Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

“…The most common AE in the 12 patients in phase 1 and phase 2 combined were pyrexia, increased aspartate aminotransferase, peripheral edema, nasopharyngitis, increased blood alkaline phosphatase, stomatitis, erythema and headache. The relatively common AE in this Japanese study were also relatively common in clinical studies of dabrafenib and trametinib combination conducted in global studies 18, 24, 25. Similarly, the majority of AE observed in this Japanese study belong to grade 1 or 2, and it has been reported that the majority of AE were grade 1 or 2 in global clinical studies as well 18, 24, 25…”

“…The median duration of response was 32.1 weeks according to the investigator's assessment and 45 weeks according to the independent assessment. The median PFS has been reported to be 9.3–11.4 months and the median duration of response has been reported to be 9.2–13.8 months in clinical studies conducted to date 18, 24, 25. Thus, the median PFS and the duration of response in phase 1 were similar to the results of clinical studies conducted to date.…”

“…Pyrexia was the most common AE in our study and was also the most common AE in the global combination studies 18, 24, 25. Incidentally, pyrexia has been reported as a common AE with BRAF‐inhibitor monotherapy in the range of 16–26% when given as monotherapy 18, 19, 26, 27.…”

Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab

“…Advances in treating metastatic melanoma with immunotherapy (Hodi et al., 2010), and with the targeted BRAF inhibitor, dabrafenib, and MEK inhibitor, trametinib, have produced important improvements in clinical outcomes (Flaherty et al., 2012a,b; Long et al., 2014; and Robert et al., 2015). Differences in the mechanisms of action suggest that combinations may lead to further improvements.…”

“…While patient numbers are small, this experience of two intestinal perforations in seven patients after one or two doses of ipilimumab, administered with dabrafenib and trametinib therapies, raises the possibility of added toxicity with the triplet combination over ipilimumab as a single agent, where grade 3–5 colitis occurs in 5% and intestinal perforations in 1.1% of patients (Ipilimumab package insert, 2014). In support of this interpretation, the clinical combination of dabrafenib and trametinib has rarely been associated with colitis, and no cases of colitis leading to colonic perforation have been reported (Hu‐Lieskovan et al., 2014; Long et al., 2014; and Robert et al., 2015). The study cohort evaluating dabrafenib 150 mg BID and ipilimumab 3 mg/kg continues enrollment with only one resolved case of grade 3 colitis in 25 patients to date.…”