Paolo A. Ascierto, MD, is the director of the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, at the National Tumor Institute Fondazione G. Pascale.

 PER® International Symposium on Melanoma and Other Cutaneous Malignancies

Paolo A. Ascierto, MD, director, Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, National Tumor Institute Fondazione G. Pascale, discusses treatment sequencing considerations for patients with advanced 

-mutant melanoma, based on findings from the phase 2 SECOMBIT (NCT02631447) and phase 3 DREAMseq (NCT02224781) trials.

Ascierto notes that each of these trials demonstrated improved overall survival when initiating treatment with immune checkpoint inhibitor–based therapy rather than targeted therapy in the first-line setting for this patient population, suggesting that resistance to targeted agents may compromise subsequent immunotherapy efficacy. Additionally, SECOMBIT evaluated a sequential "sandwich" approach, incorporating a short course of targeted therapy before transitioning to immunotherapy, which may benefit select patients with high tumor burden or elevated lactate dehydrogenase levels, Ascierto explains. These findings contribute to ongoing discussions on optimizing first-line treatment strategies in 

Videos

Paolo A. Ascierto, MD, discusses findings from the SECOMBIT and DREAMseq trials and their implications for first-line treatment selection for patients with BRAF-mutant melanoma.

Dr Ascierto on First-Line Treatment Selection in Advanced BRAF+ Melanoma

Paolo A. Ascierto, MD, director of the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy at the National Tumor Institute Fondazione G. Pascale in Naples, discusses how to choose between available combination therapies in the treatment of patients with melanoma.

There are 3 combinations of BRAF and MEK inhibitors that have shown efficacy and tolerability in the treatment of patients with melanoma. The main factor in distinguishing between the 3 regimens and guiding treatment decisions will be in their safety profiles, Ascierto says. For example, the combination of binimetinib (Mektovi) and encorafenib (Braftovi) has a strong safety profile, Ascierto notes, so for patients with pre-existing comorbidities, this may be the right option. In general, this emerging combination is good news for the treatment landscape because it provides a novel and safe option for patients.

Ascierto adds that there are ongoing trials looking at the proper sequencing of these combinations. Nivolumab (Opdivo) and ipilimumab (Yervoy) have also shown encouraging activity in these patients, so where immunotherapy fits in is something that also needs to be considered.

Paolo A. Ascierto, MD, director of the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy at the National Tumor Institute Fondazione G. Pascale in Naples, discusses how to choose between combination therapies in the treatment of patients with melanoma.

Dr. Ascierto on Choosing Combinations in Treatment of Melanoma

Paolo A. Ascierto, MD, director of the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy at the National Tumor Institute Fondazione G. Pascale in Naples, discusses investigational triplet therapies in patients with 

Triplet regimens are of interest in patients with 

-positive melanoma, explains Ascierto. There are many ongoing studies that are examining triplet therapies, including a phase I trial with dabrafenib (Tafinlar) and trametinib (Mekinist) in combination with durvalumab (Imfinzi).

There are also ongoing phase II/III trials, says Ascierto, including the KEYNOTE-022 trial, which is looking at dabrafenib and trametinib in combination with pembrolizumab (Keytruda). These data will likely be presented at the 2018 ESMO Congress.

Additionally, the combination of vemurafenib (Zelboraf) and cobimetinib (Cotellic) with atezolizumab (Tecentriq) is being explored. These trials will seek to answer whether the addition of an anti—PD-1 therapy can induce a long-term benefit in these patients, says Ascierto.

Paolo A. Ascierto, MD, director of the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy at the National Tumor Institute Fondazione G. Pascale in Naples, discusses investigational triplet therapies in patients with BRAF-positive melanoma.

Dr. Ascierto on Triplet Therapy in BRAF+ Melanoma

Paolo A. Ascierto, MD, director of the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy at the National Tumor Institute Fondazione G. Pascale in Naples, discusses the COLUMBUS trial in melanoma.

COLUMBUS was a phase III trial of encorafenib plus binimetinib versus vemurafenib (Zelboraf) or encorafenib in patients with 

-mutant melanoma. Median overall survival was 33.6 months (95% CI, 24.4-39.2) with encorafenib plus binimetinib, 23.5 months (95% CI, 19.6-33.6) with encorafenib, and 16.9 months (95% CI, 14.0-24.5) with vemurafenib.

The trial compared a new combination of BRAF and MEK inhibitors with vemurafenib monotherapy, says Ascierto. Encorafenib was shown to be superior to vemurafenib, giving physicians a new and more potent class of BRAF inhibitors.

Physicians now know that adding binimetinib to encorafenib improves survival in patients with 

-mutant advanced, unresectable or metastatic melanoma. In terms of the safety profile, encorafenib was associated with less fever and photosensitivity. This will allow patients to stay on treatment longer, says Ascierto.

Dr. Ascierto on the COLUMBUS Trial in Melanoma

Paolo A. Ascierto, MD, National Tumour Institutue “Fondazione G. Pascale,” Unit of Melanoma, Naples, Italy, discusses the sequencing of targeted therapies for patients with melanoma.

There are several clinical trials investigating the sequencing of targeted therapies, explains Ascierto. There is a particular trial looking at the sequencing of the encorafenib and binimetinib combination, nivolumab (Opdivo) and ipilimumab (Yeroy) combination, and a third arm of immunotherapy in between targeted therapy agents.

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Dr. Ascierto on Sequencing of Targeted Therapies for Melanoma

Paolo A. Ascierto, MD, director at the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, National Tumor Institute Fondazione G. Pascale, discusses findings from a phase Ib/II dose-escalation study evaluating triple combination therapy with encorafenib, binimetinib, and ribociclib (Kisqali) in patients with 

This is the first triplet combination with a CDK4/6 inhibitor in melanoma, Ascierto explains. The phase I expansion cohort enrolled 21 patients, all with 

-mutant solid tumors, which included melanoma, colorectal cancer, and brain cancer. Encorafenib was administered to patients at 200 mg, binimetinib was given at 45 mg, and ribociclib was given at 600 mg.

The data are interesting but they showed that the response rate was 56%, which was not higher than the BRAF/MEK inhibitor regimen, says Ascierto. Additionally, the progression-free survival in the expansion cohort was 9.3 months, which was not a statistical improvement over binimetinib and encorafenib combined without ribociclib.

Paolo A. Ascierto, MD, director at the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, National Tumor Institute Fondazione G. Pascale, discusses findings from a phase Ib/II dose-escalation study evaluating the triple combination therapy with encorafenib, binimetinib, and ribociclib (Kisqali) in patients with BRAF V600-mutant solid tumors and melanoma.

Paolo A. Ascierto, MD

Articles

Dr Ascierto on First-Line Treatment Selection in Advanced BRAF+ Melanoma

Dr. Ascierto on Choosing Combinations in Treatment of Melanoma

Dr. Ascierto on Triplet Therapy in BRAF+ Melanoma

Dr. Ascierto on the COLUMBUS Trial in Melanoma

Dr. Ascierto on Sequencing of Targeted Therapies for Melanoma

Dr. Ascierto on Triplet of Encorafenib, Binimetinib, and Ribociclib in Melanoma