination arm versus 15% with placebo. Overall, the most frequent AE was pyrexia, which occurred in 67% of those treated with dabrafenib/trametinib versus 15% with placebo.

"The median time to onset of the first fever was 23 days. For placebo it was 53 days, with a very long range," Long noted. "For the combination, 24% of pyrexia were serious adverse events, resulting in a hospitalization, for example."

Pyrexia was managed with paracetamol, nonsteroidal anti-inflammatories, and corticosteroids, said Long. In the study, a variety of dose withdrawals, reductions, or interruptions of one or both targeted therapies were undertaken. "At our institution, we do not dose reduce," she said. "We interrupt both drugs at the first symptom of pyrexia."

The FDA initially granted an accelerated approval to the combination of dabrafenib and trametinib for patients with BRAF-mutant metastatic melanoma in January 2014. The combination received a full approval in November 2015. Novartis, the company developing the combination, has already entered regulatory discussion for an adjuvant indication.

Long GV, Hauschild A, Santinami M, et al. Efficacy outcomes in the phase 3 COMBI-AD study of adjuvant dabrafenib (D) plus trametinib (T) vs placebo (PBO) in patients (pts) with stage III BRAF V600E/K—mutant melanoma. Presented at: 2017 World Congress of Melanoma; October 18-21, 2017; Brisbane, Australia. Presentation SMR09-1.

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The most frequent type of first recurrence was distant in both groups (62% vs 54% for combination and placebo, respectively). This was followed by local or regional recurrence, at 37% and 46% in the combination and placebo groups, respectively. "There were equal numbers of second primary melanoma, and there were some deaths at the time of recurrence: 3 in the combination arm and 1 in the placebo arm," said Long.