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Principles of Immunotherapy

Anthony J. Olszanski

With recent success stories in melanoma, breast cancer, gastric cancer, renal cell carcinoma, prostate cancer, Hodgkin's lymphoma, squamous cell lung cancer, and other malignancies, immunotherapy has emerged as perhaps the most paradigm-changing treatment strategy to occur on the oncologic front in the last 35 years. At the NCCN 20th Annual Conference, Dr. Anthony J. Olszanski offered a primer on immunotherapeutic basics, featuring the complex interplay between the immune system and cancer; a comparative look at innate and adaptive immunity; and the topics of immune surveillance, tumor escape mechanisms, and immune suppression. Several examples of cancer immunotherapies in action are briefly presented.

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Mutation Testing and Adjuvant Systemic Therapy in Cutaneous Melanoma

Anthony J. Olszanski

According to Dr. Anthony J. Olszanski, the most significant updates to the treatment of cutaneous melanoma include the recently published results of MSLT-II, which demonstrated that ultrasound-guided follow-up can be performed rather than a complete lymph node dissection, improving morbidity in patients with sentinel node metastases while not adversely affecting survival. In the adjuvant setting, the PD-1 inhibitors nivolumab and pembrolizumab are now FDA-approved, in addition to dabrafenib and trametinib, for patients with BRAF mutations.

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Full Spectrum: Efficacy and Toxicity of Immunotherapy in Metastatic Melanoma

Matthew Zibelman and Anthony J. Olszanski

Metastatic melanoma is a devastating disease that has been increasing in incidence and until relatively recently had few effective treatment options. With the approval in 2011 of ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte associated protein 4 (CTLA-4), however, that has begun to change. Ipilimumab is an immune checkpoint inhibitor, a type of immunotherapy that can down-regulate inhibitory signals affecting T-cell activation to unleash more dramatic anti-tumoral responses and offer the possibility of deep and durable remissions in up to 20% of patients. Use of this and similar agents can lead to characteristic and varied immune-related adverse events (irAEs); however, experience has shown that these can be managed with patient education, early recognition, and judicious use of systemic steroids. Newer immune checkpoint inhibitors such as those that block PD-1 or PDL-1 have shown impressive results in early studies. Most recently, pembrolizumab, an anti-PD-1 antibody, was approved by the FDA for the treatment of patients with melanoma after progression on a CTLA-4 inhibitor and, if clinically relevant, a BRAF inhibitor. This supplement presents the case of a 60-year-old man with an enlarging right neck mass who was found to have disseminated metastatic melanoma. He was started on treatment with the CTLA-4 inhibitor ipilimumab (3 mg/kg intravenous). After the third dose, the patient developed grade 3 uveitis/retinitis and immune-mediated nephritis requiring hospitalization and systemic corticosteroids. Both conditions were considered irAEs secondary to ipilimumab. The patient recovered completely from all toxicities but did not receive further doses of ipilimumab. Nonetheless, the patient experienced a complete radiographic response and at time of writing was 19 months from diagnosis without evidence of disease.

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Progress in the Management of Melanoma in 2013

Daniel G. Coit and Anthony J. Olszanski

The treatment of melanoma in 2013 has evolved significantly over the past 2 years, according to presentations at the recent NCCN 18th Annual Conference. Ipilimumab and vemurafenib have prolonged the survival of patients with advanced disease, and the research pipeline continues to evaluate a number of new agents highlighting a tremendous optimism to further improve outcomes. These new treatment options were incorporated into the NCCN Clinical Practice Guidelines in Oncology in 2012. A recent presentation of these guidelines highlighted changes in both the initial management of very thin melanomas and the ongoing importance of targeted agents and immunotherapy in more advanced disease. This presentation included refining the indication for sentinel lymph node biopsy (SLNB), which, according to the updated guidelines, is not recommended for very thin lesions (≤ 0.75 mm). Dr. Daniel G. Coit discussed the rationale for this change during the presentation, and Dr. Anthony J. Olszanski reviewed the evidence for new classes of agents that impact survival.

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Orally Administered Cancer Therapy: Breaking Down Barriers to Adherence and Quality of Life

Julia C. Shih and Anthony J. Olszanski

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Successful Imatinib Therapy for Neuroendocrine Carcinoma With Activating KIT Mutation: A Case Study

James Perkins, Patrick Boland, Steven J. Cohen, Anthony J. Olszanski, Yan Zhou, Paul Engstrom, and Igor Astsaturov

Neuroendocrine tumors (NET) and gastrointestinal stromal tumors (GIST) are believed to originate from the cells of Cajal that are randomly dispersed along the aerodigestive tract. Despite their distinct morphologic appearance, NET and GIST may share oncogenic mechanisms. Often presenting in the metastatic setting, treatment options for patients with NET are limited. This case report presents a patient with refractory metastatic NET that did not respond conventional chemotherapy. The patient was treated with a KIF11 inhibitor in a phase I clinical trial and experienced a prolonged and clinically meaningful partial response. On progression at 20 months, the patient’s tumor was sequenced to reveal a KIT exon 11 mutation. Institution of imatinib therapy achieved a rapid and sustained antitumor effect with profound clinical benefit. Despite previously reported KIT expression in NET, this is the first documented case of an activating KIT mutation in NET and of successful treatment with both a KIF11 inhibitor and imatinib, each of which was elucidated through molecular profiling of the patient’s tumor. Imatinib may be a valuable therapy in NET harboring activating KIT mutations.

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NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

Alan P. Venook, Maria E. Arcila, Al B. Benson III, Donald A. Berry, David Ross Camidge, Robert W. Carlson, Toni K. Choueiri, Valerie Guild, Gregory P. Kalemkerian, Razelle Kurzrock, Christine M. Lovly, Amy E. McKee, Robert J. Morgan, Anthony J. Olszanski, Mary W. Redman, Vered Stearns, Joan McClure, and Marian L. Birkeland

Defining treatment-susceptible or -resistant populations of patients with cancer through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies, because potential patient populations are divided into ever smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists, and information developers.

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NCCN Oncology Research Program's Investigator Steering Committee and NCCN Best Practices Committee Molecular Profiling Surveys

Razelle Kurzrock, A. Dimitrios Colevas, Anthony Olszanski, Wallace Akerley, Carlos L. Arteaga, William E. Carson III, Jeffrey W. Clark, John F. DiPersio, David S. Ettinger, Robert J. Morgan Jr, Lee S. Schwartzberg, Alan P. Venook, Christopher D. Gocke, Jonathan Tait, and F. Marc Stewart

Background: With advances such as next-generation sequencing (NGS) increasing understanding of the basis of cancer and its response to treatment, NCCN believes it is important to understand how molecular profiling/diagnostic testing is being performed and used at NCCN Member Institutions and their community affiliates. Methods: The NCCN Oncology Research Program's Investigator Steering Committee and the NCCN Best Practices Committee gathered baseline information on the use of cancer-related molecular testing at NCCN Member Institutions and community members of the NCCN Affiliate Research Consortium through 2 separate surveys distributed in December 2013 and September 2014, respectively. Results: A total of 24 NCCN Member Institutions and 8 affiliate sites provided quantitative and qualitative data. In the context of these surveys, “molecular profiling/diagnostics” was defined as a panel of at least 10 genes examined as a diagnostic DNA test in a Clinical Laboratory Improvement Amendments (CLIA)–certified laboratory. Conclusions: Results indicated that molecular profiling/diagnostics are used at 100% of survey respondents' institutions to make patient care decisions. However, challenges relating to reimbursement, lack of data regarding actionable targets and targeted therapies, and access to drugs on or off clinical trials were cited as barriers to integration of molecular profiling into patient care. Frameworks for using molecular diagnostic results based on levels of evidence, alongside continued research into the predictive value of biomarkers and targeted therapies, are recommended to advance understanding of the role of genomic biomarkers. Greater evidence and consensus regarding the clinical and cost-effectiveness of molecular profiling may lead to broader insurance coverage and increased integration into patient care.

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Melanoma, Version 2.2013

Featured Updates to the NCCN Guidelines

Daniel G. Coit, Robert Andtbacka, Christopher J. Anker, Christopher K. Bichakjian, William E. Carson III, Adil Daud, Dominick DiMaio, Martin D. Fleming, Valerie Guild, Allan C. Halpern, F. Stephen Hodi Jr., Mark C. Kelley, Nikhil I. Khushalani, Ragini R. Kudchadkar, Julie R. Lange, Anne Lind, Mary C. Martini, Anthony J. Olszanski, Scott K. Pruitt, Merrick I. Ross, Susan M. Swetter, Kenneth K. Tanabe, John A. Thompson, Vijay Trisal, Marshall M. Urist, Nicole McMillian, and Maria Ho

The NCCN Guidelines for Melanoma provide multidisciplinary recommendations on the clinical management of patients with melanoma. This NCCN Guidelines Insights report highlights notable recent updates. Foremost of these is the exciting addition of the novel agents ipilimumab and vemurafenib for treatment of advanced melanoma. The NCCN panel also included imatinib as a treatment for KIT-mutated tumors and pegylated interferon alfa-2b as an option for adjuvant therapy. Also important are revisions to the initial stratification of early-stage lesions based on the risk of sentinel lymph node metastases, and revised recommendations on the use of sentinel lymph node biopsy for low-risk groups. Finally, the NCCN panel reached clinical consensus on clarifying the role of imaging in the workup of patients with melanoma.

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Daniel G. Coit, Robert Andtbacka, Christopher J. Anker, Christopher K. Bichakjian, William E. Carson III, Adil Daud, Raza A. Dilawari, Dominick DiMaio, Valerie Guild, Allan C. Halpern, F. Stephen Hodi Jr., Mark C. Kelley, Nikhil I. Khushalani, Ragini R. Kudchadkar, Julie R. Lange, Anne Lind, Mary C. Martini, Anthony J. Olszanski, Scott K. Pruitt, Merrick I. Ross, Susan M. Swetter, Kenneth K. Tanabe, John A. Thompson, Vijay Trisal, and Marshall M. Urist