Combinations and Immunotherapies Detailed at Society for Melanoma Research 10th International Meeting

Georgina Long, BSc, PhD,

MBBS, FRACP

Up Front, Hit Hard, and Don’t Stop

In her presentation entitled, “Targeted Therapies and Future Prospects,” Georgina Long, BSc, PhD, MBBS, FRACP, told a story of where targeted therapies for melanoma are heading, within the context of the “Up Front, Hit Hard, and Don’t Stop” model of melanoma treatment.

“We have enough evidence that if you treat with a targeted therapy until someone develops progressive disease, it’s heterogenous resistance within the person. You will never be able to get on top of it. You have to treat up front with your best treatments, because otherwise it is too late; the horse has bolted,” said Long, medical oncologist and translational researcher at Melanoma Institute Australia at the University of Sydney.

Long acknowledges that early treatment data are yet to be confirmed and that toxicities will need to be considered when combining agents, but thinks that using immunotherapy with targeted combinations such as BRAF and MEK inhibitors makes good sense. “There is some good basic science and translational research that supports that approach of giving your immune therapy up front with your targeted therapy.”

Dr. Daud on Treating Metastatic Melanoma With BRAF Inhibitor Monotherapy

Daud is a clinical professor at UCSF.

According to Long, combining cell cycling inhibitors (MDN2) with a BRAF/MEK backbone poses another interesting possibility for treatment, and preclinical studies are also looking at combining BRAF and MEK with PI3 kinases.

“I think the single-agent BRAF inhibitor will not be the treatment of the future. I don’t think it will be used in sequence either. I think it will be combinations up front, hopefully combinations with immunotherapies, if they prove to be effective, or combinations with the other treatments. Single-agent BRAF inhibitors will be a treatment of the past.”

Increased OS and Reduced Toxicity With BRAF/MEK Inhibitors Combined

Problems such as resistance and some skin toxicities typically seen with BRAF monotherapy may improve with dabrafenib/trametinib combination therapy in patients withBRAF V600mutations, according to Adil Daud, MD, clinical professor of Medicine and Dermatology at University of California, San Francisco. Daud presented findings of overall survival (OS) of 23.8 months for the combination therapy coming out of part C of the phase II BRF113220 study,

Patients were randomly assigned to receive 150 mg of dabrafenib (2×/d) plus once-daily trametinib, at a dosage of either 1 mg (combination 150/1) or 2 mg (combination 150/2), or 150 mg of dabrafenib monotherapy (2×/d).

Incidence of cutaneous squamous cell carcinoma is reduced significantly with combination therapy, according to Daud. “In our study it went down from 17% to 7% despite the fact that ours was a crossover study.”

Eighty-three percent of patients in the trial crossed over to the combination therapy. Two large, randomized, phase III trials are currently ongoing: COMBI-d (dabrafenib) and COMBI-v (vemurafenib), and according to Daud, data are expected soon.

OPTiM Trial: Positive Interim OS Subset Analyses

In March 2013, initial results from the OPTiM trial demonstrated a statistically significant difference in the primary endpoint of durable response rate (DRR) in favor of talimogene laherparepvec (T-VEC) compared with granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of unresected stage IIIB, IIIC, or IV melanoma. On November 18, 2013, less than 7 months later, OS results from a predefined interim analysis of the study were announced at the Meeting of the Society for Melanoma Research in Philadelphia, Pennsylvania.

The Utility of a Specific Blood-Based BRAF Assay

Ryan J. Sullivan, MD, medical oncologist, Massachusetts General Hospital, said that there are several clinical issues that have arisen since BRAF-inhibitor therapy has become the standard of care for patients withBRAF-mutant melanoma.

“[Many] of the issues are regarding diagnosis,” Sullivan said. “How do we diagnoseBRAFmutations? How do we follow patients who haveBRAFmutations who are on BRAF inhibitor therapy? How can we look for patients who, as of yet, don’t have metastatic disease but have high-risk or intermediate risk disease and predict whether or not they will (1) develop BRAF melanoma that’s metastatic or (2) just define whether or not they have aBRAFmutation.”

At the Society for Melanoma Research 2013 Congress, Sullivan presented data on a second-generation blood-based assay that is able to quantify circulating BRAF levels. The assay was demonstrated to be highly sensitive (93%) and specific (100%) in patients with stage IV disease. Researchers wrote that “this assay may have multiple clinical uses including diagnosis, monitoring for treatment failure in the metastatic setting, and predicting and monitoring for relapse in the adjuvant setting.” Development of this assay is ongoing.

Overall survival results were shown to be 23.3 months in the T-VEC arm versus 19.0 months in the GM-CSF arm (HR = 0.79; 95% CI, 0.61-1.02;P=.0746). Differences in survival rates were pronounced in the subset of patients with stage IIIB, IIIC, or IV M1a disease (HR = 0.56; 95% CI, 0.38-0.81) or who received T-VEC as first-line treatment (HR = 0.49; 95% CI, 0.33-0.74), each comprising approximately 50% of the study population.

The most frequently observed adverse events (AEs) were fatigue, chills, and pyrexia. The most common serious AEs included disease progression in both arms, and cellulitis and pyrexia in the T-VEC arm. Serious AEs occurred in 26% of T-VEC patients and 13% of GM-CSF patients. Immune-mediated events were reported infrequently. T-VEC demonstrated a 16% DRR, defined as the rate of complete or partial response lasting continuously for at least 6 months, compared with 2% in the GM-CSF arm. Mature OS data are expected in the first half of 2014.

MK-3475 in Advanced Melanoma: OS Data From PN 001 Trial

MK-3475, an investigational anti-PD-1 immunotherapy, showed an estimated OS rate of 81%, at 1 year across all MK-3475 monotherapy dosages evaluated, according to OS data presented on a cohort of 135 patients with advanced melanoma in an ongoing phase IB clinical trial (PN 001).

The objective response rate (ORR; patients who had either a complete or partial response) across all dosages improved with longer duration of follow-up; at the time of this analysis, the ORR was 41% (9% complete response rate), as evaluated by a blinded central review committee using RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).

While the majority of responses to MK-3475 treatment occurred early (within the first 12 weeks), responses and changes from partial to complete response continued to occur after 6 months of treatment. Partial and complete responses occurred as late as 48 and 70 weeks. Median duration of response and median OS have yet to be reached for any dosage evaluated.

The Interaction of Melanoma and Its Environment

At the Society for Melanoma Research 2013 Meeting, Antoni Ribas, MD, PhD, professor of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, presented on the inhibition of BRAF and the interaction of melanoma and its environment. According to Ribas, researchers are now understanding what drives melanoma to grow and how to impact its growth with targeted therapies and the immune system.

“What we’ve been testing is [the] means to impact these immune-suppressive microenvironments by depleting macrophages that are immune-suppressive there, with a particular agent called PLX3397,” Ribas said. “That has allowed us to have better tumor responses induced by immunotherapy.”

A phase Ib open-label, dose-escalation trial is currently recruiting looking at PLX3397 in combination with vemurafenib inBRAF V600