Trial of Melanoma Triplet Combo Raises Questions

Paolo Ascierto, MD

A 3-drug regimen for advanced melanoma led to objective responses in a majority of patients with advancedBRAF-mutant disease but also proved to be somewhat toxic, a small phase II study showed.¹

Results showed that 22 of 42 patients (52.4%) had complete or partial responses when treated with the BRAF inhibitor encorafenib, the MET inhibitor binimetinib, and the CDK4/6 inhibitor ribociclib (Kisqali). The disease control rate (DCR; objective response plus stable disease) was 88%, and the cohort had an estimated progression-free survival (PFS) of 9.2 months (95% CI, 7.0-11.1).

One-fourth of patients discontinued the trial because of adverse events (AEs), most often because of elevated liver enzymes, as reported at the 2017 American Society of Clinical Oncology meeting in Chicago.

“Triple therapy with encorafenib, binimetinib, and ribociclib, in this small trial of patients with high disease burden, was associated with tumor-size reductions in more than three-quarters of patients,” Paolo Ascierto, MD, an oncologist in the Melanoma Unit at the National Cancer Institute in Naples, Italy, and coinvestigators concluded in a poster presentation. “The median PFS of 9.2 months with triple combination therapy was lower than the median of 14.9 months seen in a large phase III trial of the combination of encorafenib and binimetinib. Contributing factors may include the proportion of early discontinuation in the triple combination.”

“These results should be interpreted with caution due to the small number of patients in the study,” they added.

Encorafenib has demonstrated single-agent antitumor activity inBRAFV600-mutant melanoma, and binimetinib has demonstrated single-agent clinical activity inNRAS-mutant melanoma. Combined BRAF/MEK inhibition has demonstrated efficacy inBRAF-mutant melanoma. Preclinical data suggested that the addition of a CDK4/6 inhibitor could improve clinical activity over the 2-drug combination.

The accumulation of evidence provided a rationale for evaluating a 3-drug combination in advancedBRAF-mutant melanoma. Ascierto reported findings from a multicenter, open-label, dose-finding phase Ib trial and a subsequent phase II evaluation.

The phase Ib portion of the investigation included patients with locally advanced or metastatic melanoma, unresectable advanced or metastatic colorectal cancer, or any solid tumor with disease progression after prior therapy. The presence ofBRAFV600 mutations was documented in all cases. Phase II enrollment was limited to patients with locally advanced or metastatic,BRAFV600-mutant melanoma, and no prior exposure to a BRAF inhibitor.

During phase Ib, patients received encorafenib 200 mg once daily, binimetinib 45 mg twice daily, and 1 of 4 doses of ribociclib (100, 200, 400, or 600 mg once daily). The 600-mg dose of ribociclib was chosen for phase II evaluation.

The frequency of all-grade AEs increased from the 100- to 200-mg dose of ribociclib but remained fairly consistent thereafter. At the recommended phase II dose, 2 patients had grade ≥3 neutropenia and 1 had grade ≥3 liver enzyme elevation (AST).

The phase Ib efficacy data showed that 13 of 21 patients had objective responses, including 4 of 6 patients who received the 600-mg dose of ribociclib. During the phase II evaluation, 22 of 42 patients had objective responses, including 5 complete responses. An additional 15 patients had stable disease, resulting in a DCR (response plus stable disease) of 88.1%. Ascierto and colleagues reported that 72% of patients in the phase II trial had some degree of tumor shrinkage.

Grade 3/4 toxicity in phase II included neutropenia in 26.2% of patients, liver enzyme elevation (ALT) in 16.7%, anemia and hypertension in 9.5% each, and diarrhea and elevated AST in 7.1%. The most common AEs (all grades, >25% of patients) were diarrhea, nausea, neutropenia, fatigue, vomiting, anemia, constipation, and elevated ALT. Ten patients (23.8%) discontinued treatment because of AEs.

A discussant who reviewed the presentation said that the results with the 3-drug combination offered several contrasts with the data from a previous study of encorafenib (450 mg) and binimetinib (45 mg), which led to an objective response rate of 63% and a median PFS of 14.9 months.²

Previous studies of 2-drug combinations also had lower rates of toxicity-related discontinuation, said Grant McArthur, MD, PhD, a medical oncologist at Peter MacCallum Cancer Center in Melbourne, Australia. As compared with the 24% discontinuation rate with the 3-drug combinations, rates of 9% to 13% were reported for dabrafenib (Tafinlar)/trametinib (Mekinist), vemurafenib (Zelboraf)/cobimetinib (Cotellic), and encorafenib/binimetinib.

“Preclinical data suggested less resistance when a CDK4 inhibitor was added, but the PFS is relatively short in this study. Why?” said McArthur. “Is more pathway inhibition really better?”

He cited a need for more correlative science data and more investigation of pharmacokinetic interactions and pharmacodynamics correlations with triplet therapy.

References:

1. Ascierto PA, Bechter O, Wolter P, et al. A phase Ib/II dose-escalation study evaluating triple combination therapy with a BRAF (encorafenib), MEK (binimetinib), and CDK 4/6 (ribociclib) inhibitor in patients (Pts) with BRAF V600-mutant solid tumors and melanoma.J Clin Oncol.2017;35 (suppl; abstr 9518).
2. Dummer R, Ascierto PA, Gogas HJ, et al. Results of COLUMBUS Part 1: A Phase 3 Trial of Encorafenib (ENCO) Plus Binimetinib (BINI) Versus Vemurafenib (VEM) or ENCO in BRAF-Mutant Melanoma. Presented at: Society for Melanoma Research Annual Meeting; November 6-9, 2016; Boston, MA.