Prior ICI Associated With Longer PFS in BRAF V600E+ Melanoma Treated With Dabrafenib and Trametinib

June 4, 2020
Dylann Cohn-Emery

Partners | <b>American Oncology Network</b>

"..These findings may be susceptible to selection bias since patients with more aggressive disease may be more likely to start dabrafenib and trametinib in the first line."

Longer progression-free survival (PFS) was associated with prior immune checkpoint inhibitors (ICIs) treatment in patients with BRAF V600E–mutated melanoma who were receiving either intermittent or continuous dosing with dabrafenib (Tafinlar) and trametinib (Mekinist), according to a poster from the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

The randomized phase 2 SWOG S1320 study (NCT02196181) enrolled and treated 242 patients with stage III or IV melanoma, but 206 were randomized 1:1 to either a continuous (n = 105) or intermittent (n = 101) treatment schedule—3-weeks-off and 5-weeks-on. The poster presented at ASCO focused on a post-hoc analysis that reviewed differences in PFS based on prior ICI treatment. Overall, 37% of patients had received prior ICIs.

The median PFS for all patients with prior ICI treatment was 9 months compared with 6 months for those without prior ICI exposure (HR, 0.60; 95% CI, 0.41-0.98; P = .016). Patients who were treated on the continuous dose schedule showed a non-significant trend toward improved PFS with prior ICI therapy with a median PFS of 11 months with ICIs versus 7 months without (P = .059). Patients on the intermittent dosing schedule with and without prior ICI treatment had a 5-month median PFS versus 9 months, respectively (P = .17).

As for survival in these patients, there was no difference based on prior ICI exposure. The median overall survival was 29 months in both arms of the study (P = .51). The different dosing regimens, when analyzed separately with or without prior treatment of ICIs, showed no differences in survival (continuous, P = .66; intermittent, P = .65).

The median age for patients who received prior ICIs was 62 compared with 59 years in patients with no prior ICI exposure. There were 37% of patients with elevated lactate dehydrogenase levels who had prior ICI therapy and 39% with elevated lactate dehydrogenase levels and no prior ICI therapy. A majority of patients with prior ICI exposure had stage IVB/C disease, at 73%; 64% had stage IVB/C and no prior ICI. The number of patients with an ECOG performance status of 0 was about equal in both groups (57% with and 58% without prior ICIs).

The authors wrote that the sample size of this analysis may have limited the ability to detect interactions between prior treatment with ICIs and the treatment arm. They also wrote in their discussion that “these findings may be susceptible to selection bias since patients with more aggressive disease may be more likely to start dabrafenib and trametinib in the first line.”

Following the data presented at ASCO, investigators in this setting plan to assess long-term survival data for concurrent BRAF, MEK, and PD-1 antibody studies to look at the value of concurrent therapy compared with sequential therapy. The DREAMseq trial (NCT02224781) is ongoing in this patient population now, looking at dabrafenib and trametinib followed by ipilimumab (Yervoy) and nivolumab (Opdivo) or ipilimumab and nivolumab followed by dabrafenib and trametinib.

The authors of the analysis suggested a randomized phase 3 trial could be designed based on their findings by investigating concurrent versus sequential therapy in patients with melanoma and a BRAF V600E mutation.

Reference:

Algazi AP, Othus M, Daud A, et al. Association of prior immune checkpoint blockade (ICB) with longer progression-free survival (PFS) in patients treated with intermittent versus continuous dabrafenib and trametinib: A post-hoc analysis of S1320. J Clin Oncol. 2020;38(suppl 15):10039. doi:10.1200/JCO.2020.38.15_suppl.10039