Highlights From the World Cutaneous Malignancies Congress

The Third Annual World Cutaneous Malignancies Congress (WCMC) took place in San Francisco, California, in October 2014. The WCMC is a 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), and cutaneous T-cell lymphoma (CTCL). Immune-targeted therapies and inhibitors of hedgehog pathway signaling dot the landscape in recent investigations in the treatment of melanoma, BCC, and MCC. The following articles highlight presentations regarding immunotherapies in oncology. For additional highlights from this premier meeting, visit www.cutaneousmalignancies.com

Malignant Melanoma

Interferon remains the adjuvant therapy of choice in patients at high risk for recurrence of malignant melanoma, said Reinhard Dummer, MD.¹ 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 endpoint for OS in a meta-analysis of 12 adjuvant trials in patients with resectable melanoma.² Ulceration and stage are predictive of interferon efficacy in melanoma, such that “only patients with ulceration and microscopic [N1] disease are profiting from pegylated interferon alfa-2b,” said Dummer, vice chairman, Department of Dermatology, University Hospital Zürich, 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—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 at the Mayo Clinic campus in Scottsdale, Arizona.³ “There are several points in the hedgehog pathway where one can potentially intervene,” he said. Smoothened is a G-protein–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.⁴ 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.⁵

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 Sézary syndrome (SS) stage IB to IVB, said Steven Horwitz, MD.⁶ Lower disease stage predicted better response in this study.

Median CD30_max 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-δ and PI3K-γ 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.⁷

The anti–PD-L1 monoclonal antibody MPDL3280A 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 anti–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. “It is a soft drug that is active in skin and breaks down to inactive metabolites,” 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 the composite assessment of index lesion severity score) in 28%.⁸

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.⁹ 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.

Immune Therapies in Melanoma

In the treatment of advanced melanoma, anti–PD-1 monoclonal antibodies have proven effective as single agents. Pembrolizumab is a humanized high-affinity antibody that exerts dual ligand blockade of PD-1; nivolumab is a fully human monoclonal antibody that is also directed toward PD-1. These anti–PD-1 antibodies represent breakthroughs in extending survival, said Caroline Robert, MD, PhD.¹⁰ They perform similarly in the setting of advanced melanoma, with an objective response rate (ORR) of 32% to 34% and 1-year OS in excess of 60%. “Five years ago, only 25% to 30% of patients were still alive at 1 year,” she said.

In patients with ipilimumab-refractory advanced melanoma, pembrolizumab at 2 or 10 mg/kg was associated with an ORR of 26% and a disease control rate of 50%.

The phase 3 CA209-037 study evaluated nivolumab versus investigator’s choice of chemotherapy (ICC) in 405 patients with advanced melanoma who had progressed despite previous therapies directed against CTLA-4 or BRAF mutation.¹¹ Interim efficacy analysis showed a higher ORR in patients who received nivolumab therapy compared with ICC (32% vs 11%), with 3 complete responses in the nivolumab group. Ninety-five percent in the nivolumab group had ongoing response with a minimum of 24 weeks of follow-up, said Robert, head of dermatology at the Institut Gustave Roussy, Paris. Responses with nivolumab were observed regardless of pretreatment PD-L1 expression status, BRAF mutation status, or prior benefit from anti–CTLA-4 therapy.

The most recent advancement in the treatment of advanced melanoma is combining ipilimumab and nivolumab. Blocking these pathways represents an immunotherapy strategy that can restore tumor-specific T-cell–mediated immunity. In a phase 1 clinical study, the combination given concurrently was associated with an ORR rate of 40% and survival of 85% at 1 year and 79% at 2 years. Even better 1-year (94%) and 2-year survival (88%) was achieved when they were given sequentially.¹² Treatment responses were independent of BRAF mutation status. Almost two-thirds (64%) of patients had grade 3/4 treatment-related adverse events.

Registry Examining Real-World Management of Advanced Basal Cell Carcinoma

The real-world management of advanced BCC is being examined in the RegiSONIC Disease Registry Study, said Jean Y. Tang, MD, PhD.¹³ The goal of RegiSONIC is to learn how clinicians determine and treat advanced BCC in the real world by evaluating the effectiveness, safety, and use of systemic and local treatments in 3 BCC populations: (1) advanced BCC patients who do not have basal cell nevus syndrome (BCNS) and are naive to treatment with a hedgehog pathway inhibitor; (2) those who were previously enrolled in a trial of the hedgehog pathway inhibitor vismodegib; and (3) patients who have BCNS advanced BCC or who have multiple nonadvanced, hedgehog pathway–naive BCC.

“The study represents the largest planned, prospective, observational cohort study of patients with advanced BCC and BCNS,” said Tang, associate professor of dermatology at Stanford University in California. It is attempting to provide real-world data that will inform the medical community and improve the care of patients with advanced BCC.

RegiSONIC is a multicenter, prospective, observational cohort study in adult patients with advanced BCC or BCNS and per-protocol follow-up. The determination of advanced BCC is left to the discretion of the study clinician, and treatment, procedures, and clinic visit schedules are left to the clinician’s discretion in accordance with routine practice.

Based on the first 131 locally advanced BCC patients enrolled, locally advanced BCC appears to be determined by using a number of tumor characteristics, including size (74%), extent (61%), and location (62%). Median size of the locally advanced BCC was 20.5 mm at determination, the most frequent location was the nose (19.8%), and the most common histopathology was nodular (58.8%).

The pivotal molecular abnormality in BCC carcinogenesis is inappropriate activation of the hedgehog signaling pathway. “Essentially all BCC tumors have an overactive hedgehog signaling pathway, commonly occurring by mutational inactivation of the tumor suppressor PTCH1 gene,” she said.

Vismodegib is a small-molecule inhibitor of the hedgehog signaling pathway that has been proven effective in the treatment of locally advanced BCC. Significant ORRs with vismodegib are observed in both locally advanced and metastatic BCCs, and the clinical response to vismodegib in responders frequently occurs in a matter of weeks, said Tang.

Vismodegib appears to be an effective chemopreventive agent for BCC. Tang and colleagues showed prevention of new BCCs in patients with BCNS.¹⁴ Other data show that in operable BCC, neoadjuvant vismodegib reduces the surgical defect size by 27% at an average of 4 months of treatment. Patients must be on neoadjuvant treatment for at least 3 months to see this effect, said Tang, and they should be counseled about the significant side effects associated with the drug.

Managing Resistance to Hedgehog Inhibitor

More than half of patients with advanced BCCs develop resistance to vismodegib. In these patients, the hedgehog pathway becomes reactivated; 50% of resistant BCCs contain mutations in the SMO gene of the hedgehog pathway. Smoothened inhibitors as second-line therapy may be effective when resistance to vismodegib develops, said Tang. Itraconazole reduces hedgehog pathway signaling by 50% in vismodegib-naive tumors, and reduced BCC tumor size by 20% at 1 month of therapy. In the mouse model, “the combination of itraconazole and arsenic trioxide does an even better job of reducing tumor size,” she said. In a small sample of 5 patients, the combination was shown to reduce hedgehog signaling as well.

Immunotherapy Approaches in Merkel Cell Carcinoma

The use of immunotherapy in MCC is rational, given the increased incidence of the disease and the worse prognosis in immunocompromised patients, “suggesting that the immune system is important in controlling the disease,” said Isaac Brownell, MD, PhD.¹⁵ In addition, prognosis of MCC is improved with the presence of CD8+ tumor-infiltrating lymphocytes. There are documented cases of spontaneous regression of MCC attributed to an antitumor immune response; responses have been observed with immune-stimulating therapies such as dinitrochlorobenzene, tumor necrosis factor-alpha, and interferon; and 80% of MCC patients express non-self Merkel cell polyomavirus viral antigens. Also, the prognosis of MCC is improved with high titers of MCV VP1.

“Similar observations predicted the immune responsiveness of melanoma,” said Brownell, head, Cutaneous Development and Carcinogenesis Section, Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Active immunotherapy trials for MCC include the following agents: anti–PD-L1, adoptive T cells, interleukin (IL)-12 plasmid in vivo electroporation DNA vaccine, glucopyranosyl lipid adjuvant-stable emulsion, F16-IL2 antibody-cytokine fusion with paclitaxel, and adjuvant ipilimumab for excised MCC.

References
1. Dummer R. Changing arena of adjuvant therapy in malignant melanoma. Presented at: Third Annual World Cutaneous Malignancies Congress; October 30-31, 2014; San Francisco, CA.
2. Suciu S, Eggermont AM, Lorigan P, et al. relapse-free survival (RFS) as a surrogate endpoint for overall survival (OS) in adjuvant Interferon trials in patients (pts) with resectable Cutaneous melanoma: an individual patient data (IPD) meta-analysis. Presented at: 2014 Congress of the European Society for Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract 1089PD.
3. Sekulic A. Ongoing clinical studies in BCC. Presented at: Third Annual World Cutaneous Malignancies Congress; October 30-31, 2014; San Francisco, CA.
4. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179.
5. Tang TY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366
(23):2180-2188.
6. Horwitz S. New systemic therapies in CTCL: beyond the old paradigms. Presented at: Third Annual World Cutaneous Malignancies Congress; October 30-31, 2014; San Francisco, CA.
7. Horwitz S, Flinn I, Patel MR, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma. Presented at: 49th Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. Abstract 8518.
8. Kim YH, Krathen M, Duvic M, et al. A phase 1b study in cutaneous T-cell lymphoma (CTCL) with the novel topically applied skin-restricted histone deacteylase inhibitor (HDAC-i) SHP-141. Presented at: 50th Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract 8525.
9. Bhatia S. Emerging treatment options in MCC: chemotherapy and alternative approaches for metastatic disease. Presented at: Third Annual World Cutaneous Malignancies Congress; October 30-31, 2014; San Francisco, CA.
10. Robert C. Anti-PD-1 antibodies ± ipilimumab in melanoma. Presented at: Third Annual World Cutaneous Malignancies Congress; October 30-31, 2014; San Francisco, CA.
11. Weber JS, Minor DR, D’Angelo S, et al. A phase 3 randomized, open-label study of nivolmab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy. Presented at: 2014 Congress of the European Society for Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract LBA3_PR.
12. Kluger H, Sznol M, Callahan M, et al. Survival, response duration, and activity by BRAF mutation (MT) status in a phase 1 trial of nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). Presented at: 2014 Congress of the European Society for Medical Oncology; September 26-30, 2014; Madrid, Spain. Abstract 1085O.
13. Tang J. Real-world management of BCC: the RegiSONIC study. Presented at: Third Annual World Cutaneous Malignancies Congress; October 30-31, 2014; San Francisco, CA.
14. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366
(23):2180-2188.
15. Brownell I. Rationale and status of immune targeted therapies for MCC. Presented at: Third Annual World Cutaneous Malignancies Congress; October 30-31, 2014; San Francisco, CA.