Doublets and Triple Combinations in Metastatic Melanoma
Dabrafenib (D), trametanib (T), and ipilimumab (IPI) are each indicated for treatment of patients with metastatic melanoma (MM), with D and T approved specifically in BRAFV600 mutation-positive unresectable melanoma or MM.1,2 D and T can also be safely combined in these patients, with enhanced response rates compared with monotherapy.1,2 Combining D and/or T with an CTLA-4 antibody such as IPI may improve treatment outcomes, but the safety profile of such doublets and triplets is not known. A recent report suggested caution in combining vemurafenib (V), BRAF inhibitor, with IPI; V + IPI resulted in grade 3 elevations of liver enzymes in 6 of 10 patients that led to study discontinuation.3 To characterize the safety of D and IPI, as well as D, T, and IPI, Puzanov and colleagues conducted a phase 1 study of this doublet and triple combination in patients with BRAFV600E/K mutation-positive MM (ASCO 2014; Abstract 2511).
Patients with stage IIIc or IV BRAFV600E/K mutation-positive MM who had received no more than 1 prior treatments were eligible for this trial. Dose escalation occurred in cohorts of 3 to 6 patients followed by expansion to a maximum of 30 patients at the recommended phase 2 doses. Because 3 patients received standard doses of D and IPI (doublet) with no dose-limiting toxicities (DLTs), an expansion cohort of D plus IPI was opened and continues to enroll 30 additional patients. A single event of elevated liver enzymes resolved to grade 1 within 1 week of therapy with high-dose steroids. The most frequent adverse events (AEs) noted with the doublet to date (n = 8 patients) were pyrexia, chills, maculopapular rash, hand-foot syndrome, and pruritus. Grade 3 toxicities to date included liver enzyme elevation, squamous-cell carcinoma of the skin, flu-like symptoms, and transient ischemic attack (1 patient each). All 8 patients in the doublet cohort have had at least a 30% reduction in their sum of lesion diameters. One of these 8 patients subsequently progressed and discontinued the study.
The triplet regimen was given using standard doses of D, T, and IPI. While no grade 3/4 liver enzyme elevations were noted, 2 DLTs were observed. These included grade 4 colitis with intestinal perforation and grade 3 colitis with perforation. The most common AEs noted with the triplet included pyrexia, arthralgia, chills, decreased appetite, fatigue, and diarrhea. One patient had grade 4 renal insufficiency that reversed rapidly. In light of the observation of dose-limiting colitis, the triplet cohort of the study was closed. The researchers are considering sequential administration of IPI followed by D plus T.
On the basis of the first 8 patients, Puzanov and colleagues concluded that the doublet (D and IPI) appears well tolerated and that early assessments of efficacy suggest activity. Follow-up data will be represented at future meetings.
- Tafinlar (dabrafenib) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; March 2014.
- Mekinist (trametinib) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; January 2014.
- Ribas A, Hodi S, Callahan M, Konto C, Wolchok JD. Letter to the Editor: hepatotoxicity with combination of vemurafenib and Iipilimumab. N Engl J Med. 2013;368(14):1365-1366.