Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8/27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease-free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pre-treatment immune signature (Neoadjuvant Response Signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.

Background: We have shown that the pharmacodynamic immune response to anti-PD1 therapy peaks at 3 weeks in the peripheral blood and correlates with tumor burden (Nature 2017). These observations suggest that the presence of antigen is important in the generation of an immune response to checkpoint blockade. We hypothesized that neoadjuvant administration of anti-PD1 therapy followed by complete resection at 3 weeks and adjuvant therapy would be a safe and clinically effective approach for patients with high risk resectable melanoma. Methods: We enrolled patients with resectable Stage IIIB/C or Stage IV melanoma, who received one 200mg dose of pembrolizumab followed by curative intent resection 3 weeks after Cycle 1 Day 1. Pathologic assessment was performed at the three-week resection timepoint. Patients continued to receive one year of adjuvant pembrolizumab. Results: 30 patients have been consented since study activation in 2015. 27 patients were eligible to be enrolled and have received treatment before a data cutoff of 12/21/17. 56% of patients were stage IIIC/IV; the remainder were IIIB. 59% were male. Grade 3 adverse events occurred in six patients, with no grade 4 events and no delays in surgical management. No patients were unresectable at the time of surgery. Among 20 patients with at least one year of follow-up or a recurrence event, the 1 year recurrence-free survival (RFS) was 55%. Of the 9 patients who had recurrences, 5 are now disease free after additional therapy or resection and 2 patients remain alive with disease. 2 patients have died. After one dose of pembrolizumab, 8 of 27 (30%) of patients had a complete or-near complete (<10% viable tumor) pathologic response, all of whom are currently recurrence-free. Patients with residual viable tumor of less than 50% at time of resection had a 1 year RFS of 88%, compared to 33% for those with greater than 50% residual viable tumor. Patients with brisk TILs had a 1 year RFS of 89% compared to 27% with non-brisk TILs. Clinical responses after one dose of therapy could also be observed by FDG PET/CT imaging by 3 weeks and correlated with the degree of pathologic response. In addition, a significant increase in CD8 T cells and PD-L1 expression was observed in paired pre and on treatment tissue specimens consistent with an adaptive immune response. Conclusion: Neoadjuvant anti-PD1 therapy is safe and active in patients with resectable high risk stage III and IV melanoma. Four of five patients with stage IIIB (80%) and seven of 14 with IIIC (50%) melanoma who received neoadjuvant and adjuvant pembrolizumab were recurrence free at 1 year suggesting promising clinical activity and further research is warranted. Consistent with our published data in the peripheral blood, the clinical activity of anti-PD-1 therapy occurs early in the tumor and can be detected by gross, histologic, radiographic, and immune changes after only 1 dose of therapy. Citation Format: Alexander C. Huang, Xiowei Xu, Robert J. Orlowski, Sangeeth M. George, Lakshmi Chilukuri, Andrew Kozlov, Mary Carberry, Lydia Giles, Suzanne McGettigan, Kristin Kreider, Jennifer H. Yearley, Lakshmanan Annamalai, Gerald Linette, Ravi K. Amaravadi, Lynn M. Schuchter, Michael Farwell, John Wherry, Giorgos Karakousis, Tara Gangadhar. Safety, activity, and biomarkers for neoadjuvant anti-PD-1 therapy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT181.

logic practice. 3 However, while historically syphilology was a major focus of dermatology, it is unclear who primarily diagnoses syphilis in the modern era.Methods | We performed a retrospective review of cases of syphilis reported to the Rhode Island Department of Health between 2010 and 2014. This study was deemed exempt by the Rhode Island Department of Health institutional board review. We collected the following data: sex, age, race, sexual orientation, human immunodeficiency virus (HIV) status, chief complaint or reason for testing, clinician type, and stage of syphilis. An internet search for the physician's name was used to identify the specialty. Cases of reinfection were excluded.Results | There were 364 cases of syphilis that met study criteria. Most patients were white (229 [62.9%]), and the average age was 35.8 years. Most patients were male (335 [92.0%]), particularly men who have sex with men (MSM) (272 [74.7%]). Most patients were HIV-negative (210 [57.7%]), although 107 patients were positive (29.3%) and 47 statuses were unknown (12.9%). Of the 283 MSM, 102 were HIV-positive (36.0%).The most frequently seen clinician was in the primary care or community health care setting (129 [35.4%]), followed by infectious disease specialists (93 [25.5%]), urgent or emergency care (66 [18.1%]), and clinics for sexually transmitted infections (STI) (41 [11.3%]). Nine patients (2.5%) were diagnosed by dermatologists: 7 with an erythematous eruption and 2 others with a genital lesion. The 2 most common reasons for testing were erythematous eruption and routine screening.or offering screening to asymptomatic individuals who are at risk, dermatologists can substantially contribute to the control and elimination of syphilis.

10054 Background: Checkpoint blockade improves survival in patients with melanoma, with durable complete responses (CR) after stopping therapy. Based on data from KEYNOTE-001, immunotherapy is often continued for 24 months in patients with confirmed CR. Outcomes with treatment of less than 24 months hav not been adequately evaluated and reported. If equally efficacious, shorter courses would potentially reduce health care costs and toxicity. Methods: 45 patients with locally advanced stage III and IV melanoma who received immunotherapy (pembrolizumab, nivolumab or ipilimumab/nivolumab) as 1st line or subsequent therapy, achieved a CR, and stopped therapy were identified under an IRB approved protocol at Penn. Disease Free Survival (DFS) was defined as time from declaration of CR until recurrence or date of analysis (1/15/20). Landmark DFS from time of CR was analyzed based on duration of therapy (less than or greater than 7 months, based on early trial requirements to treat patients with confirmed CR for at least 6 months). Rationale for stopping (toxicity or CR) was also analyzed. Results: Of 45 patients with CR, 27 (60%) were treated less then 7 months (median 4.8, range 1 day to 6.7 months) and 18 (40%) were treated for greater than 7 months (median 12.4, range 7.5 to 24.2 months). Patients who were treated for less than 7 months had a median DFS from time of CR of 30.4 months (95% CI 23.7 to 37.2, range 2.9 to 65.7 months). Patients treated for greater than 7 months had a median DFS of 28.0 months (95% CI 18.9 to 37, range 8.5 to 73.7 months). Patients who stopped due to toxicity (N = 17, 40%) had a median treatment duration of 3.7 months. Their median DFS from time of CR was 30.4 months (95% CI 20.7 to 40.1, range of 2.9 to 65.7 months). Patients who stopped due to CR (N = 28, 60%) had a median treatment duration of 8.5 months. Their median DFS was 27.6 months (95% CI 21.2 to 34 range 7.2 to 73.7 months). Two of 27 (7.4%) patients treated for less then 7 months and 3 out of 18 (16%) patients treated greater than 7 months recurred after stopping. One out of 17 (5.8%) recurred after stopping for toxicity vs. 4/28 (14.3%) who stopped after CR. Conclusions: Patients who stop therapy at less than 7 months have CRs that are equally durable as those treated longer than 7 months, without reduction in landmark DFS. Patients who stopped therapy due to toxicity and then achieved a CR had no difference in DFS compared to patients treated until CR. There was no significant difference in recurrence after achieving a complete response in patients treated for a longer vs shorter treatment course.

e21503 Background: Immune checkpoint inhibitor (ICI) therapy for advanced melanoma in the first-line setting often results in durable responses and prolonged overall survival (OS) after achieving a complete response (CR). While generally well-tolerated, there are financial toxicities and treatment related adverse events (TRAEs) associated with ICI use. There are limited data to inform the optimal duration of therapy after CR, and how specific patient factors may lead to variable OS in patients (pts) with CR. Methods: Pts with locally advanced stage III or stage IV melanoma who started first-line ICI therapy with pembrolizumab, nivolumab, or ipilimumab/nivolumab (ipi/nivo) and achieved CR were identified at a single institution under an Institutional Review Board approved protocol. Pts were only included in the sample if they had initiated treatment by 2013 and discontinued therapy by February of 2021 and had documented follow-up at least 1 year after discontinuing ICI therapy. Recurrence rates were determined by the presence of any recurrence after CR. Pts were analyzed by baseline stage (III vs IV), BRAF status, use of steroids for TRAEs, time from treatment start to CR, and total duration of therapy. OS was determined by time from treatment start to death or date of last follow-up. Results: 78 Pts with CRs from ICI therapy who discontinued treatment were identified at the University of Pennsylvania. Median follow-up time was 63 months from ICI treatment start. Median age at treatment start was 65 years (range 33-94). 51 Pts (68%) had an ECOG performance status (PS) of 0 vs 24 (32%) with ECOG PS of 1-2. 21 Pts (27%) had locally advanced stage III and 57 (73%) had stage IV disease. Of stage IV pts, 8 were M1a, 16 M1b, 22 M1c, and 11 M1d. 61 (78%) pts were treated with pembrolizumab, 5 (6%) nivolumab, 12 (15%) ipi/nivo. 34 pts (44%) were treated with steroids for TRAEs. Of the 78 total pts, 13 (16.7%) developed a recurrence after stopping treatment. The median time to recurrence was 57 months (range 9-110). Melanoma specific survival was 96%. Of the pts with recurrence, 3 died of melanoma, 9 are disease free after additional local and/or systemic treatment and one patient is alive with disease. There was no significant difference ( p < 0.05) in OS based on baseline stage, BRAF status, or use of steroids for TRAEs. Pts were treated for a median of 6 months (range 1 day to 24 months). Conclusions: With over 5 years median follow-up time, the majority of pts with advanced melanoma who attain a CR from first-line ICI therapy remain disease free after treatment discontinuation. Patient factors including stage at treatment initiation, BRAF status, and steroid usage during treatment were not associated with significant variation in OS in this cohort. Most pts with recurrences remain disease free after additional local and/or systemic treatment. Few melanoma specific deaths occurred in pts with a CR to ICI who discontinued treatment.