Systemic Therapy in Metastatic Melanoma

BMS-936559, the first PD-L1 antibody, is being studied in a phase 1 trial that includes 55 patients with advanced melanoma along with 152 patients with other solid malignancies. Three patients achieved a complete response, and 5 patients had an objective response lasting 1 year. The ORR for melanoma was 17%, with disease stabilization of ≥ 24 weeks in 27% of the patients. ²⁷ Common AEs included infusion reactions, diarrhea, fatigue, rash, hypothyroidism, and hepatitis.

The second PD-L1 antibody, MPDL3280A, was studied in a phase 1 trial of 45 patients with metastatic melanoma. An ORR of 29% was observed, along with a 24-week PFS of 43%. ²⁸ Commonly noted AEs included hyperglycemia and elevated liver aminotransferases.

A newer PD-L1 inhibitor, MEDI4736, is being studied for advanced malignancies in 8 patients with melanoma. In preliminary analysis, MEDI4736 demonstrated a partial response in 1 out of 8 melanoma patients with a disease control rate of 46%.29 Although the PD-L1 inhibitors seem promising, more information will help discern their role in the management of metastatic melanoma.

Combined Anti-CTLA-4 Plus Anti-PD-1 Antibody

The combination of ipilimumab and the PD-1 inhibitor nivolumab was tested in a phase 1 trial in which both drugs were used concurrently as well as sequentially in metastatic melanoma.30 The 1- and 2-year OS in patients who were treated concurrently was 82% and 75%, respectively. Complete remission was seen in 17% of the patients, and the responses were seen irrespective of the BRAF mutation status. The responses were durable, and about 64% of the objective responses remain in remission at last follow-up. ³¹ Grade 3 to grade 4 AEs were noted in 53% of the patients, with 11 patients requiring discontinuation of the medications. More studies are required to ascertain the optimum dosage of the combination prior to its approval for use in metastatic melanoma.

Molecular Targeted Therapy

The RAS-RAF–mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway is activated in almost 90% of patients
with melanoma. ³² This pathway is normally required for the growth and survival of nonmalignant cells. In malignant transformation, mutations and/or overexpression is seen at various levels including KIT, NRAS, BRAF, and the MEK protein. This leads to activation of serine and threonine protein kinases, which lead to uncontrolled cell proliferation and survival. ³³

Novel therapeutic approaches have tried inhibiting one or more of these pathways for melanoma treatment. The most important mediator of tumorigenesis is BRAF, which is a downstream receptor of NRAS, and is mutated in almost 50% of melanoma cases. ³⁴ NRAS mutations are seen in 15% to 20% of cutaneous melanomas. ^35,36 After its activation, the RAF enzyme—coded by the BRAF gene—causes phosphorylation of the MEK protein, which activates ERK. This ERK activation leads to growth signaling and is the final pathway in several malignancies (Figure 2). ^37,38

BRAF Inhibitors

BRAF is the first mediator whose inhibition led to clinically significant outcomes in patients with melanoma. The most common BRAF mutation consists of the
substitution of glutamic acid for valine at amino acid 600 (V600E mutation) with majority of the remainder consisting of an alternate substitution (V600V or V600K). ³⁴ Vemurafenib and dabrafenib are the 2 BRAF inhibitors that have been shown to improve tumor regression, PFS, and OS considerably, especially in combination with a MEK protein inhibitor. In the phase 3 BRIM-3 trial, the vemurafenib group had a significantly prolonged PFS and OS compared with dacarbazine (13.6 months vs 9.7 months; 6.9 months vs 1.6 months, respectively). It was the first study to show improved survival with vemurafenib in both the V600E and V600K BRAF mutant melanomas. ³⁹