Three-Drug Regimen Active in BRAF-Mutant Melanoma

Antoni Ribas, MD, PhD

Triplet therapy for advanced,BRAFV600-mutant melanoma led to objective responses in 73% of a small group of patients enrolled in a phase I trial, according to updated results reported at the 2017 ESMO Annual Congress in Madrid.

Ongoing follow-up in the trial showed that 11 of 15 patients responded to the combination of pembrolizumab (Keytruda), dabrafenib (Tafinlar), and trametinib (Mekinist). Seven of the 11 responding patients had not progressed after a median follow-up of 20 months.

“Updated results of the phase I portion of the KEYNOTE-022 trial confirmed previously reported efficacy of this triplet combination,” said Antoni Ribas, MD, PhD, a professor of medicine, surgery, and molecular and medical pharmacology at the University of California at Los Angeles. “The results demonstrated durability of responses. No late or unexpected toxicities occurred with longer follow-up. The randomized phase II portion of KEYNOTE-022 is ongoing.”

The findings represented a continuation of clinical research to evaluate triplet therapy for advancedBRAFV600-mutant melanoma. Studies involving preclinical models demonstrated superior antitumor activity with the combination of a BRAF inhibitor, MEK inhibitor, and anti—PD-1 drug, as compared with a BRAF/MEK inhibitor combination.

Clinical studies of dabrafenib/trametinib combination therapy demonstrated objective responses in about two-thirds of patients and median progression-free survival (PFS) of 9 to 11 months, said Ribas. In contrast, a trial of pembrolizumab monotherapy for patients withBRAFV600-mutant melanoma (including previously untreated patients) demonstrated an overall response rate of 36% to 37% and a median PFS of 5.6 months.

Two additional PD-1/PD-L1 inhibitors have been evaluated in combination with BRAF/MEK inhibitor combinations for advanced melanoma. Collectively, the results of those trials, along with findings from KEYNOTE-022 suggested that the 3-drug approach leads to objective responses in a high proportion of patients with manageable toxicity.

The initial results of KEYNOTE-022 showed that 9 of 15 patients had objective responses (all partial responses) to the combination of pembrolizumab, dabrafenib, and trametinib. Ribas reported findings after more than a year of additional follow-up for the trial (data cutoff March 2017).

The updated safety analysis included all 15 patients. The dose-limiting toxicity (DLT)-evaluable cohort consisted of 14 patients who completed the first 6-week cycle of therapy and received at least 66% of all planned treatment. The efficacy analysis included all 15 patients, each of whom received at least 1 dose of therapy at the maximum tolerated dose, which was set at 2 mg/kg of pembrolizumab, 150 mg of dabrafenib, and 2 mg of trametinib.

The 15 patients had a median age of 47 (range, 24-71), and all but 2 had an ECOG performance status of 0.BRAFstatus was V600E in 13 cases and V600K in the remaining 2. Eight patients had M1c disease, 5 had M1b, 2 had M1a, and 1 patient had a brain metastasis. All but 2 of the patients had received no prior therapy for advanced melanoma.

Three patients developed DLTs, including 1 who developed grade 4 neutropenia, 1 who had grade 4 liver enzyme elevations (ALT and AST), and 1 who had grade 3/4 liver enzyme elevation and grade 3 gamma-glutamyltransferase (GGT) elevation.

The most common adverse events (AEs; all grades) were pyrexia (93%); chills and fatigue (67% each), diarrhea (60%); arthralgia (47%); nausea (47%); rash (40%); vomiting (40%); decreased appetite, dermatitis, and decreased neutrophil count (33% each); and headache, hypothyroidism, myalgia, and pruritus (27% each). Grade 3/4 AEs consisted of elevated AST, elevated ALT, and pyrexia in 3 patients each; and elevated GGT, neutropenia, and decreased white blood cell count in 2 patients each. No treatment-related deaths occurred.

Four patients discontinued treatment because of grade 3/4 AEs: 1 case each of ALT/GGT elevation, ALT/AST elevation, autoimmune hepatitis, and pyrexia.

Updated efficacy results showed that 10 patients achieved objective responses, including 2 complete responses. Four additional patients had stable disease. The 1 remaining patient could not be evaluated for response. The median time to response was 2.8 months, and the median duration of response had yet to be reached.

Of the 11 patients who achieved objective responses with the 3-drug regimen, 4 subsequently had progressive disease, said Ribas. Three of the 4 patients remained alive at data cutoff. The remaining 7 had ongoing responses at data cutoff. Of those 7, 4 remained on all 3 drugs, 2 remained on pembrolizumab alone, and 1 remained on dabrafenib/trametinib.

Reference:

Ribas A, Hodi FS, Lawrence D, et al. KEYNOTE-022 update: phase 1 study of first-line pembrolizumab (pembro) plus dabrafenib (D) and trametinib (T) for BRAF-mutant advanced melanoma. Presented at: 2017 ESMO Annual Congress; September 8-12, 2017; Madrid, Spain. Abstract 1216O.