Triple combination appears safe, effective for advanced BRAF V600-mutant melanoma

NEW YORK — The addition of spartalizumab to dabrafenib and trametinib appeared safe and effective for previously untreated patients with advanced BRAF V600-mutant unresectable or metastatic melanoma, according to study results presented at Chemotherapy Foundation Symposium.

All nine evaluated patients achieved a confirmed response. In addition, the safety profile for the triplet regimen appeared consistent with that observed in prior studies of these agents.

Targeted therapy and immune checkpoint inhibitors have greatly improved outcomes for patients with unresectable or metastatic BRAF V600-mutated melanoma.

The combination of the BRAF V600 inhibitor dabrafenib (Tafinlar, Novartis) and the MEK inhibitor trametinib (Mekinist, Novartis) have induced deep and rapid responses that have extended survival to 3 years or longer for this patient population.

Trials that explored the efficacy and safety of the combination of anti-PD-1 monoclonal antibodies with BRAF V600 and MEK inhibitors are underway and suggest manageable toxicity, according to study background.

Spartalizumab (PDR001, Novartis), a humanized anti-PD1 IgG4 antibody that blocks the binding of PD-L1 and PD-L2, appeared well tolerated as monotherapy in an open-label phase 1 study of patients with solid tumors, including melanoma.

Reinhard Dummer, MD, professor of dermatology at University of Zurich in Switzerland, and colleagues launched the phase 3 COMBI-i study to evaluate the efficacy and safety of spartalizumab in combination with dabrafenib and trametinib for treatment-naive patients with BRAF V600-mutant unresectable or metastatic melanoma.

All patients had stage IIIC or stage IV disease with no history of central nervous system metastases and ECOG performance status of 0 or 1.

The first part of the three-part trial was designed to determine the recommended phase 3 regimen of the triple combination. The starting doses — spartalizumab 400 mg via IV every 4 weeks, with dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily — were determined to be most appropriate.

Dose-limiting toxicity served as the primary endpoint. Secondary endpoints included safety, PFS, OS, overall response rate, duration of response, disease control rate and pharmacokinetics.

At the time of data cutoff, nine patients (median age, 45 years; range, 35-69) — all of whom had stage IV disease — had been treated in the safety portion of the study. All nine patients were white and seven (78%) were men.

Median follow-up was 5.5 months (range, 4.7-7.2).

One patient (11%) had discontinued treatment due to an adverse event. The other eight patients remained on treatment at data cutoff.

Median duration of drug exposure was 149 for spartalizumab and 167 days for trametinib and dabrafenib.

All nine patients required at least one treatment interruption or dose reduction, primarily due to adverse events.

All nine patients experienced grade 3 or grade 4 adverse events. These were primarily laboratory abnormalities and hepatotoxicity.

The most common adverse events were pyrexia (100%), chills (78%) and headache (67%).

Four patients experienced serious adverse events. These included four cases of pyrexia, and one case each of acute kidney injury, diarrhea, hepatitis, hepatotoxicity and increased transaminases.

All nine patients (100%; 95% CI, 66.4-100) achieved confirmed response by RECIST criteria, and three patients (33%) achieved a complete response. All patients achieved responses by the first baseline assessment, performed on the first day of the fourth cycle.

The other two components of the COMBI-i trial are ongoing. These include a biomarker cohort designed to evaluate changes in CD8-positive cells and PD-L1 levels after treatment, and a randomized, double-blind, placebo-controlled portion designed to compare investigator-assessed PFS between patients who received the triplet regimen and those who received dabrafenib and trametinib alone.

Treatment in all study components will continue until disease progression, death, unacceptable toxicity, loss to follow-up or withdrawal of consent. – by Mark Leiser

For more information:

Dummer R, et al. Preliminary findings from part 1 of COMBI-I, a phase 3 study of anti-PD-1 antibody spartalizumab (PDR001) combined with dabrafenib and trametinib in previously untreated patients with advanced BRAF V600-mutant melanoma. Presented at: Chemotherapy Foundation Symposium; Nov. 7-9, 2018; New York.

Disclosure:

Novartis sponsored this study. Three authors report employment relationships with Novartis.