Faculty Bibliography

IMPORTANCE/OBJECTIVE:Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known. OBJECTIVE:To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015. EXPOSURE/METHODS:Ipilimumab therapy. MAIN OUTCOMES AND MEASURES/METHODS:Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively. RESULTS:Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:To our knowledge, this is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring.

Immunotherapy has revolutionized cancer therapy and has been named the cancer advance of the year for 2016. Checkpoint inhibitors have demonstrated unprecedented rates of durable responses in some of the most difficult-to-treat cancers; however, many treated patients do not respond, and the potential for serious side effects exists. There is a growing need to identify biomarkers that will improve the selection of patients who will best respond to therapy, further elucidate drug mechanisms of action, and help tailor therapy regimens. Biomarkers are being explored at the soluble, cellular, and genomic levels, and examples in immunotherapy include serum proteins, tumor-specific receptor expression patterns, factors in the tumor microenvironment, circulating immune and tumor cells, and host genomic factors. The search for reliable biomarkers is limited by our incomplete understanding of how immunotherapies modify the already complex immune response to cancer, as well as the contribution of immuno-editing to a dynamic and inducible tumor microenvironment and immune milieu. Furthermore, there has been little extension of any candidate assay into large, prospective studies, and the lack of standardization in measurement and interpretation restricts their validity. Both tumor-infiltrating lymphocytes and PD-L1 expression within the tumor microenvironment have been recognized as having both prognostic and predictive value for patients treated with immunotherapy. Alternately, a larger panel of gene signatures, chemokines, and other factors that correlate with response has been proposed. In this article, we will explore the status of current biomarker candidates.

Mucosal melanoma is an exceedingly rare variant of cutaneous melanoma that, due to its rarity, is poorly described and infrequently studied. Primary sites of origin include the head and neck, anorectum and vulvovaginal regions. It is uniquely different from cutaneous melanoma with respect to epidemiology, etiology, pathogenesis and prognosis. The etiology and pathogenesis remain unclear. Unlike cutaneous melanoma, exposure to UV light is not an apparent risk factor. Furthermore, distinct molecular features including a lower incidence of BRAF oncogene mutations but a higher incidence of KIT oncogene mutations suggest divergent genetic etiologies. Mucosal melanomas generally present at a later stage, are more aggressive and carry a worse prognosis regardless of the stage at diagnosis. Establishing standardized treatment guidelines has been challenging due to the rarity of the disease. Early detection provides the best chance at survival but is often difficult due to anatomic location. Surgery remains the primary therapeutic intervention if complete resection is technically feasible given the anatomic location. Radiotherapy may be used to achieve local control when resection is not feasible, or adjuvantly to enhance locoregional control, but most studies have failed to demonstrate an improvement in overall survival. There are no consensus guidelines on the optimal systemic therapy, and regimens are often extrapolated from data based on therapies used to treat advanced cutaneous melanoma. Clinical trials, particularly utilizing newer targeted therapies and immunotherapies, are investigating novel treatment approaches.

Ipilimumab is a fully human, monoclonal antibody directed against Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) that has demonstrated a survival benefit and durable disease control in patients with advanced melanoma. Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis. Because clinical trials of ipilimumab excluded patients with pre-existing hepatitis B or C infection, there is a paucity of data on the safety of ipilimumab administration to that patient population. Here, we report the largest case series to date of patients with hepatitis B or C who received ipilimumab for advanced melanoma. Two of the nine patients described in this case series experienced fluctuations in their liver function tests (LFTs) and were subsequently treated with corticosteroids. Although this is a small series, the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab, and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection. The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options.

Lymphangiomatosis, a rare disorder of the lymphatic system characterized by the abnormal proliferation of lymphatic vessels, is a typically benign disorder that at times can exhibit invasive or malignant behavior. While generally considered a diagnosis of childhood, in adults the majority of cases are asymptomatic and found incidentally. Rarely, lymphatic overgrowth can occur, causing growth of lesions on imaging mimicking a metastatic process and occasionally, resulting in substantial morbidity and mortality. Here, we present such a case of lymphangiomatosis with multi-organ system involvement in liver, bone, and spleen. In addition to details of the clinical presentation and the pathologic review which led to the diagnosis, we describe our use of the tyrosine kinase inhibitor pazopanib, which may cause stabilization of lymphangiomatosis through blockade of vascular endothelial growth factor (VEGF) signaling, for systemic treatment in this unusual case.

TPS4651Background: E/GEJ adenocarcinoma has a high mortality rate despite curative intent treatment. A pathologic complete response (pCR) is associated with better overall survival (OS) but occurs in less than 30% of pts. Immunotherapy is effective in the metastatic setting. Here we aim to evaluate the contribution of immunotherapy in the neoadjuvant and adjuvant settings in pts with locoregional E/GEJ cancer. Methods: This is a multi-center, randomized phase II/III trial. Surgical candidates with locoregional E/GEJ adenocarcinoma receive carboplatin AUC 2 IV and paclitaxel 50 mg/m2 IV, both weekly x 5 during concurrent radiation (50.4 Gy) either with or without nivolumab 240 mg IV during weeks 1 and 3, followed by surgery. Pts with no post-operative disease receive nivolumab 240 mg IV every 2 weeks for 12 cycles either with or without ipilimumab 1 mg/kg IV every 6 weeks for 4 cycles. Eligibility criteria include pts with T1-N1-3M0 or T2-3N0-2M0 disease whom are candidates for surgery, no prior chemotherapy or radiation for this disease, no prior immunotherapy, no significant autoimmune disease. Pts must be disease free for adjuvant treatment. Primary neoadjuvant endpoint is pCR rate; primary adjuvant endpoint is disease free survival (DFS). Secondary endpoints include toxicity, DFS and OS. Pre- and mid-treatment diffusion weighted imaging MRI will be conducted during the neoadjuvant portion of the study. A neoadjuvant safety run in of 30 pts is underway. Overall, 278 pts will be needed to detect an absolute improvement of 15% in pCR rate in pts receiving and not receiving neoadjuvant nivolumab and 236 pts will be needed to detect a HR of 0.65 in favor of adjuvant ipilimumab/nivolumab over nivolumab (90% power, one sided alpha of 0.10). Accrual is expected over 34 months at a rate of 8 patients per month. If favorable at interim analysis. Clinical trial information: NCT03604991.

TPS9092 Background: The incidence of SCCS has increased over the past two decades, including a high risk subset with aggressive behavior. Due to a lack of high-quality clinical trials in this population, there is no standard systemic therapy for advanced SCCS. The epidermal growth factor receptor (EGFR), often highly expressed in SCCS, is implicated in UV-induced skin carcinogenesis and SCCS development. Cetuximab, a monoclonal antibody that competitively inhibits EGFR, improved disease control as first line therapy in unresectable SCCS in a single arm phase II trial. Despite impressive responses with cetuximab in some, most treated SCCS patients do not respond, and there is a need for predictive biomarkers. We hypothesize that the use of cetuximab will improve clinical outcomes in patients with advanced SCCS in the neoadjuvant setting, and that measures of antibody dependent cytotoxicity (ADCC) in tumor and/or specific genomic features of the tumor may predict response to therapy. Methods: In this pilot trial (NCT 02324608), we will enroll 20 patients with relapsed locally advanced SCCS or SCCS unamenable to definitive local therapy. The primary endpoint will measure response rate to cetuximab by RECIST criteria with secondary endpoints of progression free and overall survival, and conversion to resectability. Molecular tumor correlates include analyzing DNA mutations and measuring downstream activation of EGFR signaling and ADCC, correlating these with clinical benefit. Patients will receive cetuximab at 400mg/m2 ? 1 followed by weekly doses of 250mg/m2 for 8 weeks prior to surgery. Patients will be evaluated for subsequent definitive surgical resection, or definitive radiotherapy if surgical resection is not possible. Postoperative adjuvant radiotherapy will be permitted. Patients will undergo pretreatment biopsies, and post-treatment tissue will be harvested at surgery or through a biopsy at the conclusion of cetuximab. Paired skin and tumor samples will be evaluated through partial DNA (FoundationOne??) and RNA sequencing, IHC analysis of EGFR signaling components, and measurement of ADCC. The trial is currently screening eligible subjects. Clinical trial information: 02324608.