Long-Term Data Deepen Dabrafenib/Trametinib Benefit in Melanoma

Keith Flaherty, MD

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) continued to demonstrate impressive overall survival (OS) and progression-free survival (PFS) findings for patients with BRAF-mutant metastatic melanoma in 3-year follow-up data from the phase III COMBI-d study.

At the February 15, 2016, data cutoff for the 3-year analysis, which was presented at the 2016 ASCO Annual Meeting, 58% of patients remained on therapy. The 3-year PFS rate with the combination was 22% versus 12% with single-agent dabrafenib. The 3-year OS rate was 44% with dabrafenib plus trametinib compared with 32% with dabrafenib alone.

"This is the longest OS follow-up among randomized phase III trials evaluating a BRAF plus MEK inhibitor in patients with BRAF-mutant metastatic melanoma," said lead investigator Keith T. Flaherty, MD, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School. "With additional follow-up, and now 3-year maturity, dabrafenib plus trametinib continued to show significant benefit over dabrafenib monotherapy, despite crossover."

In the phase III COMBI-d trial, 423 patients with BRAF V600E/K-mutant melanoma were randomized to receive dabrafenib with trametinib (n = 211) or placebo (n = 212). At the time of the 3-year follow-up, 26 patients had crossed over from the single-agent group to the combination. The primary endpoint of the study was investigator-assessed PFS and secondary endpoints included OS, overall response rate (ORR), duration of response, and safety.

Baseline characteristics were well balanced between the two arms. The median ages of patients in the combination arm was 55 years and most were male (53%). The most common stage of cancer was M1c (67%) and 73% of patients had an ECOG performance status of 0. The majority of BRAF alterations were found in V600E (85%) and approximately one-third of those in each arm had elevated LDH levels.

The median OS with dabrafenib and trametinib was 25.1 months compared with 18.7 months with dabrafenib alone (HR, 0.71; 95% CI, 0.55-0.92; P = .0107). Median PFS was 11.0 versus 8.8 months (HR, 0.67; 95% CI, 0.53-0.84; P = .0004) and the ORR was 69% versus 53% (P = .0014), for the combination and dabrafenib alone, respectively.

Overall, 48% of patients in the combination arm went on to receive post-study anticancer therapy compared with 62% with the single-agent arm. The most common post-progression therapies in the combination and monotherapy arms, respectively, were ipilimumab (19% vs 31%), radiotherapy (24% vs 27%), chemotherapy (18% vs 24%), and small molecule targeted therapy (10% vs 15%).

For those with elevated LDH levels (n = 76), the combination showed a 3-year PFS rate of 13% versus 4% with single-agent dabrafenib. The 3-year OS rates in this group were 25% with the combination and 14% with the single-agent. Those with normal LDH levels (n = 133) had 3-year PFS rates of 27% and 17% and the 3-year OS rates were 54% and 45%, with the combination and single-agent, respectively.

"The best outcomes based on clinical features were those with normal LDH and fewer than 3 disease sites, as we've previously shown with less mature data," said Flaherty. "These results confirm that long-term survival can be achieved with this combination and it should be an important consideration for patients with BRAF mutation-positive advanced melanoma. It is particularly striking to note the excellent outcome for those with lower burden of disease at baseline."

Whole-exome sequencing was conducted on tumor and matched blood samples from 127 patients selected based on clinical response and LDH. For this analysis, 60% of patients had normal LDH levels in the combination arm versus 69% in the single-agent group.

The analysis found that CDKN2A mutations and deletions were significantly associated with a worse OS (P = .027) and PFS (P <.001). In those with CDKN2A loss, the 3-year OS rate was 55% with the combination versus 24% with dabrafenib alone. These findings coupled with preclinical work suggests a role for the combination of dabrafenib, trametinib, and a CDK 4/6 inhibitor, noted Flaherty.

Additionally, those with a higher overall mutation rate experienced prolonged OS with the combination. In this group, the 3-year OS rate surpassed 80% (P = .01); however, there was not a significant association for mutation burden and PFS (P = .3).

"Another interesting feature that was associated with overall survival but not progression-free survival was overall mutation burden rate," said Flaherty. "Although this is a small subset, it is interesting to note how exceptionally well this subset did while receiving targeted therapy."

All-grade adverse events (AEs) occurred in 97% of patients in each arms, with fewer grade 3/4 events in the combination arm (48% vs 50%). The most common all-grade AEs with the combination versus single-agent were pyrexia (59% vs 25%), fatigue (29% vs 37%), nausea (36% vs27%), headache (34% vs 29%), chills (32% vs 17%), and diarrhea (31% vs 17%). The incidence of cutaneous squamous cell carcinoma was 12% with single-agent dabrafenib and 4% with the combination. Additionally, other skin-related AEs were lower with the combination.

"The safety profile did not change with longer follow-up," noted Flaherty. "We do follow these patients treated with this regimen for proliferative skin lesions and other malignancies that have been sparsely reported, and we are pleased to see there has not been a significant change in those infrequent but still concerning events."

The combination of dabrafenib and trametinib continues to be explored across a number of settings. In addition to melanoma, the FDA granted a breakthrough therapy designation to the combination for patients with non—small cell lung cancer (NSCLC).

Flaherty K, Davies MA, Grob JJ, et al. Genomic analysis and 3-y efficacy and safety update of COMBI-d: A Phase III study of dabrafenib (D) + trametinib (T) vs D monotherapy in patients with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. J Clin Oncol. 2016;34 (suppl; abstr 9502).

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In those with both normal LDH and less than 3 disease sites at baseline (n = 76) the 3-year PFS rate was 38% with dabrafenib plus trametinib versus 15% with dabrafenib alone. The 3-year OS rates were 62% and 45%, with and without trametinib, respectively.