Targeted therapy, immunotherapy tackle metastatic melanoma

Banff, Alberta - There has been a rapid revolution in the treatment of metastatic melanoma since the identification of driver oncogenes such as BRAF and its mutations more than a decade ago, according to a clinical researcher at the Vanderbilt-Ingram Cancer Center, Nashville, Tenn.

Speaking at the annual Canadian melanoma conference about lessons learned from the use of BRAF inhibitors to treat metastatic melanoma, Igor Puzanov, M.D., M.S.C.I., F.A.C.P., associate director of phase 1 drug development, clinical director, Renal Cancer Melanoma/Renal Cancer Program, division of hematology-oncology, Vanderbilt University Medical Center, noted that melanoma is a mix of subtypes characterized by specific mutations and about 50 percent carry BRAF mutations.

“BRAF kinase is an important mediator of cellular proliferation,” Dr. Puzanov says. “A therapy such as vemurafenib is a selective RAF inhibitor and effective in this subgroup.”

Optimizing the impact

In general, two approaches can be taken to treat metastatic melanoma: immunotherapy, which targets the host, and targeted therapy, which targets the tumors.

There may be numerous combinations of treatment options at the beginning of therapy, but once patients experience disease progression, the options become more limited, Dr. Puzanov says.

Inhibition of BRAF(V600E) has demonstrated anti-melanoma activity in both cell and animal-based models (Tsai J, Lee JT, Wang W, et al. Proc Natl Acad Sci U S A. 2008;105(8):3041-3046).

A pivotal phase 3 trial in 2010 compared vemurafenib with dacarbazine in 675 patients with metastatic melanoma. The BRAF inhibitor produced significant gains in terms of the relative reduction in the risk of either death or disease progression. In addition, vemurafenib-treated patients had greater progression-free survival (Chapman PB, Hauschild A, Robert C, et al. N Engl J Med. 2011;364(26):2507-2516).

Optimizing the impact of the BRAF inhibitor in patients with metastatic melanoma will require investigation to find the best dosing regimen to achieve objectives such as regression and stasis, according to Dr. Puzanov.

Anticipating AEs

A limitation of BRAF inhibitor therapy with vemurafenib or dabrafenib, another highly selective RAF inhibitor, is the development of cutaneous adverse events such as keratoacanthomas, with some side effects developing as early as one week after initiation of therapy (Chu EY, Wanat KA, Miller CJ, et al. J Am Acad Dermatol. 2012;67(6):1265-1272).

Other side effects that have been reported with BRAF inhibitor therapy include rash, photosensitivity, fatigue, pruritus, fever, elevated liver function tests, and palmar-plantar dysesthesia.

A survey of physicians’ perceptions about unmet needs in the treatment of metastatic melanoma presented at this year's annual meeting of the American Society of Clinical Oncology in Chicago found the majority of respondents, consisting of oncologists and dermatologists, had used ipilimumab and vemurafenib and cited toxicity and tolerability as challenges with these treatments.

Toxicity and tolerability of treatments is of particular concern in pediatric patients. A current study is enrolling patients with surgically incurable melanoma that harbors BRAF(V600) mutations.

The study will examine various dose cohorts in patients ages 12 to 17 being treated with vemurafenib, with a goal to determining the maximum tolerated dose/recommended dose, as well as the efficacy and tolerability of vemurafenib in these patients. The amount of dosage administered daily will vary depending on the weight of the patient.

While BRAF inhibitors are very effective when they are administered, patients typically develop resistance to the therapies within a year. Resistance is brought on by several means including activation of alternative signaling pathways and reactivation of the MAP kinase pathway.

Battling resistance

Faced with the challenge of resistance, clinicians are devising other treatment strategies such as adding immunotherapy in the form of ipilimumab, anti- PD-1/PDL-1 antibodies, PEG-IFN with or without another targeted therapy such as a MEK inhibitor.

Future combination regimens will likely be based on mechanisms of resistance and/or activation of oncogenic pathways. Anti-angiogenic agents such as bevacizumab may possibly be part of the combination treatments.

To respond to the issue of resistance that develops to BRAF inhibitor therapy, investigators are studying in vitro modeling of resistance using patient tumor or peripheral blood circulating tumor cells, with a goal to develop promising therapies to overcome the challenge of resistance.

Monitoring response and monitoring relapse would be part of the strategy to avoid or delay the development of resistance. The use of circulating tumor cells instead of serial tumor biopsies would also be beneficial if the cells prove comparable in their resistance mechanisms.

Disclosures: Dr. Puzanov is a consultant for Roche, Genentech and GlaxoSmithKline.