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Immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs), but haematological irAEs are rare. We report a case of presumed complement-mediated thrombotic microangiopathy (CM-TMA) in a 78-year-old man with metastatic melanoma following treatment with ICIs. Following two doses of combination nivolumab and ipilimumab therapy, he developed microangiopathic haemolytic anaemia, thrombocytopenia and increased creatinine. ADAMTS13 activity was preserved, CH50 was high, haptoglobin was depleted and a blood film demonstrated fragments. Given this constellation of findings, a diagnosis of CM-TMA was made. Immunotherapy was held and the patient received steroids and supportive care. Six months after his last dose of immunotherapy, he has no evidence of melanoma or CM-TMA. CM-TMA should be suspected in patients on ICI with unexplained anaemia and thrombocytopenia with preserved ADAMTS13 activity. Suspicion of complement dysregulation may have therapeutic implications, such as the necessity of complement pathway inhibition.

Malignant peripheral nerve sheath tumor (MPNST)-like melanoma is a rare malignancy with overlapping characteristics of both neural sarcoma and melanoma. Although the genomics of cutaneous melanoma has been extensively studied, those of MPNST-like melanoma have not. To characterize the genomic landscape of MPNST-like melanoma, we performed a single-center, retrospective cohort study at a tertiary academic cancer center. Consecutive patients with a confirmed histologic diagnosis of MPNST-like melanoma were screened, and those whose tissues were locally available were included in this analysis. Archival tissue from six patients (eight samples) was submitted for whole-exome and transcriptome sequencing analysis. We compared these data with available genomic studies of cutaneous melanoma and MPNST. NF1 was altered (mutated, deleted, or amplified) in 67% of patients. Genes related to cell cycle regulation were frequently altered, with frequent deletion of ZNF331, which, to the best of our knowledge, has not been previously described in cutaneous melanoma. The serine protease inhibitor SERPINB4 was deleted in 100% of the patients. We show that MPNST-like melanoma presents overlapping genomic features with cutaneous melanoma and MPNST, but it is unique by the frequency of loss of function of ZNF331 and SERPINB4.

Background and aims: Current guidelines state that infliximab is contraindicated for the treatment of immune checkpoint inhibitor-related hepatitis (ir-hepatitis) due to the risk of inducing further liver damage. As this recommendation is largely based on the use of infliximab for rheumatologic diseases, we evaluated the efficacy and hepatotoxicity of infliximab in patients with steroid-refractory immune-related adverse events (irAEs). Methods: We retrospectively reviewed consecutive patients treated with infliximab for irAEs at Princess Margaret Cancer Centre. To assess hepatotoxicity, we compared the mean value of ALT, AST, and total bilirubin (BT) before and after infliximab treatment. We used logistic regression to assess factors associated with infliximab efficacy. Results: Between January 2010 and February 2019, 56 patients were identified. The median age of the patients was 63 (27–84) years. Colitis was the most frequent toxicity (66%), followed by pneumonitis (11%). Infliximab was used to treat ir-hepatitis in one patient. The median number of infliximab doses was 1 (1–3) and led to toxicity resolution in 43 (76%) patients. The mean ALT, AST, and BT levels before and after infliximab treatment were not statistically different. The patient treated for ir-hepatitis had a complete recovery, with no incremental liver toxicity. Conclusions: In this dose-limited setting, infliximab was effective in resolving irAEs and did not induce hepatotoxicity.

Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0–17% for anti-PD1/L1 ± anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM. We performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 ± anti-CTLA4 ICI between 2014–2019. Clinical and genomic characteristics were collected from a chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan–Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and identify clinical variables associated with ICI outcomes. We identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed metastatic disease &lt, 2 years after their initial diagnosis. Bone metastases were present in 12% of patients. The median cPFS was 2.7 months, and the median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with a good prognosis: ≥2 years from the initial diagnosis to metastatic disease (n = 25), LDH &lt, 1.5 × ULN (n = 45), and absence of bone metastases (n = 66). We developed a Metastatic Uveal Melanoma Prognostic Score (MUMPS). Patients were divided into 3 MUMPS groups based on the number of the above-mentioned prognostic variables: Poor prognosis (0–1), Intermediate prognosis (2) and Good prognosis (3). Good prognosis patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor prognosis disease (1.8 months cPFS, 3.9 months OS), p &lt, 0.0001. We developed MUMPS—a prognostic score based on retrospective data that is comprised of 3 readily available clinical variables (time to metastatic diagnosis, presence of bone metastases, and LDH). This MUMPS score has a potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS score in selecting ICI treatment management for mUM.

9579 Background: High-risk melanoma has variable prognosis. Adjuvant immuno- (IO) and targeted therapy (TT) are approved for stage III-IV resected disease. However, a significant proportion of patients (pts) are cured by local treatment alone or relapse despite adjuvant therapy. Liquid biopsy with ctDNA assays have been used to predict response to treatment and identify pts at higher risk of progression/death. Personalized ctDNA assays are a highly sensitive approach that may enhance upfront risk stratification and early detection of relapse. Methods: Serial ctDNA Monitoring as a predictive Biomarker in advanced neoplAsms (SAMBA) is a Princess Margaret prospective ctDNA kinetics study (NCT03702309) in high-risk melanoma pts. Plasma is collected pre-op (pre-local treatment, if feasible), post-op (after surgery), and every 3-6 months (m) until radiological progressive disease (rPD). Personalized amplicon based NGS assays by Inivata (RaDaR) were used to detect somatic variants in ctDNA identified through whole-exome sequencing of matched tumor tissue. Progression free survival (PFS) and overall survival (OS) from the time of surgery were estimated with the Kaplan Meier and compared with the log-rank test. Results: As of December 2021, 82 of 100 planned pts have been enrolled. A total of 191 samples from 47 pts have been analyzed. Median age was 66 years (27-87), 33 were male (70%). Seven (15%), 30 (64%) and 10 (21%) were stage II/III/IV respectively. All pts had surgery and 8 (17%) adjuvant radiation. No systemic therapy was given to 11 pts (23%); 30 (64%) had IO and 6 (13%) TT. rPD occurred in 13 pts (28%). Median follow up was 24 months. A median of 48 variants were included in the personalized ctDNA panel design (35-52). ctDNA was detected (ctDNA+) at any time point in 12/47 pts (26%), of which 5/12 (42%) were BRAF and NRAS wt on tissue. Median PFS was 4.9 months (m) for ctDNA+ pts and not reached (NR) for ctDNA- pts at post-op (HR = 2.71 CI 0.60-12.31, p = 0.179). Median OS was 23.1 m vs NR in ctDNA+ vs ctDNA- pts (HR = 8.9, CI 1.45-54.77, p = 0.004). Two ctDNA+ pts had neoadjuvant IO and became ctDNA- before surgery. One, free of disease after 12 m, had ctDNA- in 4 follow up samples. The other pt was ctDNA+ in the post-op sample and relapsed within 3 m. Four of 45 (9%) pts had ctDNA+ at post-op. Two of them, including a pt who had neoadjuvant IO, did not receive adjuvant therapy and had rPD within 3 m. The other 2 pts received adjuvant IO; ctDNA cleared and pts remain free of disease at 12 and 34 m. Three pts with rising ctDNA over time experienced rPD after a median of 4 m (2-7). Conclusions: Personalized ctDNA analysis with RaDaR may improve risk of death stratification and selection of pts who could benefit from adjuvant treatment. Detection of ctDNA may precede rPD. Follow-up will continue in pts with rising ctDNA who have not yet had rPD. Pts accrual and sample collection are ongoing, and additional data will be presented. Clinical trial information: NCT03702309.

e21575 Background: Adjuvant systemic therapies (ST) for patients with resected stage III melanoma have improved relapse-free survival; however, the role of adjuvant radiotherapy (RT), previously the mainstay adjuvant treatment, is undefined in the modern ST era. Real-world data detailing clinical practice changes and its impact on outcomes are needed to help inform the choice of adjuvant therapy for patients with resected stage III melanoma. Methods: In this single-center retrospective study, patients from Princess Margaret Cancer Centre with resected stage III cutaneous melanoma treated between 2010 and 2019 and fitting the 2016 Cancer Care Ontario guidelines for adjuvant RT were included. Demographic, pathological, and clinical data were abstracted from electronic medical records. PFS was defined as the time from lymph node dissection to local-regional recurrence in the treated nodal basin or distant recurrence. OS was defined as time from lymph node dissection to death by any cause. The Log-rank method was applied to assess survival endpoints. A p-value < 0.05 was considered statistically significant. Results: From 4,959 records reviewed, 109 patients were identified. Median age at time of surgical resection was 59.4 years (23.6-89.8), and 74 (68%) were male. Type of adjuvant therapy and number of local-regional recurrences (LR) are expressed in the table. The median follow-up among those alive at last follow-up was 54.2 months (range 1.9-122). The proportion of patients receiving adjuvant RT was higher between 2010 and 2014 than it was between 2015 and 2019 (59% to 26%), whilst the proportion of those receiving adjuvant ST progressively grew (3% to 50%). LR > 90 days following lymph node dissection as the first site of relapse or synchronously with progression to metastatic disease was rare in patients treated with either adjuvant RT (6.8%) or adjuvant ST (14.3%, chi-square p = 0.33). Median progression free survival was 12.3 months in patients treated with adjuvant RT and 43.8 months in patients treated with adjuvant ST (p = 0.007). Overall survival was not significantly different (p = 0.08). Conclusions: The advent of ST has changed our institution’s clinical practice with ST replacing RT as the primary adjuvant treatment modality. Our data suggests that in the current adjuvant treatment landscape, omission of RT does not seem to increase rates of local-regional recurrences, and patients with resected stage III melanoma can be safely spared from adjuvant RT without detrimental effect on survival.[Table: see text]

BackgroundMetastatic uveal melanoma (mUM) is a rare disease for which no systemic therapy has demonstrated overall survival (OS) benefit. There are no robust data on prognostic factors for OS in patients with mUM treated with immune checkpoint inhibitors (ICI).Retrospective and non-randomized prospective studies have reported response rates of 0-37% for anti-PD1/L1 +/-anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM.MethodsWe performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 +/-anti-CTLA4 ICI between 2014–2019. Clinical and genomic characteristics were collected from chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan-Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and to identify clinical variables associated with ICI outcomes.ResultsWe identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed stage IV disease < 2 years after their initial diagnosis. Bone metastases were present in 12% of patients. For the entire cohort, the median cPFS was 2.7 months and median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with good prognosis: ≥ 2yrs from initial diagnosis to stage IV (n=25), LDH Metastatic Uveal Melanoma Prognostic risk Score (MUMPS). Patients were divided into 3 MUMPS risk groups based on the number of the above-mentioned prognostic variables: Poor risk (0-1), Intermediate risk (2) and Good risk (3). Good risk patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor risk disease (1.8 months cPFS, 3.9 months OS); PConclusionWe developed a MUMPS risk score, based on retrospective data, that is comprised of 3 readily available clinical variables (time to stage IV diagnosis, presence of bone metastases, and LDH). This MUMPS risk score has potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS risk score in selecting ICI treatment management for mUM.

BackgroundPatients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer.MethodsWe analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality.FindingsThirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off.InterpretationCOVID-19–related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.

PurposeAnti-programmed cell death protein 1 (PD1)±anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1±anti-CTLA4 ICI in patients with advanced melanoma.MethodsWe performed a single-center retrospective cohort analysis of patients who received anti-PD1±anti-CTLA4 ICI for advanced melanoma between 2012 and 2019. Primary tumor type, BRAF and NRAS mutation status, and other covariates were abstracted from chart review. Log-rank tests and multivariable Cox regression models were used to assess differences in clinical progression-free (cPFS) and overall survival (OS).ResultsWe identified 230 patients who received 249 lines of anti-PD1±anti-CTLA4 ICI for unresectable or metastatic disease. Of these patients, 74% were cutaneous, 11% mucosal, 8% unknown primary and 7% acral. BRAF and NRAS mutations were identified in 35% and 28% of patients, respectively. In multivariable analyses of the entire cohort, acral or mucosal primary tumor type, >3 metastatic sites, elevated LDH were predictive of shorter cPFS and OS. Combination ICI therapy was associated with longer cPFS (HR 0.57, 95% CI 0.38 to 0.86, p=0.007) and OS (HR 0.42, 95% CI 0.28 to 0.65, pNRAS (HR 0.24, 95% CI 0.10 to 0.62, p=0.003, n=69) and BRAF V600E/K (HR 0.47, 95% CI 0.24 to 0.90, p=0.024, n=86) mutant melanoma but not BRAF/NRAS wild-type (n=94) melanoma.ConclusionsIn our cohort, primary melanoma tumor type and genomic subtype were independent predictive markers of cPFS and OS for patients with metastatic melanoma receiving anti-PD1 ICI. Primary tumor type and genomic subtype—including NRAS—should be further evaluated in prospective clinical trials to determine their value as predictive markers. Biologic subtypes may facilitate clinical decision-making when recommending combination ICI treatment (anti-PD1±anti-CTLA4) versus anti-PD1 alone for patients with metastatic melanoma.

BACKGROUND Pancreatic cancer plays an important role in cancer-related mortality. Few studies have been performed in Brazil to characterize patients affected by this disease. We aimed to describe the clinico-pathological characteristics and the survival of patients with pancreatic cancer seen at AC Camargo Cancer Center (ACCCC). METHODS We included patients ≥ 18-year old, with a histologically confirmed diagnosis of exocrine pancreatic cancer, that attended at least one visit at ACCCC from 2008 to 2016. RESULTS The study included 739 patients. Median age at diagnosis was 64 years. Most patients were male. About 5% presented a family history of pancreatic cancer. A total of 40% had diabetes and 51.4% presented with ECOG performance status 1. Tumors most often arose in the pancreatic head and roughly half of the patients had metastatic disease at presentation. Median overall survival of patients with potentially resectable disease submitted to surgery at ACCCC was 35.4 months. Median overall survival times of patients with the unresectable and metastatic disease were 14.1 and 9.3 months, respectively. CONCLUSIONS The features of our population match those of studies done in developed countries. We believe multicentric data from patients with pancreatic cancer in Brazil could enable more effective preventive and therapeutic approaches to the disease.

Background: Metastatic pancreatic adenocarcinoma (MPA) represents a highly lethal condition. Despite the improvements seen with FOLFIRINOX, there is no randomized data to guide treatment selection beyond this regimen. We aimed to evaluate the outcomes of patients with MPA progressing on FOLFIRINOX who were treated with Gemcitabine-based chemotherapy afterwards. Methods: We included patients aged 18 years or older, treated for MPA with FOLFIRINOX in the first-line setting and who experienced disease progression, with Eastern Cooperative Oncology Group (ECOG) performance status 0–2, and treated with at least one cycle of Gemcitabine-based chemotherapy in second or further lines of treatment. We used descriptive statistics to characterize the study population and Cox proportional-hazards models to describe factors associated with survival. As an exploratory analysis, we compared the outcomes of patients treated with single-agent Gemcitabine with those of patients undergoing Gemcitabine-based polychemotherapy. Results: The study population consisted of 42 patients. Median age was 59 years and 78.6% of patients presented ECOG 0–1. Thirty-three patients (78.6%) were treated with Gemcitabine-based chemotherapy in the second-line setting and 27 patients (64.3%) were treated with single-agent Gemcitabine. Objective response rate and disease control rate were 2.4% and 33.4%, respectively. Median progression-free survival (PFS) and median overall survival (OS) were 2.9 and 5.5 months, respectively. Six-month PFS and OS rates were 19.2% and 46.2%, respectively. We observed no significant difference in OS according to the type of Gemcitabine-based chemotherapy, despite numerically improved disease control rate and PFS for those treated with Gemcitabine-based polychemotherapy. In multivariate analysis, ECOG 2 ( vs. ECOG 0–1) was the only factor significantly associated with inferior PFS and OS. Conclusions: a subgroup of patients with MPA derives benefit from treatment with Gemcitabine-based regimens after FOLFIRINOX. There is a suggestion that Gemcitabine-based combinations, in particular Gemcitabine plus Nab-Paclitaxel, provide superior outcomes compared to single-agent Gemcitabine. Additionally, treatment in this setting should be offered carefully to patients with ECOG 2, as they present shorter survival and increased risk of toxicity.

e21575 Background: Targeted therapy with BRAF and MEK inhibitors constitute part of the standard treatment for BRAF V600 mutated melanoma. Timely detection of BRAF mutation is necessary for clinicians and patients to make treatment decisions. We aimed to map the BRAF testing timelines from the time of request until the reported result in order to assess obstacles to timely BRAF reporting in our community, and its impact on the initiation of systemic therapy. Methods: In this single-center retrospective study, we included adult patients referred to the Medical Oncology Department at the Princess Margaret Cancer Centre (PM) from January 2019 to August 2019 with histologically confirmed cutaneous or mucosal melanoma and BRAF molecular testing performed in 2019. The Log-Rank method was applied to detect differences in BRAF turnaround time and time to treatment initiation in specified subgroups. A p value < 0.05 was considered statistically significant. Results: Sixty-six cases were identified. The median age was 64 (24-88), and 42 (64%) were male. At the time of BRAF request, 10 (15%) patients had stage II, 33 (50%) had stage III, and 23 (35%) had stage IV disease. Twenty-eight (43%) were positive for the BRAF V600E/K mutation by ARMS assay and 4 (6%) for other variants by NGS test. Thirty-three (50%) patients had the BRAF test available at their first PM Medical Oncology visit. Median time between BRAF request and result was 17 days; when a reflex BRAF test was ordered by the Pathology Department, the median turnaround time was 12 days (95% CI 8-15), compared to 20 days (95% CI 16-23) if the order was requested by another specialist ( p < 0.001). Median time to transfer samples between institutions was 6 days. If the BRAF test was processed within the institution where the biopsy was performed, the BRAF median turnaround time was 13 days (95% CI 6-19) compared to 19 days (95% CI 16-21) if a sample was transferred to another institution ( p = 0.02). In total, 49 patients had systemic therapy. Median time between the first visit with Medical Oncology and treatment initiation was 29 days and was not statistically different if the BRAF result was available or not (28 vs. 34 days; p = 0.09). In the subgroup with stage IV disease (Table), 20 patients received systemic therapy; the median time to treatment initiation was 24 days and differed with BRAF result availability (20 vs. 31 days, p = 0.03). Conclusions: The current BRAF testing timeline at the PM varies from days to weeks. A major factor impacting this timeline is transfer time, which can be streamlined by pathology reflex testing. Delays in turnaround time appears to impact subsequent timing and type of therapeutic interventions, especially in patients with stage IV disease.[Table: see text]

9557 Background: Melanoma has a high probability of central nervous system (CNS) spread. Although first line nivolumab and ipilimumab resulted in 56% response rate and 29.2 months median overall survival (OS) in patients with melanoma brain metastases (MBM), there is paucity of data for patients who develop MBM after prior systemic therapy. As this subgroup is often underrepresented in clinical trials, we aimed to evaluate the OS of non-treatment naïve patients who develop MBM and identify factors related to survival. Methods: In this single-center, retrospective study, consecutive melanoma patients with > 90 days from exposure to either immune checkpoint inhibitor (ICI), targeted therapy (TT), or chemotherapy, to CNS relapse were included. OS was defined as the time between CNS relapse and death by any cause. The Log-Rank method was used to calculate OS. Cox regression analysis was used to identify differences between subgroups. Variables with a p value < 0.1 were included in a multivariate model. A p value < 0.05 was considered statistically significant. Results: Between 2012 and 2018, 135 patients were identified. Median age was 57 (29-92) years, 92 (68%) were male, and median number of prior systemic therapies was 2 (1-6). One-hundred and nine (81%) patients had cutaneous melanoma; acral lentiginous melanoma (ALM) comprised 11 (8%) patients. Molecular studies were available for 123 patients, of whom 61 (50%) were BRAF V600 mutant. Eighty-nine (66%) patients had prior ICI, of whom 33 (37%) had prior exposure to both anti-PD1 and anti-CTLA-4, either as monotherapy or combination. Amongst the BRAF V600 mutant population, 48 (79%) had prior TT. Radiotherapy was given to 112 patients, of whom 55 (49%) had SRS. Median follow-up was 41 (95% CI 30-51) months. Median OS was 6.4 (95% CI 5.3-7.5) months. Patients with ALM, > 3 MBM, ECOG 2-4 and active treatment at CNS relapse (< 30 days from last dose of treatment to MBM diagnosis) were at increased risk of death, whilst subsequent treatment with ICI was related to better survival (Table). On multivariate analyses, age ( p = 0.007), subtype ( p = 0.04), number of MBM ( p = 0.01), active treatment at CNS relapse ( p < 0.001) and subsequent ICI ( p = 0.002) remained statistically significant. Exploratory analyses suggested subsequent treatment with anti-PD1 + anti-CTLA-4 (n = 42) compared favourably to subsequent anti-CTLA-4 only (n = 21) (13 x 7 months, p = 0.004), and was independent of prior ICI. Conclusions: Previously treated melanoma patients who develop MBM have a poor prognosis, but subsequent ICI therapy seems to be associated with better OS. Further clinical investigation to identify optimal anti-PD1-based therapies is warranted for non-treatment naïve patients who develop MBM.[Table: see text]

2640 Background: Endocrine immune-related adverse events (irAEs) are frequent with immune checkpoint inhibitors (ICIs); however, ICI-related insulin-dependent diabetes mellitus (IDDM) is a rare but serious endocrine irAE. We describe the characteristics of patients who developed ICI-related IDDM across five academic Canadian cancer centres. Methods: In this multicentre, retrospective study, we included both patients who developed IDDM and patients with non-IDDM (NIDDM) or pre-DM who became insulin-dependent while on treatment with ICI. We collected data on primary tumor type, ICI regimen (single agent or combination), time to development of IDDM from ICI initiation, comorbidities, laboratory parameters at the time of IDDM diagnosis, tumor response and survival. A p value < 0.05 was considered statistically significant. Results: We identified 27 patients between July 2016 and August 2019. Median age was 60 (39-79) years, 20 (74%) were male, 15 (55%) had melanoma and 4 each (15%) non-small cell lung cancer (NSCLC) and renal cell carcinoma. Seven (26%) patients had prior NIDDM or pre-DM; 5 (18%) had an auto-immune disease (2 psoriasis, 2 inflammatory bowel disease, and 1 systemic lupus erythematosus). Laboratory parameters at presentation and management of IDDM are presented in the Table. Mean A1c was not statistically different between patients with or without prior NIDDM or pre-DM (8.4% vs. 8.6%; p = 0.9). All IDDM events were irreversible; 1 (4%) patient died of diabetic ketoacidosis. At time of IDDM diagnosis, 17 (63%) patients were receiving single agent anti-PD1 and 10 (37%) anti-PD1-based combinations (7 anti-CTLA-4, and 3 other compounds). Median time for development of IDDM from ICI initiation was 2.7 months (95% CI 0.2-5.3). Patients receiving combination ICI developed IDDM earlier than those treated with single agent (1.4 vs 4.8 months; p = 0.05). Amongst patients with metastatic disease (n = 24), 9 (38%) had a complete response and 7 (29%) had a partial response. Two patients (8%) were treated in the adjuvant setting; 1 (4%) received consolidation ICI. IDDM led to ICI discontinuation in 12 (44%) patients. After a median follow up of 21 months from ICI initiation, median survival was 30 months (95% CI NE) and was not reached in patients with melanoma and NSCLC. Conclusions: ICI-related IDDM is a rare and typically irreversible irAE that occurs early in the course of treatment and develops earlier with combination ICI. In this cohort, patients who developed ICI-related IDDM had a high tumor response rate and prolonged survival, especially melanoma and NSCLC patients. Prospective evaluation of autoantibodies to predict development of IDDM is ongoing.[Table: see text]

e15038 Background: Recurring oncogenic non-V600E BRAF mts have been identified in many cancer types. Preclinical data indicate that some BRAF non-V600E mts can be targeted with BRAF + MEK inhibitors. BEAVER is an investigator-initiated study designed to test the safety and efficacy of binimetinib and encorafenib (B+E) in patients (pts) with non-V600E BRAF mts. Methods: Key eligibility criteria are: pts with advanced solid tumors with BRAF non-V600E activating (class 1 and 2) or inhibitory (class 3) mts, and no prior BRAF/MEK inhibitors. Pts receive binimetinib (45mg PO BID) and encorafenib (450mg PO daily) on a 28-day cycle until intolerable toxicity or progression. The primary objective is OR rate (ORR) as per RECIST 1.1. In this Simon 2-stage trial, ≥1 of 7 pts need to have an objective response (OR) before commencing second stage of study (26 pts total). Secondary objectives include: safety, DCR, PFS, and OS. Exploratory objectives include: genomic profiling of tumors, evaluating circulating tumor DNA dynamics and development of patient derived xenograft (PDX) models. Results: From June 2019 to Feb 2021, 12 pts were screened and 9 pts enrolled; 9 are evaluable for safety and 8 for efficacy. Tumor types were melanoma and colon (n=2 each), as well as gallbladder, lung, breast and uterine cancers (n=1 each). Median age was 62 yrs (range 40-72). Median number of prior treatments was 2 (range 0-6). 1 pt had a class 1, 3 pts had class 2, and 5 pts had class 3, non-V600E BRAF mts. The median number of cycles was 2 (range: 1-7). Common treatment-related adverse events were mostly grade ≤ 2, and included: Blurred vision (78%), fatigue (67%), nausea (44%), vomiting (33%), and rash (33%). Dose reductions were required in 4/9 pts (44%) due to: blurred vision (22%), central serous retinopathy (11%), malaise (11%) and increased lipase (11%). Drug-related grade 3 AEs occurred in 2/9 pts and included: malaise (11%), confusion (11%), fatigue (11%) and increased lipase (11%). All eye toxicities were reversible with dose interruption. ORR was 12.5% (1/8) with one unconfirmed PR in a melanoma pt (BRAF G469S), treated for 6.5 months. One gallbladder cancer pt (BRAF D594N) had SD, and 6 pts had PD as best response. Genomic profiling was performed on archival tumors for 8 pts. Two PDX models were established. Responses to B+E in PDX models mirrored responses in 2 corresponding pts who had PD. Genomic and molecular profiling of pt tumors and corresponding PDXs identified multiple potential mechanisms of B+E resistance including: activation of EGFR and Akt pathways and inactivation of NF1 and Rb1. Conclusions: Preliminary data confirmed the safety of B+E and showed preliminary evidence of anti-tumor activity in advanced cancer pts with non-V600E BRAF mts. This study met the criterion for advancing to stage 2. Enrolment in the BEAVER trial and correlative biomarker analyses are ongoing. Clinical trial information: NCT03839342.

In this article, we review the literature on the current advances in targeted therapies for metastatic gastric cancer aimed at improving patient care. We conclude that the key to guiding targeted therapy is individual biomarkers, which are not completely elucidated. HER2 overexpression is the only predictive biomarker currently in use. Furthermore, it is necessary to understand that gastric tumors are heterogeneous; therefore, is impossible to evaluate a novel biological compound without evaluating personal biomarkers. The selection of patients who are able to receive each treatment is paramount for improving advanced gastric cancer survival and reducing unnecessary costs.

e22072 Background: Malignant Peripheral Nerve Sheath Tumor (MPNST)-like melanoma is a rare entity wherein cutaneous melanoma mimics histomorphological features of MPNST. The genomic landscape of MPNST-like melanoma has not been previously described. We report the genomic findings of 6 patients diagnosed with MPNST-like melanoma. Methods: We identified consecutive patients with confirmed histological diagnosis of MPNST-like melanoma. Archival tissue was submitted for whole exome and transcriptome sequencing analysis and genomic findings were compared to publicly available data on the genomic landscape of both melanoma and limited genetic descriptions of MPNST. Results: Six patients diagnosed with MPNST-like melanoma between November 2002 and July 2018 had archival tissue available (8 samples). Mean age at diagnosis was 60.5 years (38-74). The mean tumor mutational burden (TMB) was 35.72 mutations/exon coding megabase, ranging from 4.27 to 86.36. NF1 alterations were found in 4 (67%) of cases: one had 3 truncating mutations (W696 + X1870_splice + R1590C) associated with NF1 amplification, one had a deep deletion and another two had truncating mutations (I1908L and W696 + A1530V). Two tumors had non-V600 BRAF mutations that predict alteration in kinase function. We observed deletions of cell cycle regulators: CDKN2A and CDKN2B in 33%; and ZNF331 (19q13.42) in 83% of cases. SERPINB4 (18q21.3), described previously as a tumor suppressor in oral squamous cell carcinomas, was deleted in all samples. The patient with NF1 amplification and truncating mutations received immunotherapy due to metastatic disease and achieved a complete response; his tumor had a TMB of 72.6. Another patient who died of metastatic melanoma, treated with chemotherapy in the pre-immunotherapy era, lacked any NF1 mutation but had a Q61K NRAS mutation; the tumor had a TMB of 15. The remaining patients were treated with surgical resection alone and continue on follow-up. Conclusions: MPNST-like melanoma shares some frequently altered genes in cutaneous melanoma but possesses an excess of NF-1 mutations or deletions, in keeping with its neural-like phenotype. The high frequency of SERPINB4 alterations suggests a critical tumor suppressor role in this subtype of melanoma, warranting further investigation. Additionally, cell cycle dysregulation caused by deletion of ZNF331 and CDKN2A/B may be important in MPNST-like melanoma carcinogenesis.

3098 Background: Therapeutic augmentation of the intestinal microbiome to improve immunotherapy outcomes is an active area of investigation. Microbial Ecosystem Therapeutics (METs) are consortia of human-derived bacteria designed to be reproducible, scalable and safe alternatives to fecal transplant. MET4 is a first-in-class consortium of taxa associated with immune checkpoint inhibitor (ICI)-responsiveness. Here we describe preliminary results of MET4-IO, an interventional trial assessing the safety and ecological effects of MET4 in ICI recipients. Methods: MET4-IO is a randomized investigator-initiated trial, evaluating MET4 in solid cancer patients treated with ICI. MET4-IO involves 3 cohorts of 65 total patients: Group A, a safety cohort of 5 patients already on ICI; Group B, patients starting ICI, randomized 3:1 to receive MET4 or not; Group C, patients on ICI who experience radiological progression but not clinical deterioration, randomized 1:1 to receive MET4 or not. Stool and blood samples are collected at baseline and 4-5 additional time-points. For this interim analysis, 16S rRNA gene sequencing was performed on fecal specimens. Shannon diversity, relative abundance (RA), number and fold-change of MET4 taxa > RA 0.01 were assessed and compared to controls. Results: As of January 26, 2020, 21 patients were enrolled (A = 5,B = 12,C = 4), and 15 (71%) received MET4. The mean age was 65.9 years, 40% were females, 52% had head and neck cancer and 19% melanoma. Sixteen patients (76%) were treated with an anti-PD1 agent as monotherapy and 5 with a combination of anti-PD1 and anti-CTLA4 antibodies. G3-4 toxicities (CTCAEv5.0) attributed to ICI were observed in 13% vs. 17% of MET4 exposed and control patients, respectively. Three patients (20%) experienced toxicities attributed to MET4, all grade 1 except G2 dyspepsia in 1 patient. A greater number of MET4-associated taxa were detectable in MET4 recipients than controls (p < 0.01), with a trend towards higher cumulative RA (p = 0.10). No significant change in Shannon diversity after MET4 was observed, however controls were more likely to lose diversity overtime than MET4 recipients (p = 0.05). Colonization with MET4 varied by recipient and by taxon. Bifidobacterium, Collinsella and Enterococcus were significantly more common and abundant in MET4 recipients than controls. Conclusions: In this cohort, MET4 treatment was safe and associated with higher MET4-associated taxa in recipients than controls. Further analyses including peripheral blood immunophenotyping are ongoing. Clinical trial information: NCT03686202 .

e15227 Background: Infliximab is used to treat steroid-refractory immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICI). Current dogma holds that infliximab is contraindicated in immune hepatitis; steroid refractory disease should be managed with mycophenolate mofetil (MMF). This is based on anecdotal reports of infliximab-induced hepatotoxicity in patients with rheumatologic diseases who received multiple infusions of the drug. In this series of 56 consecutive cases of infliximab-treated patients, we assessed the efficacy of infliximab in resolving specific steroid-refractory irAEs and evaluated the risk of hepatotoxicity from this drug. Methods: We reviewed consecutive patients treated with infliximab for steroid-refractory irAE at a tertiary cancer center between January 2010 and February 2019. To judge hepatotoxicity, we used the Wilcoxon signed rank test to compare the mean value of ALT, AST and total bilirubin (BT) between 0-4 weeks before and after infliximab therapy. We compared factors associated with infliximab efficacy by logistic regression. A p value < 0.05 was considered statistically significant. Results: Mean age was 61.9 years. The majority had a diagnosis of melanoma (62%); 45% had a combination of two ICI before toxicity onset, of whom 73% received an anti-PD1 and an anti-CTLA-4. Colitis was the most common toxicity (66%), followed by pneumonitis (11%). Infliximab was used to treat immune related hepatitis (ir-hepatitis) in 1 patient (2%). Median number of infliximab doses was 1 (1-3), with resolution of toxicity in 76% of patients. Colitis was likely to resolve with infliximab in comparison to other irAE [OR 0.2(95% CI 0.05-0.73)]. Univariate logistic regression did not demonstrate statistical difference in toxicity outcome when ICI were given either as monotherapy (p = 0.3) or combination (p = 0.97). Mean BT, ALT and AST levels before and after infliximab were not statistically different (see table), with no evidence of infliximab-induced hepatotoxicity. The patient treated for ir-hepatitis had a complete recovery, with no further hepatotoxicity. Conclusions: Infliximab was effective in treating irAE and was not associated with hepatotoxicity in this dose-limited setting. Infliximab may be an alternative to MMF in steroid-refractory ir-hepatitis and should be tested prospectively in a randomized trial. [Table: see text]

Background: FOLFIRINOX stands a major breakthrough in the management of metastatic pancreatic adenocarcinoma (MPA). Nonetheless, significant side-effects have been reported using standard FOLFIRINOX. We aimed to compare survival outcomes, response rates and toxicity of patients treated with standard or modified FOLFIRINOX in MPA. Methods: We included patients aged ≥18 years old, with pathologically confirmed MPA, treated with FOLFIRINOX in the first-line setting. Patients submitted to at least one cycle of full-dose FOLFIRINOX were grouped in the standard FOLFIRINOX group. Results: Patients treated with standard FOLFIRINOX were younger and had less comorbidity. We observed no differences in overall survival or in progression-free survival between the two treatment arms. The only variable independently associated with OS was log10[neutrophil-to-lymphocyte ratio (NLR)]. Modified FOLFIRINOX was associated with a lower dose reduction rate, but a slightly increased incidence of severe toxicity. Conclusions: Modified FOLFIRINOX presents the same activity against MPA as standard FOLFIRINOX. We found no significant differences in toxicity, possibly due to patient selection and a higher dose reduction rate in the standard FOLFIRINOX arm. NLR stood as an important prognostic marker and further research is needed to comprehend its biological meaning in pancreatic cancer.

Objective: to evaluate the impact of enzyme replacement therapy for Gaucher Disease on clinical and laboratory parameters after two, five and ten years of treatment. Methods: data were collected from patient records and analyzed using BioEstat software (version 5.0). Student's t-test, Analysis of Variance (ANOVA), Wilcoxon test and Kruskal–Wallis test were used for statistical analysis. Hepatomegaly and splenomegaly were analyzed using the Kappa test. Results: there was a significant increase in hemoglobin levels (p-value