PMO Live 2015 – Highlights from Saturday, July 25

PMO Live Day 4 Highlights

The final day of the 2015 Fourth Annual World Cutaneous Malignancies Congress (WCMC) opened with a review of yesterday’s presentations by the meeting chair, Dr. Sanjiv Agarwala. He stressed the multidisciplinary nature of the day’s proceedings that makes WCMC unique among cutaneous malignancy conferences. Not only does it cover a spectrum of important tumor types (melanoma, basal-cell carcinoma, cutaneous T-cell lymphoma, and Merkel-cell cancer), but it also provides valuable information for dermatologists, surgeons, medical and radiation oncologists, researchers and basic scientists, as well as nurses and other healthcare providers who manage patients with cutaneous malignancies. Today’s first session was focused on current approaches to nonmelanoma skin cancers.

Current Approaches to Therapy—Case Studies in Nonmelanoma Cutaneous Malignancies

Today’s opening session began with a review by Dr. Sanjiv Agarwala of yesterday’s presentations and a preview of today’s sessions. The opening session was a review of current approaches to nonmelanoma cutaneous malignancies. Using a case-based approach with several patient cases, Dr. Karl Lewis discussed current approaches to treating locally advanced and metastatic basal-cell carcinoma (laBCC and mBCC). He highlighted the efficacy and safety of surgical approaches, topical therapy, and systemic therapy with vismodegib and sonidegib in treating laBCC and mBCC. Dr. Lewis reviewed the data from the ERIVANCE and STEVIE studies with vismodegib and the BOLT study with sonidegib, and showed a summary of the safety and efficacy of these agents in patients with laBCC and mBCC. Both agents are effective in clearing lesions and increasing progression-free survival in these patients. He stressed, however, that the long-term impact of these Hedgehog inhibitors on the natural history of mBCC is unknown, and that more information is needed about mechanisms of resistance to these agents, as well as development of agents against alternative SMO binding sites and molecular targets such as PI3K. Dr. Madeleine Duvic then discussed current therapy for cutaneous T-cell lymphoma, including current management guidelines for this heterogeneous group of skin cancers, but focusing on mycosis fungoides (MF) and Sezary syndrome (SS). Using a case-based approach, she showed the current treatment algorithm for MF based on the stage of disease and the presence of patch/plaque disease, including the safety and efficacy of skin-directed topical therapies (eg, bexarotene and PUVA), radiation therapy, and systemic targeted agents (eg, brentuximab, denileukin, vorinostat, and romidepsin), which are used in extensive and refractory disease. She followed a similar course in her discussion of current treatment of SS, including first-line combination immunotherapy and second-line targeted therapies with histone deacetylase (HDAC) inhibitors and emerging agents (eg, alemtuzumab). She concluded that treatment of MF and SS depends on the stage of disease, and that better combinations of topical and systemic therapies are needed for these cutaneous malignancies. Dr. Manisha Thakuria then presented a case-based discussion of current approaches to therapy of Merkel-cell carcinoma (MCC), a rare but aggressive malignancy with debatable optimal treatment. Using several typical case studies of patients with MCC, she highlighted the National Comprehensive Cancer Network (NCCN) guidelines for diagnosis and workup of MCC, particularly as it relates to imaging techniques and the need for sentinel lymph node biopsy. Dr. Thakuria then traced the NCCN algorithm for treating MCC with wide surgical excision and radiation therapy in lymph node–negative disease, as well as principles of radiation therapy and chemotherapy with carboplatin ± etoposide in metastatic disease. She cautioned that careful follow-up of MCC patients treated with any of these modalities is important due to the risk for recurrence, with 91% of recurrences occurring within 2 years of initial diagnosis. This session was followed by a vigorous question-and-answer session in which many attendees presented management challenges in their own patients for the panel to consider. Interestingly, melanoma experts weighed in on therapy for MCC, cutaneous T-cell lymphoma, and BCC, demonstrating the multidisciplinary nature of this meeting.

Emerging Therapies in Advanced Melanoma

This key session at WCMC 2015 focused on emerging therapies in advanced melanoma, including adjuvant therapy and recent advances in immunotherapy. Dr. Vernon Sondak began the session with a presentation on the current state-of-the-art in the use of adjuvant therapy for unresectable, high-risk melanoma. He discussed recent data on the efficacy and toxicity in the adjuvant use of interferon to delay recurrence and improve overall survival in melanoma. Dr. Sondak also alluded to emerging adjuvant management approaches based on recent FDA approval of new agents, including the use of ipilimumab, the combination of BRAF+MEK inhibitors, and anti–PD-1 monoclonal antibodies. He concluded that better prognostic markers are needed to identify patients at risk of relapse, especially in the sentinel lymph node–negative population, and that the drugs and doses that work best in advanced disease may not be the ones that work best in the adjuvant setting. Dr. Steven O’Day followed this presentation with an up-to-the-minute review of immune checkpoint inhibitor therapy for patients with advanced melanoma. Although immuno-oncology approaches include vaccines, cytokine therapy, and adoptive cell therapy, his talk focused on data with targeted immune checkpoint blockade, specifically the use of monoclonal antibodies against CTLA-4 and the PD-1/PD-L1 pathway. He reviewed the role of CTLA-4 in the cell-mediated immune response and the mechanism of action and the most recent safety and efficacy data with the CTLA-4 blocker ipilimumab. Dr. O’Day then presented a rationale for using anti–PD-1/PD-L1 therapy and showed efficacy and safety results from the most current clinical trials with nivolumab monotherapy in ipilimumab-naïve and -pretreated patients, where durable response rates >30% were seen along with a 70% progression-free survival and a median 3-year overall survival of 40%. Finally, Dr. O’Day presented the data on the use of the combination of ipilimumab + nivolumab, stratified by PD-L1 expression, BRAF status, and tumor stage, that had just been released at the 2015 American Society of Clinical Oncology (ASCO) meeting. Overall response rates of 50% to 60% were observed with combination therapy compared with ipilimumab alone, although toxicity with the 2 drugs was greater than with ipilimumab monotherapy. Despite these exciting results, Dr. O’Day cautioned that there is still quite a bit of work to be done in the immuno-oncology arena in melanoma, including finding predictive biomarkers, selecting sequential versus concurrent therapy, determining the optimal duration of therapy, and finding new combination immunotherapies and combinations of cytotoxic therapy + immunotherapy. Finally, Dr. Robert Andtbacka discussed oncolytic immunotherapies in development for melanoma, including data from the randomized OPTiM phase 3 clinical trial (intralesional T-VEC vs subcutaneous granulocyte-macrophage colony-stimulating factor in advanced melanoma), the use of plasmid-encoded DNA IL-12 (ImmunoPulse) electroporation, and results from the phase 2 CALM clinical trial and extension cohort (as presented at ASCO 2015) on the use of Coxsackievirus A21 (CVA21); these data served as examples of the mechanism of action for oncolytic immunotherapies, and suggested a significant role for immunotherapy in treating advanced melanoma. He summarized his presentation with the fact that locally injected oncolytic immunotherapies are well tolerated with low toxicity, that they exhibit an effect on injected lesions as well as uninjected tumors that appears to be immune-mediated, and they can enhance the effect of other immunotherapies and therapeutic combinations. In this regard, Dr. Andtbacka ended his presentation with a look toward the future where clinical trials of ipilimumab ± T-VEC, pembrolizumab ± T-VEC, and ipilimumab + HF-10 are in various stages of clinical development, and trials with pembrolizumab + IL-12 electroporation and pembrolizumab ± CVA21 are being planned. Needless to say, the discussion that followed this session was extremely animated, with many questions from the attendees around optimal treatment strategies, cost of therapy, and management of immune-mediated toxicities. “This was very enlightening,” said Dr. Axel Hauschild, who chaired the session.

A Keynote Lecture on Genetic Testing for Melanoma

Dr. Grant McArthur, the Lorenzo Galli Chair in Melanoma, Peter MacCallum Cancer Centre, University of Melbourne, and co-head of Cancer Therapeutics and Practitioner Fellow at the National Health and Medical Research Council, Melbourne, Australia, gave a keynote presentation on the state-of-the-art in genetic testing for melanoma. Since testing for predictive biomarkers can help direct therapy, and testing for prognostic biomarkers can guide intensity of follow-up, he focused his remarks on when to test, which genes to test for, and what platforms to use in testing, using the subtypes of the BRAF/RAS/NF1/triple wild-type somatic melanoma genome as a backdrop. Molecular testing in melanoma is dominated by oncogenes, and Dr. McArthur reviewed the various oncogenic markers available for testing and their clinical utility in selecting targeted therapy, including mutations in BRAF, NRAS, KIT, and TP53. He also suggested that metastases should be tested for multiple mutations, and that testing should include all actionable mutations in exon 15, including less common BRAF mutations.

Emerging Therapies in Advanced Nonmelanoma Cutaneous Malignancies

The next session in WCMC 2015 focused on emerging therapies for advanced basal-cell carcinoma (BCC), cutaneous T-cell lymphoma (CTCL), and Merkel-cell cancer (MCC). Dr. Aleksandar Sekulic opened the session with a presentation on advances and challenges in treating BCC. Although data with vismodegib in inoperable locally advanced or metastatic BCC (laBCC or mBCC) have shown this agent to be effective, issues of treatment-related toxicity and resistance have been encountered. Dr. Sekulic addressed these issues by reviewing who to treat based on extent and location of disease and the patient’s clinical characteristics, how long to treat, how to manage therapeutic resistance, and how to manage treatment-emergent adverse events (eg, L-carnitine for muscle spasms). He also discussed using vismodegib as neoadjuvant therapy prior to Mohs surgery in selected patients, which is being tested in the VISMOHS phase 2 clinical trial. Dr. Sekulic also touched on the FDA approval yesterday of sonidegib, another Hedgehog inhibitor for patients with laBCC who are not candidates for surgery or radiation therapy or who have had disease recurrence. Dr. Larisa Geskin then made a presentation on “what’s new in treating CTCL?” She indicated that there has been an explosion of research in CTCL, including high throughput technologies that have resulted in identification of diagnostic and prognostic biomarkers, recent FDA approval of 4 novel agents (vorinostat, romidepsin, pralatrexate, and brentuximab vedotin), and numerous novel drugs in current clinical trials, including HDAC inhibitors, monoclonal antibodies directed against several cell-surface markers in CTCL (including anti-KIR antibodies), small molecules, and other targeted therapies. Dr. Geskin’s talk reviewed the latest clinical data in these areas, including an exhaustive listing of dozens of exciting new clinical trials with both topical and systemic therapies, combination therapies, and stem-cell transplantation. Dr. Shailender Bhatia then spoke on emerging treatment options for MCC. He suggested that cytotoxic chemotherapy was a “poor” standard of care for advanced MCC since clinical benefits are not durable, and that “there is a strong need for rational, biology-driven drug development in MCC.” Although intratumoral CD8+ T-cell infiltration is associated with better clinical outcomes, the immune system appears to be dysfunctional or “exhausted” in the MCC tumor microenvironment, supporting a rationale for immunotherapeutic approaches to this cancer. Dr. Bhatia then reviewed the efforts in immunotherapy of MCC, including clinical trials with intratumoral IL-12 or GLA (a synthetic TLR-4 agonist), systemic use of the immune checkpoint inhibitors pembrolizumab and avelumab, and treatment with MCC polyomavirus-specific autologous T-cells or natural killer cells. He also discussed other approaches, including targeted therapies for debulking prior to surgery, and optimal use of radiation therapy. “Multidisciplinary management is most appropriate for advanced MCC patients” was Dr. Bhatia’s final message. As in the session on advances in melanoma therapy, this session prompted vigorous discussion. “Excellent presentations,” opined Dr. Paul Nghiem as he opened the session for discussion.

Advances in the Prevention and Early Detection of Cutaneous Malignancies

The final session at WCMC 2015 focused on prevention of melanoma and early detection of melanoma and MCC. Dr. Axel Hauschild opened the session with a review of melanoma epidemiology in Europe, and then presented updated results from the SCREEN trial, a screening of more than 360,000 people in Northern Germany. Follow-up for >6 years after the SCREEN study demonstrated a 34% increase in the incidence of melanoma in this region, with a 48% decrease in melanoma mortality. It remains unclear whether the screenings or the awareness campaigns associated with the SCREEN study led to these results. Dr. Hauschild then reviewed modern techniques in melanoma screening, including various forms of dermoscopy and electroimpedance spectroscopy. He also reviewed another primary prevention trial, a prospective randomized trial on more than 1600 subjects in Australia that demonstrated the benefit of regular sunscreen use in preventing melanoma, especially invasive tumors. Dr. Hauschild closed by showing the effort in the United States to proactively screen people for melanoma so that the tumors can be caught early and treated effectively. Dr. Paul Nghiem then presented his perspectives on the use of assays for the polyomavirus associated with MCC (MCPyV) for early detection of MCC. In this regard, the key questions are: Is there a “gold standard” for MCPyV detection in MCC, does tumor viral status have prognostic significance, and should we routinely test for MCPyV in MCC? Dr. Nghiem presented data that showed there is no perfect, gold standard test for MCPyV, that virus-negative patients are significantly more likely to progress and die of MCC, such that we should be more aggressive in treating virus-negative MCC. The final presentation of the day was by Dr. Michael Midgen, representing the winners of the best poster abstract at WCMC 2015. His presentation was on “Composite Assessment of Treatment Response in Patients with Locally Advanced Basal-Cell Carcinoma: Sonidegib Efficacy Using 2 Sets of Response Criteria.” In this analysis, treatment responses in the BOLT study in patients with locally advanced BCC (laBCC) were evaluated using 2 sets of criteria: BCC-mRECIST and BCC-mRECIST–like (similar to criteria used in other studies with less stringent requirements for complete response). The data demonstrated a high response to sonidegib (which just yesterday received FDA approval for laBCC), and both evaluation criteria supported the clinical benefit of sonidegib in this difficult-to-treat patient population.

This brought us to the end of WCMC 2015, and Dr. Agarwala closed the meeting and invited everyone to attend next year’s Congress—the 2016 Fifth Annual WCMC will be in Washington, DC—during PMO Live 2016, taking place on September 28-October 2, 2016—please plan to attend! Thank you to all of our sponsors and exhibitors!

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