November 2014, Part 4
Targeted Agents, Immunotherapy, and Other Treatments Are Emerging for Cutaneous Malignancies
Interferon remains the adjuvant therapy of choice in patients at high risk for recurrence of malignant melanoma, said Reinhard Dummer, MD. A systematic review favored high-dose interferon versus observation on relapse-free survival but not overall survival (OS) in patients with high-risk resected primary melanoma. Recently, however, relapse-free survival was found to be a surrogate end point for OS in a meta-analysis of 12 adjuvant trials in patients with resectable melanoma (Suciu S, et al. ESMO 2014. Abstract 1089PD). Ulceration and stage are predictive of interferon efficacy in melanoma, such that â€śonly patients with ulceration and microscopic [N1] disease are profiting from pegylated interferon alfa-2b,â€ť said Dummer, vice chairman, Department of Dermatology, University Hospital ZĂĽrich, Switzerland. Two years of treatment with interferon in the adjuvant setting is warranted, he said.
For high-risk melanoma patients with macrometastases (N1b disease and higher), interferon has a minor impact, but adjuvant ipilimumab after surgery offers an improvement in recurrence-free survival, said Dummer. Specifically, in the EORTC 18071 trial, 3-year recurrence-free survival rates were 46.5% in patients randomized to ipilimumab (10 mg/kg every 3 weeks for 4 doses) versus 34.8% in a placebo group â€“ a 25% relative reduction in risk with ipilimumab. Median recurrence-free survival was 26.1 months in the ipilimumab group and 17.1 months in the placebo group (P=.0013). The impact on recurrence-free survival with ipilimumab was observed in patients with microscopic metastases (33% risk reduction) and with macroscopic metastases (17% risk reduction). About half of the patients discontinued ipilimumab because of side effects, most within the first 16 weeks.
Basal Cell Carcinoma
In the treatment of advanced BCC, the Hedgehog pathway is already being targeted with the smoothened inhibitor vismodegib, said Aleksandar Sekulic, MD, PhD, associate professor of dermatology, Mayo Clinic Scottsdale, AZ. â€śThere are several points in the Hedgehog pathway where one can potentially intervene,â€ť he said. Smoothened is a G proteinâ€“coupled receptor protein encoded by the SMO gene of the Hedgehog pathway. Other potential targets in the pathway are at the level of Hedgehog binding to Patched or downstream of Smoothened at the level of the Gli protein. In addition to vismodegib, smoothened inhibitors in development are sonidegib (phase 2), LEQ506 (phase 1), BMS-833823 (phase 1/2), TAK-441 (phase 1), IPI-926 (phase 1/2), and PF-04449913 (phase 1).
Vismodegib was associated with overall response rates of 30% in metastatic BCC and 43% in locally advanced BCC in the pivotal phase 2 trial (N Engl J Med. 2012;366:2171-2179). Responses with sonidegib in a phase 2 trial were comparable. In Gorlin syndrome, vismodegib significantly reduced the diameter of existing BCCs and the number of new BCCs compared with placebo (N Engl J Med. 2012;366:2180-2188).
An open-label trial of neoadjuvant vismodegib followed by Mohs surgery was associated with a 31% decrease in the anticipated surgical defect among patients who completed 3 months of treatment; results from a phase 2 placebo-controlled trial are pending. Vismodegib plus radiation therapy is being studied in a phase 2 trial of patients with locally advanced BCC.
Cutaneous T-Cell Lymphoma
Brentuximab vedotin is a chimeric anti-CD30 monoclonal antibody linked to monomethyl auristatin E, a synthetic antitubulin agent, that
is being studied in CD30-positive CTCL. Response rates in the range of 70% were obtained with brentuximab vedotin across the spectrum of baseline CD30 expression in patients with mycosis fungoides (MF) or SĂ©zary syndrome (SS) stage IB to IVB, said Steven Horwitz, MD. Lower disease stage predicted better response in this study.
Median CD30max was higher in responders to brentuximab vedotin compared with nonresponders (15.5% vs 3.0%; P=.037), and those with CD30 expression <5% were less likely to respond than those with CD30 expression >5% (P<.005).
The CCR4 receptor, present in all stages of CTCL, is another target, said Horwitz, associate attending physician, Memorial Sloan Kettering Cancer Center, New York City. KW-0761 (mogamulizumab) is a monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity compared with conventional antibodies. A phase 1/2 study in patients with previously treated CTCL, including MF and SS, showed good tolerability and an overall response rate of 42%. A phase 3 study is comparing progression-free survival in patients randomized to KW-0761 or vorinostat in patients with relapsed/refractory CTCL.
IPI-145 is a potent oral inhibitor of both the PI3K-? and PI3K-? isoforms that inhibits malignant B- and T-cell survival. Early evidence suggests single-agent activity of IPI-145 in CTCL and peripheral T-cell lymphoma (Horwitz S, et al. ASCO 2013. Abstract 8518).
The antiâ€“PD-L1 monoclonal antibody MPDLÂ3280A targets PD-L1 on antigen-presenting cells or tumor cells and prevents interaction with PD-1 on T cells; it has shown encouraging clinical activity in MF/CTCL. A phase 2 study with the antiâ€“PD-1 monoclonal antibody MK-3745 in CTCL (MF/SS) is opening, said Horwitz.
Histone deacetylase (HDAC) has a role in modulating cellular pathways such as proliferation, apoptosis, migration, and differentiation. Adverse effects limit the use of systemic HDAC inhibitors. SHP-141 is a topically applied HDAC inhibitor that inhibits isoforms 1, 2, 3, and 6. â€śIt is a soft drug that is active in skin and breaks down to inactive metabolites,â€ť he said. In a phase 1b study in early-stage CTCL, SHP-141 applied to index lesions produced a clinical objective response (>50% improvement by CAILS) in 28% (Kim YH, et al. ASCO 2014. Abstract 8525).
Merkel Cell Carcinoma
Cytotoxic chemotherapy works well early in MCC, but the response is short-lived. MCC may be too aggressive for immunotherapy, but targeted therapies may be beneficial, said Shailender Bhatia, MD. Because MCC is a neuroendocrine tumor, there appears to be a role for targeting the somatostatin receptor with a somatostatin analog. A trial of pasireotide in MCC and melanoma is ongoing.
Single-fraction high-grade (8 Gy) radiation therapy has been effective with rapid onset of palliation and minimal toxicity in MCC, said Bhatia, assistant professor of medical oncology, University of Washington, Seattle. Single-fraction high-grade radiation is potentially immunogenic and is convenient for patients who are located far from a radiation facility.
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