Volume 13 Supplement 1
Combining targeted and immunotherapy: BRAF inhibitor dabrafenib (D) ± the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation-positive unresectable or metastatic melanoma (MM)
- Igor Puzanov1
© Puzanov; licensee BioMed Central Ltd. 2015
Published: 15 January 2015
Dabrafenib, trametinib, and Ipilimumab are each indicated for treatment of patients (pts) with metastatic melanoma (Dabrafenib+trametinib in BRAF V600 mutation–positive metastatic melanoma). Dabrafenib and trametinib can be safely combined and prolong progression-free survival compared with monotherapy. Combining Dabrafenib+trametinib with the CTLA-4 antibody Ipi has the potential to improve treatment outcomes, but the safety profile is unknown. A recent report suggested caution in combining the BRAF inhibitor vemurafenib (V) with Ipilimumab; V+Ipilimumab resulted in G3 elevations of ALT in 6/10 pts leading to study discontinuation (NEJM2013 368; 14). The present study was designed to characterize the safety of Dabrafenib±trametinib+Ipilimumab, select recommended phase 2 doses (RP2Ds), and report efficacy.
Pts with stage IIIc/IV BRAF V600E /K mutation–positive MM and ≤1 prior treatments are eligible. Dose escalation occurs in cohorts of 3-6 pts followed by expansion (≤30 pts) at the RP2D. At data cutoff (Nov 8, 2013), 10 pts were enrolled: 4 received D+Ipi (doublet), 2 received D only (withdrawn before Ipi treatment), and 4 received D+T+Ipi (triplet).
Median age of the 10 pts was 59.5 y (range, 32-75 y). Doublet: D 150 mg bid + Ipi 3 mg/kg q3w × 4 doses was well tolerated and selected as RP2D. No G3/4 ALT elevations or dose-limiting toxicities (DLTs) were observed. The most frequent adverse events (AEs; ≥2) were chills, fatigue, hand-foot syndrome, pyrexia, and maculopapular rash. Of 4 pts, 2 are ongoing and 2 stopped treatment (disease progression). Pts are currently being enrolled at this dose level in the expansion. Triplet: At current doses (D 100 mg bid/T 1 mg qd+Ipi 3 mg/kg q3w × 4), 2 out of 7 patients developed G3 colitis complicated by perforation.The triplet combination enrollment was therefore stopped. The most frequent AEs (≥2) were pyrexia, chills, arthralgia, insomnia, and maculopapular rash. One pt had G4 renal insufficiency that reversed rapidly.
To date the combinations of D+Ipi and D+T+Ipi appear to be tolerable and have not been associated with significant hepatotoxicity in MM, suggesting differences between BRAF inhibitors when combined with Ipi. However, combination of dabrafenib+trametinib+Ipilimumab was stopped early after 2 out of 7 patients developed colon perforation soon after initiating Ipilimumab therapy.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.