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The purpose of this study was to explore the associations between age and frailty with immune-related adverse events (irAEs) among patients with cutaneous malignancies receiving immune checkpoint inhibitor (ICI) therapy.A retrospective review of all patients receiving ipilimumab, nivolumab, or pembrolizumab for treatment of cutaneous malignancies at the Wilmot Cancer Institute between 1 Jan 2011 and 3 Apr 2017.A total of 120 patients (age70 N = 68, age ≥70 N = 52; range, 26-93) were identified. 44.1%[95%CI:32-57%] of patients age70 and 31.4%[95%CI:19-46%] of patients age ≥70 experienced ≥1 irAE on 1st line ICI therapy (P = 0.158). A total of 3 adults died of irAEs (2 age ≥70; 1 age70). Patients ≥70 were more frequently treated with anti-PD-1 monotherapy than dual checkpoint blockade or ipilimumab (P 0.01) in the first line setting. Among patients on first line anti-PD-1 monotherapy for cutaneous melanoma, 21 were age70 and 20 were age ≥70, with similar observed rates of irAEs (52.4%[95%CI 29.8-74.3] and 63.2%[95%CI 38.4-83.7]). Indirect frailty markers in patients age ≥70 such as having fallen in the prior six months, ECOG PS ≥2 or Charlson comorbidity scores ≥11 experienced similar rates of response and toxicity. Among 9 patients with a PS = 3, 8 died, 6 due to progressive disease. No deaths due to irAEs occurred in this frail subgroup.Anti-PD-1 monotherapy for older adults with cutaneous malignancies have similar response and irAE rates when compared to those of younger patients. Deaths from disease progression were more frequent than those from toxicity in both age subgroups.

Background: Patients with advanced melanoma primarily refractory to single agent PD-1 blockade therapy have an option of receiving the CTLA-4 blocking antibody ipilimumab, but if ipilimumab should be given as a single agent or in combination with the anti-PD-1 nivolumab has not been established prospectively. Methods: Patients aged >18 with metastatic or unresectable melanoma without objective response to anti-PD-1 therapy given without CTLA-4 therapy were randomized 3:1 to receive either ipilimumab 3mg/kg + nivolumab 1mg/kg q3 wks x4 cycles followed by nivolumab 480mg q4wks (ipi/nivo) up to 2 years, or ipilimumab 3mg/kg q3weeks x4 cycles (ipi). Additional key eligibility criteria included ECOG Performance Statue (PS) 0-2, no active central nervous system metastases, autoimmune disease, or need for steroids at doses of >10 mg of prednisone or the equivalent. The primary endpoint was progression free survival (PFS). Disease assessments were performed every 12 weeks until progression. Secondary endpoints included overall survival (OS), objective response rate (ORR), and toxicity. All patients were to submit a fresh tumor biopsy and whole blood for correlative endpoints prior to cycle 1 and again at week 5. Results: 92 eligible patients were enrolled, 69 to ipi/nivo, 23 to ipi. Median age was 64 and 69 in the ipi/nivo and ipi arm respectively. 67% and 65% were male. 65% of patients in both arms had ECOG PS of 0. With a median follow up of 25.3 months, the hazard ratio (HR) for PFS was 0.63 (90% CI 0.41, 0.97) with a statistically significant 1-sided p-value of 0.04 favoring ipi/nivo. The 6-month PFS estimates were 34% (90% CI: 25%-44%) and 13% (4%-27%) for ipi/nivo and ipi respectively. ORR was 28% for ipi/nivo (95% CI 17%-40%) and 9% for ipi (95% CI: 3%-34%). With a median follow up of 24.4 months, 39/69 patients in the ipi/nivo arm and 12/23 patients in the ipi arm had died. 12-month OS was 63% (90% CI 52%-72%) in the ipi/nivo arm and 57% (38%-71%) months in the ipi arm. HR for OS was 0.94 (90% CI 0.54, 1.62) in favor of ipi/nivo with a p-value of 0.42. Adverse event rates were similar in both arms. One treatment related death was reported in the ipi/nivo arm due to disseminated intravascular coagulation and one treatment related death was reported in the ipi arm due to colonic perforation. Conclusions: This is the first prospective randomized study comparing ipi/nivo to ipi alone in patients with melanoma without response to anti-PD1 therapy. Ipi/nivo was associated with improved progression free survival as compared to ipi alone. The response rate of 28% to ipi/nivo as compared to 9% to ipi alone implies that patients who do not respond to PD-1 alone can be rescued with ipi/nivo. The toxicity of combination therapy was manageable. Ipi/nivo is an appropriate standard in patients with metastatic melanoma who do not respond to single-agent PD-1 therapy. ClinicalTrials.gov Identifier: NCT03033576 Funding: NIH/NCI grants: U10CA180888, U10CA180819, U10CA180821, U10CA180868; Other grants: SU2C-AACR-CT06-17 Citation Format: Ari M. Vanderwalde, James Moon, Kari Kendra, Nikhil I. Khushalani, Frances Collichio, Jeffrey A. Sosman, Alexandra Ikeguchi, Adrienne I. Victor, Thach-Giao Truong, Bartosz Chmielowski, David C. Portnoy, Michael C. Wu, Kenneth F. Grossmann, Antoni Ribas. S1616: Ipilimumab plus nivolumab versus ipilimumab alone in patients with metastatic or unresectable melanoma that did not respond to anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT013.

Rivaroxaban (Xarelto; Johnson & Johnson Services, Inc) is a direct oral anticoagulant (DOAC) that works by directly inhibiting the active site of factor Xa (FXa). Rivaroxaban is metabolized and cleared via the kidney and liver. The results of various studies have shown that patients with severe renal impairment should receive reduced dosages of rivaroxaban or another anticoagulant due to impaired clearance. Although it is not required, monitoring rivaroxaban is useful in some conditions; however, the assays required for such monitoring are not readily available. Herein, we present a case of a 68-year-old Caucasian male patient who was receiving rivaroxaban (20 mg/day) for atrial flutter and had mild renal impairment. The patient was found to have increased effect of rivaroxaban due to further impairment of renal clearance caused by several renally cleared medications. This case highlights the importance of closely examining the renal function of and medication list for a patient before starting DOACs such as rivaroxaban.

11538 Background: Sarcoma subtypes are often defined by recurrent molecular alterations. The purpose of this study is to review the utility of next generation sequencing (NGS) in sarcoma patients and report clinical outcomes to matched therapies. Methods: The records of all patients seen at the University of Rochester Medical Center (URMC) with sarcoma and NGS profiling between 8/2013 and 3/2020 were reviewed. Responses to agents targeting reported alterations were analyzed. In patients with fluorescent-in-situ hybridization (FISH) testing, fusion events by NGS were compared with FISH results. All highlighted pathogenic alterations on the NGS profile report as well as variants of uncertain significance (VUS) were recorded. Results: Seventy-five patients met inclusion criteria. Of these, 25 received a treatment based on identified alterations; 1 had a complete response (CR), 4 had partial responses (PR), and 4 experienced disease stabilization (SD). We identified two patients with MET amplified sarcoma that responded to treatment with crizotinib. One other patient with a diagnosis of leiomyosarcoma was found to have an unusually high total mutational burden (TMB) and experienced complete pathologic response to dual checkpoint blockade. In 4 cases, testing resulted in a change in subtype diagnosis. Several rare and novel fusions were identified; a sarcoma with TPM4-NTRK3 fusion responded to larotrectinib, while a sarcoma with PML-JAK1 fusion did not respond to ruxolitinib, and a sarcoma with IL7R-BCL2 fusion progressed on venetoclax. Table summarizes matched therapies in responders. Conclusions: NGS profiling led to a targeted therapy with a clinical benefit rate of 12% in this cohort. NGS profiling led to a change in diagnosis in 5% of this cohort. Multi-institutional collaborations to track outcomes of matched therapy would help determine the utility of therapies in rare cancers and unusual alterations.[Table: see text]

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy with a steadily increasing incidence. Advancing age, fair skin, ultraviolet light exposure, and immunocompromise are risk factors. Sixty to eighty percent are associated with the Merkel cell polyomavirus, and the remainder carry a high mutational burden. Recently immunotherapy has been shown to be a highly effective and well tolerated treatment. The disease is also very chemosensitive similar to small-cell lung cancer. Ongoing trials are evaluating the role of adjuvant immunotherapy and novel immunotherapy agents as well as targeted therapy and endocrine therapy with somatostatin analogues. Also included in this review is our institution's experience with MCC in 6 patients treated with pembrolizumab, 5 of whom experienced an excellent response.

Melanoma is significantly more common and is associated with a poorer prognosis in patients with an underlying B-cell malignancy. This study reports on the management of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) and a subsequent diagnosis of melanoma. In the Wilmot Cancer Institute CLL cohort, which includes 470 patients followed for 2849 person-years, 18 patients (3.8%) developed 22 melanomas. Fourteen melanomas were invasive, a significantly higher rate as compared with the age and sex matched general population (standardized incidence ratio [SIR] 6.32 (95% CI 3.45; 10.60). Melanomas were most often detected (n = 15; 68.2%) through active surveillance in a dermatology clinic. Most melanomas (n = 17; 77.3%) were detected at a non-advanced stage (pathological stage grouping III). The most common management was wide local excision without sentinel lymph node biopsy (n = 13, 59.1%). Management for the 4 (18.2%) patients with metastatic disease included the immune checkpoint inhibitor (ICI) pembrolizumab (n = 1), systemic chemotherapy with dacarbazine (n = 1), and palliative care (n = 2). The patient treated with ICI is in sustained remission of her melanoma after 23 cycles of therapy while her TP53 disrupted CLL continues to respond to ibrutinib therapy. We conclude that patients with CLL may benefit from active surveillance for melanoma leading to early excision of locally-manageable disease. In patients with metastatic melanoma, combined treatment with targeted kinase inhibitors and ICIs can be successful and tolerable. Larger prospective studies should be considered to further evaluate these approaches.