Number of Baseline Melanoma Sites Predictive of OS in Dabrafenib/Trametinib Study

Georgina Long, MD

Georgina Long, MD

Dabrafenib (Tafinlar) combined with trametinib (Mekinist) continued to demonstrate durable efficacy for patients withBRAFV600E/K-mutant melanoma across patient subgroups in a 3-year analysis of the phase III COMBI-d study, with the amount of baseline sites of metastasis identified as a predictor of overall survival (OS) ≥36 months, according to findings presented at the 2016 Society for Melanoma Research (SMR) Congress.

The 3-year progression-free survival (PFS) rate with the combination was 22% (95% CI, 16-28) and the 3-year OS rate was 44% (95% CI, 37-51). Thirty-one patients (17%) had PFS of 36 months or longer, and 76 patients (41%) had OS of 36 months or longer. At the data cutoff, 40 patients (19%) remained on the combination regimen, including 23 of the 31 (31%) patients who experienced a PFS longer than 36 months, and 36 of 76 (47%) of those who experienced an OS longer than 36 months.

“Baseline number of organ sites with metastasis was the most predictive factor for patients with OS greater than or equal to 24 months going on to achieve OS greater than or equal to 36 months,” lead investigator Georgina V. Long, BSc, PhD, MBBS, and colleagues noted in a poster detailing the findings. Long is chair of Melanoma Medical Oncology and Translational Research at the Melanoma Institute of Australia (MIA) and Royal North Shore Hospital, University of Australia.

In the COMBI-d study, 211 treatment-naïve patients received 150 mg of dabrafenib twice a day plus 2 mg of trametinib once a day. The study also included 212 patients who received dabrafenib alone plus a placebo. At the data cutoff (February 2016), all living patients had at least 36 months of follow-up from the date of randomization.

In those with PFS <36 months, the ORR was 65% versus an ORR of 94% in those with a PFS of &ge;36 months. Similarly, the ORR in those with an OS <36 months was 59% compared with 88% in those with an OS of &ge;36 months. Further reinforcing the connection between response to therapy and long-term outcomes. Of responses, those who had a complete response (CR) had better long term outcomes. In the CR group, 18 patients (60%) had a PFS &ge; 36 months and 86% had an OS &ge;&nbsp;36 months.

&ldquo;A higher overall response rate was observed in patients with PFS and/or OS &ge;36 versus <36 months, commonly due to an increase in the number of patients achieving a complete response,&rdquo; the authors wrote in their poster.

Those with <3 organ sites with metastasis (n = 92) had a 3-year PFS of 27% versus 7% in those with &ge;3 (n = 91). A similar correlation was seen for OS and LDH levels. The 3-year OS rate was 23% in those with elevated LDH levels (n = 66) compared with a 3-year OS rate of 51% in those with normal LDH (n = 119).

&ldquo;Patients treated with dabrafenib plus trametinib in COMBI-d who had outcomes &ge;24 months but <36 months more often had higher baseline disease stage, number of organ sites with metastasis, and sum of lesion diameters, but normal LDH, compared with those with OS &ge;36 months,&rdquo; the authors observed. &ldquo;Regression tree analysis identified number of organ sites with metastasis as the most predictive baseline factor for achieving OS &ge;36 months in patients who had OS &ge;24 months with dabrafenib plus trametinib.&rdquo;

A regression tree analysis explored characteristics of those who achieved an OS &ge;36 months versus those who reached 24 months but not 36. Overall, those with &ge;3 organ sites of metastasis (n = 38) had a 3-year OS of 71% compared with 92% in those with <3 sites of metastasis (n = 53).

&ldquo;Longer-term follow-up analyses are needed to further characterize the durability of PFS and OS achievable with dabrafenib plus trametinib,&rdquo; the authors said. &ldquo;Continued monitoring of outcomes with extended follow-up may be warranted to determine which patients exhibit the greatest benefit with dabrafenib plus trametinib.&rdquo;

The combination of dabrafenib and trametinib was initially granted an accelerated approval in January 2014, based on phase I/II data. A full approval was granted to the combination in November 2015, based on findings from the COMBI-d study and also from the COMBI-v study, which compared the combination with the BRAF inhibitor vemurafenib. Both studies demonstrated an improvement in OS.

Factors that were associated with PFS and/or OS &ge; 36 months were lower disease stage, ECOG performance status, LDH level, number of organ sites with metastasis, and sum of target lesion diameters. Those with a higher ORR also were more likely to experience PFS and/or OS &ge;36 months.

Reference:

Long GV, Flaherty KT, Schadendorf D, et al. Patient characteristics associated with &ge;36-mo clinical benefit with combination dabrafenib and trametinib (D+T) in COMBI-d. Presented at: Society for Melanoma Research Annual Meeting; Boston, Massachusetts, November 6-9, 2016.