e23269 Background: Most cases of malignant melanoma are cutaneous, with ≈50% having a BRAF driver mutation that predicts response to MAPK pathway inhibitors. A small minority of melanoma cases harbor an activating KIT mutation, most notably in mucosal and acral melanomas (15-20%) and occasionally in those arising from chronic sun-damaged skin (2-3%). Only about a third of KIT mutated melanomas respond to targeted therapy with Imatinib, yet data is scarce and limited, especially in older patients. We sought to characterize the efficacy and toxicity of Imatinib in KIT-mutated melanoma patients over 65. Methods: We identified electronic medical records of patients over 65 that were treated with Imatinib for KIT mutated melanoma at our institution over the years 2017-2023. Data was retrospectively collected including demographics, disease characteristics, response patterns and toxicity. Results: 10 patients were identified, 50% were males. The median age at treatment initiation was 75 years (71-100). 3 patients had cutaneous primary, 3 had Vulvar/vaginal primary, 3 had acral primary and 1 had anal canal primary. All patients had normal Lactate dehydrogenase at treatment initiation and ECOG performance status was 0-2 (median 0). 9 patients received Imatinib for stage IV disease with an overall response rate (ORR) of 55% (44% partial response, 11% complete response). Median duration of response was 4 months. Responses were seen in acral melanoma (67%), vulvar/vaginal melanoma (67%) and cutaneous melanoma (33%). Median Progression free survival was 4.3 months (1.8-44), median overall survival from treatment initiation was 22.6 months (4-64). 6 patients were treated as 2nd line with an ORR of 67% and 3 were treated as 3rd line with an ORR of 33%. There was one patient with M1d disease who did not respond to treatment either systematically or intracranially. 6 patients had Exon 11 mutations (V560D/G/E, N564S and L576P) of which 4 responded (67%). 2 had Exon 17 mutations (N822C/K) of which 1 responded (50%) and the 2 others had an Exon 14 (F681I) and Exon 13 (K642E) mutation that did not respond to treatment at all. Toxicity was moderate with 90% of patients experiencing any grade AE, yet only 1 experienced toxicity requiring dose interruption with two Grade 3 toxicities - Pneumonitis and decreased neutrophil count, leading to temporary treatment interruption, dose reduction and a course of corticosteroids. The rest of the patients experienced only Grade 1-2 toxicity. 4 patients needed dose reductions, there were no treatment discontinuations due to toxicity. Conclusions: Treatment with Imatinib for elderly KIT mutated melanoma patients is safe and well tolerated with no treatment discontinuations recorded. The response rate is encouraging yet seems to vary according to the KIT mutation present as previously reported. The duration of response is usually short-lived and alternative/combination treatments are still needed for this patient population.

Melanoma is the deadliest form of skin cancer. The median age at diagnosis is 66. While most patients are treated with immunotherapy, the use of targeted therapy is a valid alternative for patients whose tumors harbor a BRAF or c-KIT driver mutation. These agents, while effective, come with a variety of side effects which limit their use, especially in older patients. We sought to assess the efficacy and toxicity of these agents in older melanoma patients. Melanoma patients over 65 treated with BRAF/MEK or c-KIT inhibitors were retrospectively identified, and their data were analyzed for treatment efficacy and toxicity. All data were compared using the Chi-square test for categorical comparisons and the Kruskal-Wallis method for median comparisons. One hundred and sixteen patients were identified. One hundred and six patients were treated with BRAF/MEK inhibitors. The assessed response rate (RR) was 83% and was comparable across different subgroups, including advanced line patients and those with a more aggressive disease. The median progression free survival (PFS) was 7.9 months, and the median overall survival (OS) was 15.7 months. Twenty-seven percent experienced grade 3-4 toxicity leading to a 24% treatment discontinuation rate. Another 10 patients were treated with the c-KIT inhibitor imatinib, for whom the assessed RR was 55%. The median PFS was 4.3 months, and the median OS was 22.6 months. Forty percent needed dose reductions, yet none had to stop treatment due to adverse effects. The use of targeted therapy in older patients is effective yet challenging due to toxicity. Deploying mitigation strategies can help maximizing their usefulness.

Background Ameloblastoma is a rare odontogenic neoplasm frequently located in the mandible. Standard treatment involves radical bone resection and immediate reconstruction, causing functional, aesthetic, and psychological impairments. The BRAF V600E mutation is present in approximately 80% of mandible ameloblastomas, and BRAF inhibitors have demonstrated sustained responses in unresectable cases. Methods We identified ameloblastoma patients planned for ablative surgery and screened them for BRAF V600E mutation. Neoadjuvant BRAF inhibitors were offered to facilitate jaw preservation surgery. Retrospective data collection encompassed treatment regimens, tolerability, tumor response, and conversion to mandible preservation surgery. Results Between 2017 and 2022, a total of 11 patients received dabrafenib (n = 6) or dabrafenib with trametinib (n = 5). The median age was 19 (range = 10-83) years. Median treatment duration was 10 (range = 3-20) months. All (100%) patients achieved a radiological response. Ten (91%) patients successfully converted to mandible preservation surgery with residual tumor enucleation. One patient attained complete radiological response, and surgery was not performed. Among the 10 surgically treated patients, all exhibited a pathological response, with 4 achieving near complete response and 6 partial response. At a median follow-up of 14 (range = 7-37) months after surgery, 1 case of recurrence was observed. Grade 1-2 adverse effects were reported in 8 (73%) patients, with a single case of grade 3 (hepatitis). Dose modification was necessary for 3 patients, and 4 experienced treatment interruptions, while 1 patient permanently discontinued therapy. Conclusions Neoadjuvant BRAF inhibition may offer a safe and effective strategy for organ preservation in mandible ameloblastoma treatment.

9566 Background: Several studies have demonstrated that patients who experience irAE as a result of ICI treatment, exhibit significantly improved outcomes compared to patients without toxicity. However, data regarding the impact of specific irAE is currently lacking. Methods: This is a real world single-site cohort of advanced melanoma patients who were treated with ICI as first line between 2014 and 2020. This study explores the effects of specific irAE on treatment efficacy. Results: Three hundred and ninety-five (395) patients were treated with either monotherapy anti PD-1 (65.4%), combination ICI (24.3%), or anti CTLA-4 (10.3%). Median age was 68 years (12-99y), and 57% were male. The median follow up was 24.5m. Any-grade irAEs were seen in 72% (n = 299), and 26% experienced high-grade irAE (n = 104). The most frequent irAE were dermatologic (n = 110, 27.8%), vitiligo (n = 48, 12.1%), rheumatologic (n = 68, 17.2%), gastro-intestinal (n = 66, 16.7%), and endocrine (n = 61, 15.4%). The development of irAE was associated with a significantly longer median PFS (19.3m vs 4.5m; HR 0.46, p < 0.001) and median OS (55m vs 16.9m; HR 0.44, p < 0.001). Specific irAE that were significantly associated with survival benefic were rheumatologic (HR 0.34 for PFS, p < 0.001; HR 0.38 for OS, p < 0.001), dermatologic (HR 0.58 for PFS, p < 0.001; HR 0.54 for OS, p = 0.001), vitiligo (HR 0.30 for PFS, p < 0.001; HR 0.29 for OS, p < 0.001) and endocrine (HR 0.6 for PFS, p = 0.01; HR 0.52 for OS, p < 0.001). After adjustment for ECOG performance status, LDH level, type of ICI protocol and M-substage - the rheumatologic, dermatologic and vitiligo irAE remained significant on multivariate analysis for both PFS and OS. Conclusions: The development of rheumatologic, vitiligo and other dermatologic irAE during ICI treatment, is correlated with a noteworthy survival advantage. These irAE may reflect a hyper-activated immune response and thus can serve as meaningful clinical biomarkers.

Introduction: Modern systemic therapy has revolutionized the treatment of melanoma. Currently, patients with clinically involved lymph nodes require lymphadenectomy with associated morbidities. Positron Emission Tomography - Computed Tomography (PET-CT) has demonstrated accuracy in melanoma detection and response to therapy. We aimed to identify whether a PET-CT directed lymphatic resection after systemic therapy is oncologically sound. Materials and methods: Retrospective review of patients who underwent lymphadenectomy after systemic therapy for melanoma with a preoperative PET-CT. Examined demographic, clinical, and perioperative parameters including extent of disease, systemic therapy and response, and PET-CT findings compared to pathological outcomes. We compared patients with "as or less than expected" outcomes on pathology against those with "more than expected" pathological outcomes. Results: Thirty-nine patients met inclusion criteria. In 28 (71.8%), pathological outcomes were "as or less than expected" by PET-CT, and in 11 (28.2%) pathological outcome were "more than expected". "More than expected" occurred more frequently with advanced disease at presentation with 75% presenting with regional/metastatic disease versus only 42.9% in the "as or less than expected" group (p 1/4 0.015). Poor response to therapy also trended towards the "more than expected" group with only 27.3% favorable response versus 53.6% favorable response in the "as or less than expected" group, not statistically significant. Extent of disease on imaging failed to predict pathological concordance. Conclusion: PET-CT underestimates pathological extent of disease in the lymphatic basin in 30% of patients after systemic therapy. We failed to identify predictors of more extensive disease and warn against limited PET-CT directed lymphatic resections. (c) 2023 Elsevier Ltd, BASO - The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Background: Successful treatment with Immune Checkpoint Inhibitors (ICI) requires the balanced activation of the immune system. Over-activation may result in immune-related adverse events (irAEs), which often require steroidal treatment. This study examined the possible impact of steroids on treatment efficacy in melanoma patients concerning initiation timing and dosage. Methods: A retrospective, single-center analysis of patients with advanced melanoma who underwent first-line ICI therapy during 2014–2020 was conducted. Results: Among the 415 patients, two-hundred patients (48.3%) were exposed to steroids during the first line, most of them due to irAEs (n = 169, 84.5%). Nearly a quarter of them were exposed to steroids within the first four weeks of treatment. Surprisingly, steroidal exposure was associated with better progression-free survival (PFS; HR = 0.74, p = 0.015); however, early exposure (within four weeks of treatment) resulted in a significantly shorter PFS compared to late exposure (adjusted HR 3.2, p < 0.001). Conclusions: Early exposure to corticosteroids during the priming phase of ICI therapy could impede the establishment of an effective immune response. These results suggest that caution should be exercised when considering the use of steroids for the management of early-onset irAEs.

IntroductionImmunotherapy has revolutionized the prognosis of patients with metastatic melanoma. To date, the most active regimen is the combination of ipilimumab + nivolumab (ipi-nivo) achieving a response rate of nearly 60% and a median survival (OS) of 6 years. However, approximately 40% of patients experience primary resistance, while around 50% experience secondary resistance, highlighting the need for an effective second-line treatment option The recently published results on the use of lenvatinib + pembrolizumab in the advanced line setting led to the adoption of this regimen at our institution. Here we present our experience with this regimen, focusing on efficacy and safety.MethodsElectronic medical records of patients treated at a tertiary referral melanoma center, with at least one cycle of anti PD-1 + lenvatinib from 2020 to 2023 were analyzed for baseline demographic characteristics, disease related characteristics and treatment outcomes.ResultsForty-two patients were identified. The Response rate (RR) was 28% and the disease control rate was 38%. Responses were seen across different melanoma subtypes, including 67% in acral melanoma, 20% in uveal melanoma, and 25% in mucosal melanoma. Patients with a more aggressive disease manifested by elevated lactate dehydrogenase (LDH) achieved a RR of 26%, while patients with active central nervous system (CNS) metastases had a RR of 31%, and an intra-cranial RR of 23%. Responses were seen across lines of treatment, with a 25% RR in the second and third lines, and a 36% RR in the fourth and fifth lines. The median progression free survival was 3 months, and the median survival was 11 months. The treatment was not easily tolerated with 31% of the patients experiencing grade 3-4 toxicity, which was manageable through dose interruptions and reductions. Only 7% of patients discontinued the treatment due to toxicity.ConclusionLenvatinib in combination with anti-PD1 had demonstrated both relative safety and efficacy in patients with metastatic melanoma of all subtypes in the advanced line setting. We are eagerly anticipating the mature results of the LEAP-004 study hoping that this regimen will receive regulatory approval, paving the way for its widespread adoption in daily practice worldwide.

Background and ObjectivesNeurologic immune-related adverse events (n-irAEs) reportedly occur in up to 8% of patients treated with immune checkpoint inhibitors (ICIs) of all age groups. We investigated the association between age and n-irAEs in patients treated with ICIs and examined the effect of n-irAEs on survival outcomes in a large cohort of patients with melanoma.MethodsWe conducted a retrospective analysis of patients with advanced melanoma treated with ICIs at Ella Institute for Immuno-oncology and Melanoma between January 1, 2015, and April 20, 2022. The outcomes of interest were defined as the investigation of age-related frequency and severity of n-irAEs, the need for ICI interruption, the treatment required for n-irAE management, the safety of ICI reintroduction, and n-irAE's effect on survival.ResultsICI was administered to 937 patients. At least one irAE occurred in 73.5% (n = 689) of them. Among the study population, 8% (n = 76) developed a n-irAE, with a median age of 66 years in female and 68 years in male patients at onset. The median follow-up after n-irAE was 1,147 days (IQR: 1,091.5 range: 3,938). Fewer irAEs occurred in patients older than 70 years (median: 3 events, p = 0.04, CI 2.5-4.7) while specifically colitis and pneumonitis were more common in the 18-60 age group (p = 0.03, 95% CI 0.8-0.38, p = 0.009, 95% CI 0.06-0.2). Grade >= 3 toxicity was seen in 35.5% of patients across age groups. The median time from ICI administration to n-irAE development was 48 days across age groups. Common n-irAE phenotypes were myositis (44.7%), encephalitis (10.5%), and neuropathy (10.5%). N-irAE required hospitalization in 40% of patients and steroids treatment in 46% with a median of 4 days from n-irAE diagnosis to steroids treatment initiation. Nine patients needed second-line immunosuppressive treatment. Rechallenge did not cause additional n-irAE in 71% of patients. Developing n-irAE (HR = 0.4, 95% CI 0.32-0.77) or any irAE (HR = 0.7195% CI 0.56-0.88) was associated with longer survival.DiscussionN-irAEs are a relatively common complication of ICIs (8% of our cohort). Older age was not associated with its development or severity, in contrast with non-n-irAEs which occurred less frequently in the elderly population. Rechallenge did not result in life-threatening AEs. Development of any irAEs was associated with longer survival; this association was stronger with n-irAEs.

Abstract For decades, cancer research and treatment focused on the cellular level, viewing cancer as a genetic disease of cell transformation. In the era of chemotherapy and radiotherapy, studies from the second half of the 19th century suggesting an association between the microbiota and cancer were almost neglected. The main focus of the field was limited to identification of specific viruses and bacteria that may serve as direct carcinogens leading to the recognition of 7 viruses (i.e., human papillomavirus, hepatitis B virus, and Kaposi sarcoma–associated herpesvirus) and 1 bacterium (Helicobacter pylori) as human carcinogens by the International Agency for Research on Cancer (https://monographs.iarc.who.int/agents-classified-by-the-iarc/). Shortly after the publication of the first draft of the human genome project in February 2001, the Nobel laureate microbiologist Joshua Lederberg raised the question: “Is human identity all in the genes?” It took more than a decade later and the development of multiomic techniques to confirm that his answer “each one of us is a small ecological community” was correct (Lederberg J. Keynote Address: Beyond the Genome. Brooklyn Law Rev 67). This ecological notion became relevant to cancer prevention, prediction, and treatment following the immunotherapy revolution and the understanding of the metabolic and immunologic roles of the microbiota in health and disease. Recently, the microbiota was recognized as an emerging hallmark of cancer following a large body of research showing its role in tumorigenesis, treatment efficacy and toxicity, and initial data regarding the role of microbial modulation in cancer therapy (Cancer Discov 2022;12(1):31–46). In the current review, we will focus on the role of fecal microbiota transplantation, the first microbial modulation technique that is used mainly in low-complexity conditions such as recurrent Clostridium difficile infections (Aliment Pharmacol Ther 2017;46(5):479–493), as a possible cancer therapeutic. However, to better understand the suggested roles of fecal microbiota transplantation in medical oncology, we first need to understand cancer as an ecological niche and the role of the microbiota in tumorigenesis and cancer treatment, specifically immunotherapy.

Background: Merkel cell carcinoma (MCC) is a rare and aggressive malignancy of the skin, affecting predominantly the fair-skinned older population exposed to high levels of ultraviolet light. Immune suppression is considered a significant risk factor. With the recent advances in the field of immunotherapy, the treatment paradigm for advanced MCC, traditionally based on chemotherapy, has largely shifted to anti-PD-L1 and PD-1 agents such as avelumab and pembrolizumab, respectively. However, real-world data remain sparse. The aim of this study was to assess real-world evidence of the effectiveness of avelumab in a diverse group of patients with MCC in Israel. Methods: The electronic databases of five university hospitals in Israel were searched for all consecutive patients with MCC treated with at least one dose of avelumab in 2018-2022. Data on baseline, disease-related, treatment-related, and outcome parameters were collected and analyzed. Results: The cohort included 62 patients of whom 22% were immune-suppressed. The overall response rate to avelumab was 59%. The median progression-free survival was 8.1 months, and the median overall survival, 23.5 months, with no differences between immune-competent and immune-suppressed patients. Treatment was well tolerated; any-grade toxicity developed in 34% of patients, and grade 3-4 toxicity, in 14%. Conclusions: Avelumab was found to be effective and safe for the treatment of advanced MCC in a diverse group of patients, including some with immune suppression. Further studies are warranted to evaluate the optimal sequence and duration of treatment and to assess the potential role of avelumab for earlier stages of MCC.

Purpose Molecular profiling is crucial in naïve non-small cell lung cancer (NSCLC). While tissue-based analysis is challenged by turnaround time and scarcity of tissue, there is increasing demand for liquid biopsy. We aimed to analyze the use of upfront liquid biopsy as a molecular profiling approach. Methods This retrospective multicenter, non-interventional study compared findings and turnaround times of liquid vs. standard-of-care (SOC) tissue-biopsy molecular profiling. The study included naïve advanced NSCLC patients with available liquid biopsy (Guardant360 CDx). Results A total of 42 consecutive patients (60% men; median age, 69.5 [39–87] years; 86% stage IV NSCLC) were identified between September 2017 and December 2020. Liquid-biopsy analysis provided results for all 42 patients, whereas the tissue-based analysis failed in 5 (12%) patients due to insufficient tumor samples. In 17 patients, 18 actionable driver mutations were identified. Eleven mutations were detected by both approaches (i.e., concordance of 61%), 4 only by liquid biopsy and 3 only by tissue biopsy. The median time from the molecular request to receiving the molecular solid report on the last biomarker was 21 (range: 5–66) days, whereas the median time from blood draw to the liquid-biopsy results was 10.5 (7–19) days. The median time between the availability of liquid-biopsy findings and that of the last biomarker was 5 days. Treatment changes following the liquid-biopsy results were observed in 3 (7%) patients. Conclusion Performing liquid-biopsy upfront is feasible and accurate and allows a shorter time for treatment in NSCLC, especially when tumor tissue is scarce.

9544 Background: The immune-system manipulation by immune-checkpoint inhibitors (ICI) has led to unprecedented clinical advances in melanoma. The management of the consequent immune-related adverse events (irAEs) is based mostly on steroids and other immune-modulators. Methods: A real world single-site cohort of metastatic melanoma patients who were treated with immunotherapy as first line between 2014 and 2020. This study explores the effect of dose, timing, and duration of steroid exposure on treatment efficacy. Results: Four hundred and forty patients were treated with either anti PD-1 (n = 285, 65%) or combination of anti PD-1 and ipilimumab ICI (n = 112, 25%), or ipilimumab alone (n = 43, 10%). The median age was 68 years [12-99y], and 57% were male. Any-grade irAEs were seen in 71% of the patients, and 49% were exposed to steroids. The median steroid dose was 0.75mg/kg prednisolone equivalent [0.03- 80mg/kg], the median duration of steroidal treatment was 11.2 weeks [0.1-316w] and the median time to onset of steroids was 7.6 weeks [0-193w]. Both experiencing irAEs, and the associated steroid exposure were associated with a significant progression free survival (PFS) benefit [HR 0.47, p < 0.001; 95%CI 0.39-0.6 and HR 0.77, p = 0.026; 95%CI 0.60-0.97, respectively], regardless of dose and duration. Notably, within those who were exposed to steroids, an earlier onset of < 4 weeks from immunotherapy initiation was significantly associated with a shorter PFS [HR = 3.5, p < 0.001 (95%CI 2.32-5.45)]. This observation resulted significant also on multivariable analysis including other prognostic variables – ECOG PS, M-stage, LDH and protocol. Conclusions: Steroidal treatment during the immunotherapy priming phase (first 4 weeks) might have a deleterious effect on its’ efficacy and should be explored in larger prospective cohorts.

IntroductionImmunotherapy has revolutionized metastatic Melanoma therapy. The most active regimen is combination therapy of Ipilimumab-Nivolumab (Ipi-Nivo) with response rates (RR) of ~60% and median overall survival (OS) of ~6 years. Immune-related adverse events (irAE) are common (~60% develop grade 3-4) and pose a challenge when treating frail patients. We sought to examine whether Ipi-Nivo therapy is feasible in elderly metastatic melanoma patients.MethodsElectronic records of patients treated at the Ella Lemelbaum Institute with Ipi-Nivo between the years 2017-2021 were screened for age. Elderly patients were defined as age 75 and older (group A) and were matched with records of patients age <75 (group B). Records were analyzed for baseline parameters, immunotherapy regimen, RR, toxicity and progression-free survival (PFS).ResultsTwenty-six relevant patients age >75 (median 77) were identified and were matched to 34 younger patients (median age 57). No statistically significant differences were noted in terms of baseline parameters except for BRAF mutation status (group A 15%, group B 47%, p=0.008). Response rate in group A was 38% and is consistent with previously published data. Median PFS was the same for both groups (A = 5.5 months, B= 7.5 months, p=NS). Treatment was similarly tolerated: 35% of group A patients completed 4 cycles of therapy compared to 28% for group B (p=NS). Grade 2-4 irAE were the same (A=58%, B=66%, p=NS) and there was no difference in the need for hospitalization for G3-4 events between the groups. (A=63%, B=69%, p=NS). Further division into 4 age groups (>80 vs 75-79 in group A and 65-74 vs <65 in group B) found no difference in terms of response rate or G3-4 toxicity.ConclusionIpilimumab-Nivolumab combination therapy in elderly metastatic Melanoma patients seems to be well tolerated and efficient in selected elderly patients based on performance status and comorbidities, just as in younger patients. This regimen seems to be a feasible treatment option for this age group.

Introduction: Uveal melanoma (UM) is a subtype of melanoma arising from the ocular region. Despite various local therapies available, a significant portion of patients develop distant metastases, primarily to the liver. While cutaneous melanoma is very sensitive to immunotherapy, UM is known to be less responsive and patients were excluded from pivotal clinical trials. To date, there is no standard first line therapy for metastatic UM and clinical trial participation is encouraged. While UM is considered a radio-resistant tumor, there is a role for radiotherapy (RT) as palliative treatment and possibly for immune sensitization. This a retrospective analysis aimed at addressing the role of combination checkpoint inhibitors (ICI) with RT as a synergistic treatment in metastatic UM patient. We hypothesized that concurrent RT would improve the clinical response to immunotherapy. Methods: Retrospective chart review of patients with metastatic UM treated with ICI at Ella Lemelbaum Institute between 2015 and 2021. Patients’ electronic medical records were analyzed for baseline characteristics, response rate and survival data. Patients were grouped according to receipt of concomitant RT. Study was approved by local IRB and statistical analyses done using Stata V.17 Results: Thirty-nine patients were treated with immunotherapy. Fifty percent were treated with anti-programmed cell death (PD)-1 and 50% with anti-PD1– anti CTLA4 combination therapy. Nine patients were treated concomitantly with immunotherapy and external beam RT or with stereotactic body RT (group A) and 29 patients were treated with immunotherapy alone (group B). Overall response rate was significantly higher in group A (44% versus 10%, p = 0.004). Median progression-free survival was longer for patients in group A (22 months versus 3 m, Hazard Ratio (HR) = 0.37, p = 0.036). Median overall survival was also longer for group A (26 months versus 7.5 m, HR = 0.34, p = 0.03). Toxicity was comparable between the groups. Conclusions: RT may improve response to immunotherapy with ICI in metastatic UM patients and may confer an advantage in survival. Further prospective, larger studies are warranted.

Background: Metastatic spread of malignant melanoma to the abdomen presents a therapeutic challenge. Targeted and Immune-therapies dramatically improve patients' survival, yet some patients may still benefit from surgical intervention. This study investigates the outcomes of surgical treatment of abdominal metastatic melanoma in the era of modern therapy. Methods: This is a retrospective study of all patients who underwent surgical resection for abdominal metastatic melanoma between the years 2009-2021 (n = 80). We examined the clinical, operative, perioperative, and oncological outcomes of these patients. Results: The cohort included a therapeutic group (T, n = 43) and palliative group (P, n = 37). The rate of overall post-operative complications was lower in the T group (n = 3, 9.3%) compared to the P group (n = 10, 27.1%) (p = 0.04), but no difference in major complications rate (p = 0.41). The median follow-up was 13.4 months (range, 0.5-107), with an estimated 2- and 5-years survival of 66.5% and 45.3% respectively. The estimated 2- and 5years survival of the T group was 76.61% and 69.65%, and 49.01% and 28.01% in the P group (p = 0.005). Univariate analysis identified Therapeutic resection (HR 3.2, p = 0.008), isolated lesions (HR 1.47, p = 0.033) and major complication score (HR 1.8, p=<0.001) to be correlated with survival. On multivariate analysis, Therapeutic resection (HR 2.53, p = 0.042) and major complication score (HR 1.62, p = 0.004) remained significant independent factors correlated with survival. In patients who progressed on treatment, and their progression was treated with surgical resection 46.1% where able to be maintained on the same preoperative treatment strategy. Conclusion: We have demonstrated that abdominal metastesectomy is a safe and oncologically efficacious therapy in selected patients. Especially in the era of modern therapeutics, patients with isolated disease site, limited resectable progression on therapy, or patients with symptomatic metastases should be considered for surgical resection.

3149 Background: Ameloblastoma is a rare benign but locally aggressive odontogenic neoplasm, with 2% of cases representing ameloblastic carcinoma or metastatic ameloblastoma. It affects young adults with high recurrence rates after surgery. The standard therapy is radical bone resection with subsequent functional, aesthetic & psychological impairments. Therefore, other therapeutic options, including neoadjuvant approach, should be considered. Sixty to 70% of mandible Ameloblastoma carry a BRAF mutation, usually V600E, and previous case reports have shown durable responses to treatment with BRAF inhibitors in these patients. We sought to explore the possibility of neoadjuvant BRAF or BRAF+MEK inhibition as neoadjuvant treatment in mandible Ameloblastoma. Here we present results of 12 patients with locally advanced disease who were treated with BRAF with or without MEK inhibitors. Methods: Patients who were unable to undergo jaw preservation surgery for locally advanced Ameloblastoma with a BRAF V600E mutation were treated with Dabrafenib or Dabrafenib-Tratmetinib in an EAP form. Patient records were analyzed for baseline parameters, treatment regimen, toxicity, response to therapy and the ability to convert to a mandible preservation surgery. Data were collected and analyzed in accordance with Sheba Medical Center IRB approval. Statistical analyses were done with STATA v.17. Results: Twelve patients were treated with Dabrafenib/ Dabrafenib-Tratmetinib between 2017-2021. Five patients received BRAF-MEK inhibitors and 7 BRAF inhibitor alone. Median age was 21. Ten patients(83%) showed excellent response to therapy and have successfully converted from planned radical bone resection to mandible preservation surgery. The other 2 patients are still on therapy and have also showed deep responses that enable conversion to mandible preservation. Median time to surgery was 10 months. With median follow up of 18 months, no cases of recurrence were documented. Rate of adverse events was as expected with only 1 case of G3-4 (hepatitis). Conclusions: Targeted therapy with BRAF with or without MEK inhibition may serve as an important therapeutic tool for locally advanced Ameloblastoma with the potential of organ preservation treatment, and is an important example of oncological therapy assisting in non-cancerous tumors.

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal–epithelial transition ( MET ) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48–91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47–69), whereas it was 68% (95% CI, 50–82) in treatment-naïve and 50% (95% CI, 35–65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7–14.3), whereas it was 10.6 months (95% CI, 5.5–15.7) in first-line and 9.1 months (95% CI, 3.1–15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2–23.1). In patients with measurable brain metastases ( n = 11), the intracranial ORR was 46% (95% CI, 17–77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting.

Background TNFα is a cytokine produced by immune cells and by tumor cells. The soluble forms of membrane TNF receptors 1/2 (sTNF-R1/2) act as decoy to neutralize TNFα, and are highly abundant in cancer patients. Elimination of sTNF-R1/2 may therefore unmask endogenous TNFα, to presumably exert anti-neoplastic effects and reverse resistance to immune checkpoint inhibitors. Immune Apheresis (IA) is a procedure designed to specifically capture sTNF-R1/2 from plasma by passing it over an affinity column. Here we employed Immunicom's LW-02 Immunopheresis® device for removal of sTNF-R1/2 from plasma of cancer patients. Methods In cohort A, patients with melanoma, RCC, NSCLC or TNBC refractory to standard therapy were treated with IA only. IA treatment of 2 plasma volumes was done x3/week, for three treatment cycles (4 weeks each) up to a total of 36 treatments. Cohort B patients currently receive concurrent IA and Nivolumab therapy (240mg q2 weeks starting on week 5). sTNF-Rs removal and circulating inflammatory biomarkers were measured by immuno-assays, such as multiplex cytokine detection and mass cytometry. Pre- and post-treatment tumor biopsies were analyzed for tumor markers and TILs by immunohistochemistry. Results Cohort A included six patients (3 Melanoma and 3 TNBC): three patients completed full study regimen, and three others were withdrawn due to clinical progression. AEs included chills (4/6), fever (2/6), anemia (6/6), central line thrombosis (1/6) and pulmonary embolism (1/6) All were Grade 2 except G3 anemia (1/6). There were no treatment related SAE's. sTNF-Rs levels were significantly reduced, followed by enhanced detection of TNFα, and IFNγ in some cases. In two patients, CD8 counts and PD-1 and PD-L1 expression were increased. Congruently, blood mass cytometry showed reduction in Treg subsets and differential increase of CD8 subsets following treatment. Conclusions The use of Immunicom's LW-02 Immunopheresis® device in combination with Terumo BCT Spectra Optia Apheresis System is safe and efficient in the removal of sTNF-Rs from blood plasma. Subsequent immuno-assay analyses indicated formation of inflammatory response which may facilitate effects of immunotherapy, yet to be investigated in cohort B. Trial Registration NCT04142931 Ethics Approval Sheba Medical Center Ethics Committee, 6136-19 Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal