PMO Live 2015 – Highlights from Friday, July 24

Welcome to the 2015 Fourth Annual World Cutaneous Malignancies Congress!

Chaired by Dr. Sanjiv Agarwala, and with an advisory committee that included Drs. Axel Hauschild, Aleksandar Sekulic, Madeleine Duvic, and Paul Nghiem, the Fourth Annual World Cutaneous Malignancies Congress will feature multidisciplinary perspectives on skin cancer. Over the next 2 days, we will be hearing presentations from dermatologists and medical and surgical oncologists on the hottest topics related to understanding the molecular biology and personalized medical and surgical treatment options for melanoma, basal-cell carcinoma, cutaneous T-cell lymphoma, and Merkel-cell tumors. In addition, advances in genetic testing and prevention and early detection of cutaneous malignancies will be covered. “This is an interactive meeting,” Dr. Agarwala said, “with an excellent mix of molecular biology, scientific, and clinical presentations.”

Clinical Presentations of Cutaneous Malignancies

The opening session of WCMC 2015 focused on the clinical presentations of melanoma, basal-cell carcinoma (BCC), cutaneous T-cell lymphoma (CTCL), and Merkel-cell cancer (MCC), as presented by Drs. Roger Lo, Steven Nelson, Joan Guitart, and Jaehyuk Choi, respectively. The overarching theme of the presentations in this session was the heterogeneous clinical presentations of these malignancies, making accurate diagnosis and disease assessment challenging. Dr. Venna presented his perspectives on melanoma; as a dermatologist, he views skin cancer screening and prevention as major undertakings, and his presentation focused on these topics. Dr. Venna showed that there was an increased risk of melanoma in individuals who take phosphodiesterase 5A inhibitors (eg, men with erectile dysfunction who take sildenafil), but that coffee consumption may reduce melanoma incidence by 20%, but only if the coffee is caffeinated. He also discussed in-depth elements of melanoma detection by inspection and dermoscopy, as well as optimal screening techniques. Finally, Dr. Venna discussed current data on sentinel lymph node biopsy (SLNB) for various forms of melanoma, especially thin and very thin T1b lesions. Dr. Bichakjian reviewed the clinical characteristics of BCC as an example of a nonmelanoma skin cancer (NMSC), which affects more than 3 million individuals in the United States and costs the healthcare system nearly $5 billion annually. Overall, 60% to 80% of NMSCs are BCC, and there is a clear correlation between BCC incidence and exposure to UV radiation. He described the pathogenesis and characteristics of several different subtypes of BCC based on current clinical and histologic classifications, including sclerotic and morpheaform types. Dr. Bichakjian also touched on Gorlin syndrome (nevoid BCC syndrome). Finally, he briefly reviewed nonsystemic (topical, surgical, and radiation) treatment approaches to BCC, and indicated that subsequent speakers will deliver comprehensive presentations on current and emerging systemic treatment options for BCC. Dr. Guitart took the audience on a roller coaster ride through the clinical, laboratory, and histologic presentations of multiple forms of CTCL, including mycosis fungoides, Sezary syndrome, and other types of cutaneous lymphoma. His vivid images of affected patients were very effective in conveying the heterogeneity of this complex collection of cutaneous/hematologic malignancies and how debilitating, deforming, and lethal they can be. Dr. Nghiem rounded out the session with a talk on the clinical presentation of MCC, including diagnosis, disease staging, and prognostic factors associated with these tumors. He posed the question, “Why is MCC important?” Dr. Nghiem showed that MCC can be more lethal than melanoma, the incidence of MCC has quadrupled since 1986, and there are several novel treatment approaches to these cutaneous malignancies. He also spoke about the most recent data on stage-related survival data in MCC and the role of the patient’s immune system in determining clinical outcomes and survival. Finally, Dr. Nghiem discussed the viral etiology of MCC and touched on National Comprehensive Cancer Network (NCCN) guidelines on initial treatment approaches for these cutaneous cancers. Every presentation in this session was followed by a vigorous discussion, with probing questions from attendees. “Marvelous discussions,” suggested one attendee. “I can’t find this diversity of content at any other meeting.”

Understanding the Molecular Biology of Cutaneous Malignancies: Application to Clinical Practice

The next session of WCMC focused on the latest data on the molecular biology of melanoma, BCC, CTCL, and MCC, with a perspective on how to translate these data to more effective targeted therapy. Dr. Roger Lo reviewed the latest data on identifying new molecular targets in melanoma, especially in BRAF-resistant cells, and how targeting certain molecular pathways has translated into improved survival of melanoma patients. He touched upon the use of immune checkpoint and kinase-targeted therapies. In discussing BRAF inhibitor resistance in melanoma, Dr. Lo reviewed RTK and N-RAS upregulation and BRAF amplification as molecular mechanisms of acquired resistance. He presented a genomic classification map of cutaneous melanoma as developed by the Cancer Genome Atlas Network. Finally, Dr. Lo proposed an algorithm based on our current knowledge of the landscape of tumor heterogeneity, clonal diversity, and mutational signatures in melanoma patients with acquired BRAF-inhibitor resistance. This presentation was followed by a review of molecular pathways of tumor growth and development in BCC by Dr. Steven Nelson. He asked, “Why do we need to know molecular pathways?” In response to his own question, Dr. Nelson presented the history and our current understanding of the Hedgehog (Hh) pathway and other molecular defects (EGFR and AKT mutations, p53 overexpression, and CXCR4 expression) that drive growth and aggressiveness of BCC, and how the advent of Hh pathway-targeting agents such as vismodegib and other Smo inhibitors (saridegib, erismodegib, taladegib) has revolutionized the treatment approach to BCC. Dr. Joan Guitart then spoke about the development of CTCL from skin-resident T-cell subsets and the underlying molecular mechanisms that may contribute to a transformation of these resident cells to malignant T-cell clones. He cautioned, however, that pathognomonic molecular drivers are lacking in CTCL, that gene defects in CTCL are complex, and, with rare exceptions, have thus far failed to provide prognostic or therapeutic guidance. Nevertheless, it is clear that growth and progression of CTCL is linked to immunosuppression, while maintenance of CD8-positive T-cells is crucial for positive clinical outcomes in this cutaneous malignancy. Finally, Dr. Jaehyuk Choi spoke about the molecular pathophysiology of MCC, especially related to the discovery of the Merkel-cell polyomavirus (MCPyV), the first polyomavirus discovered to cause cancer in humans. He presented preclinical and clinical evidence of the relationship between MCPyV and the development of MCC, and how these data have resulted in rationally designed therapeutic targeting of a viral oncoprotein. However, Dr. Choi posed a number of unanswered questions in MCC, including: what are the actionable driver genes in MCPyV, which of the functions of viral oncoproteins are critical for MCC pathogenesis, are viral oncoproteins targetable with small-molecule inhibitors, what is the role of targeted therapies in MCC, and how do we treat patients who fail immunotherapy? This session elicited a lively discussion among the faculty and with attendees.

Surgical and Locoregional Therapies of Melanoma

Surgical and intralesional approaches to early-stage primary melanoma are the subjects of intense investigation and some controversy, and the next session of WCMC explored some of these treatment options. Dr. Merrick Ross presented his perspectives on surgical treatment of melanoma across the disease spectrum, focusing not only on issues of excision margins and indications for SLNB in stage I-II melanoma, but also on neoadjuvant strategies for advanced nodal disease (stage III) and even the possibility of metastasectomy in stage IV disease. He provided guidelines for margins of excision depending on lesion size in early melanoma, and durability of disease control by locoregional therapies in stage III disease, especially in light of the toxicities associated with systemic targeted agents. Dr. Ross pointed out that it was necessary to select the right patient population for surgical or locoregional therapy of advanced melanoma, depending on whether curative intent can be accomplished and local or distant recurrence can be prevented. He cited data from several clinical trials, including MSLT I, where complete resection of advanced melanoma with SLNB resulted in 4- and 5-year overall survival rates of 30% to 40%. Dr. Ross also presented a case for neoadjuvant therapy of stage III-IV melanoma for patients in whom systemic therapy with BRAF inhibitors or immune checkpoint blockers is being considered. “So why do surgery for stage IV melanoma?” he asked. He suggested that cure with surgery plus adjuvant therapy can be accomplished in stage IV with this approach, at a lower cost and toxicity burden to the patient than systemic therapy. Dr. Sanjiv Agarwala then presented an overview of intralesional therapy in melanoma, including the use of current and emerging agents. He provided an expert perspective on intralesional agents currently in development and showed clinical data on their safety and efficacy in stage III-IV injectable, but unresectable, melanoma. The goals of intralesional therapy include local disease control, systemic effects, and delaying or preventing the need for systemic therapy. Moreover, intralesional therapy presents a potential as neoadjuvant therapy. He showed results from the OPTiM trial with TVEC, where overall response rates and overall survival with TVEC was superior to granulocyte-macrophage colony-stimulating factor. Similarly, PV-10 (Rose Bengal disodium) was tested in a phase 2 clinical study in patients with locally advanced cutaneous melanoma that showed a 51% response in target lesions and a 33% response rate in nontarget lesions, suggesting a systemic effect. PV-10 is currently being tested in a randomized phase 3 trial. He also reviewed other intralesional agents that are in earlier stages of clinical development. Dr. Agarwala concluded that in the current era of melanoma therapy, intralesional approaches may have value (with a local direct effect and a systemic immune effect), that several agents in development appear promising, and that combination therapies of intralesional plus systemic therapies (eg, TVEC + ipilimumab or pembrolizumab) may be the best way to integrate the intralesional agents into clinical practice. Finally, Dr. David Brodland presented his perspectives on the benefits of Mohs surgery over standard excision in cutaneous melanoma. In a visually stunning presentation, Dr. Brodland showed details of the Mohs procedure, and that local cancer recurrence rates following Mohs surgery were 0.2% to 0.3% compared with ~6% with standard wide excision. He showed evidence from clinical trials that the Mohs technique with a narrow 6-mm tumor-free margin is noninferior to wide excision with standard 1- to 2-cm margins in curing the patient and preventing recurrence. Dr. Brodland concluded that Mohs surgery provides very high cure rates and may be tissue conservative when needed, and is particularly useful for melanoma lesions that occur on the head and neck. To illustrate this, he presented intra- and postoperative images of several challenging cases of cutaneous melanoma on the face illustrating the surgical technique. However, patients who require SLNB are not candidates for the Mohs technique. This session elicited a vigorous discussion among attendees, and it was apparent that there are still a number of unsettled issues in the area of locoregional and surgical management of melanoma patients.

Current Approaches to Therapy—Case Studies in Malignant Melanoma

Selecting a targeted therapy for patients with malignant melanoma requires consideration of a number of factors, including the cancer’s mutation status (eg, BRAF V600) and disease characteristics (eg, aggressiveness, symptoms, and site(s) of metastasis). In a case-based format, the next session of WCMC 2015 dealt with issues surrounding selection of appropriate targeted agents in malignant melanoma, both from an oncologist’s and dermatologist’s perspective, as well as management of cutaneous toxicities associated with melanoma therapy. Dr. Grant McArthur began the session by discussing approaches to theBRAF+ melanoma patient. He reviewed the range of therapies targeting the BRAF/MEK/ERK pathway, including dabrafenib, vemurafenib, trametinib, and cobimetinib. He posed the question, “How do you choose a first-line targeted therapy in malignant melanoma?” In response, he presented clinical data from the BRIM7 studies in discussing treatment of one of his own patients, an asymptomatic melanoma patient who was BRAF+ and had small brain metastases. Professor McArthur also reviewed the latest data on BRAF-directed therapy for melanoma that had been presented at the 2015 American Society of Clinical Oncology meeting, including a trial with the emerging agents encorafenib + binimetinib, showing progression-free survival benefits over conventional therapy. He also focused on adverse events associated with targeted BRAF inhibitors used alone or in combination, and his approach to BRAF-inhibitor resistant disease with MEK inhibitors or immune checkpoint inhibitors for BRAF/MEK inhibitor–resistant disease. Dr. John Thompson then presented his perspectives on treatment options for melanoma patients with brain metastases, which are found in 30% of patients at diagnosis and occur in an additional 30% of melanoma patients within 1 to 2 years after diagnosis. Radiation therapy and radiosurgery (Gamma KnifeTM) are current standards of care for brain metastases, but result in median survivals of only 3 to 6 months and are associated with significant adverse effects and cost. Using several fascinating case studies, Dr. Thompson showed efficacy data from several clinical trials with ipilimumab in patients with melanoma plus brain metastases, and suggested that the combination of ipilimumab plus an anti–PD-1 agent (eg, nivolumab) may be appropriate in these cases. Dr. Mohammed Kashani-Sabet provided a dermatologist’s perspective on follow-up of patients with malignant melanoma who had been treated by a medical or surgical oncologist. Why follow up?—to detect recurrent and additional primary melanomas which occur in up to 5.5% of patients, reinforce sun-protective behavior, screen for familial melanoma susceptibility genes, and provide psychosocial support. He reviewed the 2015 National Comprehensive Cancer Network guidelines for follow-up and imaging of melanoma patients at various stages of disease, but cautioned that the guidelines do not take into account certain patient factors, such as tumor burden in the lymph nodes and whether the patient is being treated with adjuvant therapy. Dr. Kashani-Sabet concluded with “What Do I Do?” in these patients, providing his perspectives on how dermatologists should follow melanoma patients according to the stage of disease, using periodic clinical and imaging evaluations. Dr. Mario Lacouture then tackled the issue of the manifestations and management of cutaneous toxicities of melanoma therapy. He reviewed the adverse events associated with BRAF and MEK inhibitors (eg, acneiform rash in 62% and xerosis in up to 20% of treated patients), and with immune checkpoint inhibitors (eg, rash and pruritus, vitiligo, mucositis, blistering conditions, alopecia); he highlighted their impact on patients’ psychosocial function, overall health, quality of life, and in causing interruption of anticancer therapy. Dr. Lacouture suggested a number of management approaches for these adverse events, stressing an early, proactive approach. After a lively discussion that followed the session, Congress participants were afforded a “Meet the Experts” networking opportunity to engage the faculty in an informal setting to discuss issues on the diagnosis, assessment, and management of cutaneous malignancies. Congress participants were also able to view the posters on emerging data in melanoma and BCC, and visit the exhibit booths from Congress supporters.

In reviewing the day, it was evident that the speakers had fostered debate and discussion, with interaction among basic scientists and clinicians from various disciplines including dermatology, clinical oncology, and surgical oncology. Much more is coming tomorrow, including current and emerging approaches to melanoma and nonmelanoma cutaneous malignancies, and advances in prevention and early detection of skin cancer.

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