Search

Serial evaluation of circulating tumor DNA may allow noninvasive assessment of drivers of resistance to immune checkpoint inhibitors (ICIs) in advanced urothelial cancer (aUC). We used a novel, amplicon-based next-generation sequencing assay to identify genomic alterations (GAs) pre- and post-therapy in 39 patients with aUC receiving ICI and 6 receiving platinum-based chemotherapy (PBC). One or more GA was seen in 95% and 100% of pre- and post-ICI samples, respectively, commonly in TP53 (54% and 54%), TERT (49% and 59%), and BRCA1/BRCA2 (33% and 33%). Clearance of ≥1 GA was seen in 7 of 9 patients responding to ICI, commonly in TP53 (n = 4), PIK3CA (n = 2), and BRCA1/BRCA2 (n = 2). A new GA was seen in 17 of 20 patients progressing on ICI, frequently in BRCA1/BRCA2 (n = 6), PIK3CA (n = 3), and TP53 (n = 3), which seldom emerged in patients receiving PBC. These findings highlight the potential for longitudinal circulating tumor DNA evaluation in tracking response and resistance to therapy.

Enfortumab Vedotin (EV) is approved for metastatic urothelial carcinoma (mUC) progressing post-platinum and PD1/L1 inhibitor therapy. Erdafitinib is approved for post-platinum mUC with activating somatic genomic alterations (GAs) in FGFR2/3. Information on the activity of EV in mUC with FGFR2/3 alterations will facilitate optimal clinical management. In this multi-center, retrospective analysis, we assessed the overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) to EV in mUC patients with and without FGFR2/3 GAs including mutations and fusions. Multivariable cox-regression and logistic regression analyses with 2-tailed p-values were used to evaluate the association of GAs with outcomes. A majority of the evaluable 60 patients were male (44/60, 78%), exhibited ECOG performance score 0–1 (53/60, 88.3%) and had a median age of 70.5 (range 48 – 88) years when starting EV. GAs in FGFR2/3 did not influence the ORR (p=0.32), OS (p=0.79) or PFS (p = 0.32) with EV. In conclusion, FGFR2/3 GAs did not appear to compromise major outcomes with EV in mUC. Larger studies are required to further evaluate the impact of FGFR2/3 GAs on the activity of EV and the optimal sequencing of EV and erdafitinib in mUC.

Supplemental Digital Content is available in the text., Patients with advanced melanoma treated with immune checkpoint inhibitors can experience ongoing disease control after treatment discontinuation without subsequent systemic anticancer therapy. We previously defined a novel outcome, treatment-free survival (TFS), as the time between protocol therapy cessation and subsequent therapy initiation/death. We assessed the effect of established prognostic variables [lactate dehydrogenase (LDH), programmed death ligand 1 status, BRAF mutation status, performance status, and sex] on TFS in different treatment scenarios: treatment until toxicity/progression with frequent early cessation (nivolumab plus ipilimumab), treatment until toxicity/progression with a well-tolerated regimen (nivolumab), and treatment for a short fixed duration (ipilimumab). Data were pooled from 1077 patients with advanced melanoma treated in the CheckMate 069 and 067 trials. TFS was defined as the area between the Kaplan–Meier curves for time to therapy cessation and time to subsequent therapy initiation/death. TFS was estimated by restricted mean (r-mean) survival time at 36 months since randomization. Clinically meaningful TFS (r-mean TFS 3.7–12.7 months) was observed across all patient subgroups. TFS was longest in patients treated with nivolumab plus ipilimumab. The largest differences in r-mean TFS were observed with LDH in the nivolumab plus ipilimumab and ipilimumab treatment groups (TFS difference 4.7 and 4.9 months, respectively). In the nivolumab group, there was little difference in TFS across subgroups (r-mean TFS 3.7–5.5 months). TFS was sensitive to prognostic subgroup differences; however, duration of treatment affected the sensitivity of TFS. These results provide further support for TFS as a clinical outcome measure.

PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

155 Background: Lorigerlimab (MGD019) is an investigational, bispecific Fc-bearing (IgG4) DART molecule designed to enhance CTLA-4 blockade on dual expressing, tumor infiltrating lymphocytes, while maintaining maximal PD-1 blockade on PD-1 expressing cells. Lorigerlimab has approximate dose proportional PK across 1–10 mg/kg IV dosing Q3W, with sustained PD-1 receptor occupancy evident at doses ≥1 mg/kg Q3W. MGD019-01 is a global first-in-human dose finding and activity estimating study of lorigerlimab in advanced solid tumors (AST). Methods: The exp phase of MGD019-01 evaluates single agent safety, PK, and antitumor effects of lorigerlimab at the recommended dose for exp of 6 mg/kg IV Q3W in 4 tumor specific cohorts. Confirmed responses were noted in each cohort. Preliminary results of the mCRPC cohort are reported here. Response evaluable pts received ≥1 dose and had ≥1 postbaseline imaging evaluation. Measurable lesions were evaluated per RECIST v1.1 and skeletal metastases assessed by bone scan. Prostate specific antigen (PSA) response was defined as a ≥50% (PSA50) or ≥90% (PSA90) PSA decline from baseline with confirmation ≥3 weeks later. Expression of proliferation marker, Ki67, and inducible costimulator (ICOS) by peripheral T cells was assessed by flow cytometry. Results: At data cutoff (9/10/22), 127 pts with AST received ≥1 dose of lorigerlimab 6 mg/kg. Median exposure was 10 weeks (range, 0.1, 94.4) with median of 4 infusions. 6 pts remain on therapy; 36 discontinued for PD (n=13), AEs (n=17), or patient/physician decision (n=6). Treatment related adverse events (TRAE) occurred in 109/127 (85.8%) pts. TRAEs occurring in ≥15% of pts were fatigue, pruritus, hypothyroidism, pyrexia. Rates of grade ≥3 TRAEs and immune-related AEs were 32.3% and 7.9%, respectively. AEs leading to drug discontinuation occurred in 22.8% of pts. There were no fatal AEs related to lorigerlimab. In the mCRPC exp cohort (n=42), pts had a median of 2 prior lines of therapy for CRPC, >80% received prior ART or taxanes; 88% had visceral (liver, 26%; lung, 26%) or nodal disease and 95% had bone metastases. 42 pts were PSA response evaluable; 35 were RECIST evaluable. ORR was 25.7% (9/35; 9 confirmed PRs). Median duration of response was 16.1 weeks (range 6–25+ weeks). 5 responders remain on study, 4 discontinued for unrelated fatal AEs: COVID-19 (2) cardiac arrest (1) C. difficile infection (1). Confirmed PSA50 and PSA90 response rates were 28.6% (12/42) and 21.4% (9/42), respectively. Increased frequencies of Ki67+ and ICOS+ T cells were observed on day 8 posttreatment compared to pretherapy per the flow cytometry analyses from 35 pts. Conclusions: Lorigerlimab demonstrates a manageable safety profile with evidence of encouraging and durable antitumor activity in a chemotherapy refractory mCRPC population. Randomized evaluation of lorigerlimab in mCRPC is warranted. Clinical trial information: NCT03761017 .

540 Background: Determining a benefit from ICIs radiographically may take months and may be confounded by pseudoprogression. The NLR & RDW are readily accessible inflammatory markers from routine peripheral blood analysis and have been associated with outcomes in malignancies. We evaluated the association of early changes in NLR and RDW within 4 weeks after initiating ICI with any regression of tumor (ART) and overall survival (OS) in mUC. Methods: This study included de-identified data from Dana-Farber Cancer Institute in pts with mUC who were treated with ICIs from 2015 to 2020. Age, gender, setting (untreated vs. post-platinum), sites of metastasis (mets), performance status (PS), platelet count, RDW, and NLR at baseline and 3-4 weeks after initiating the ICI were collected. The primary objective was to assess the association of early increase in NLR by ≥1.0 from baseline or RDW at 3-4 weeks (as a continuous variable) post-ICI therapy with ART and OS. ART was assessed via subsequent imaging at any time point while on ICI. A multivariable logistic regression model and Cox proportional-hazards model were employed to identify the association of NLR changes with ART and OS, respectively, using backward selection. Results: A total of 330 pts were evaluable. The median age was 70 years, 72.1% (n = 298) were male and 69.4% (n= 227) received post-platinum ICI (remaining were platinum naïve). 46.5% (n = 146) experienced ART and the median OS was 13 months (11.14-16.14). An increase in NLR ≥ 1 in 3-4 weeks was associated with a lower rate of ART (OR: 0.41, 95% CI 0.24-0.70; p: 0.001) and worse OS (hazard ratio [HR]: 1.84, 95% CI 1.37-2.46; p < 0.0001) on multivariable analysis (Table). Higher RDW values at 3-4 weeks were associated with worse OS (HR: 1.08, 95% CI 1.03-1.14; p: 0.0004) but were not associated with ART. Conclusions: In pts with mUC initiating ICI, an early increase in NLR ≥ 1 and higher RDW in 3-4 weeks were associated with poor outcomes. Early changes in these readily available variables may enable early modification or intensification of therapy to improve outcomes. External validation of these findings is warranted. [Table: see text]

Purpose: Patients discontinuing immuno-oncology regimens may experience periods of disease control without need for ongoing anticancer therapy, but toxicity may persist. We describe treatment-free survival (TFS), with and without toxicity. Patients and Methods: Data were analyzed from the randomized phase III CheckMate 214 trial of nivolumab plus ipilimumab (n = 550) versus sunitinib (n = 546) for treatment-naïve, advanced renal cell carcinoma (aRCC). TFS was estimated by the 42-month restricted mean times defined by the area between Kaplan–Meier curves for two time-to-event endpoints defined from randomization: time to protocol therapy cessation and time to subsequent systemic therapy initiation or death. TFS was subdivided as TFS with and without toxicity by counting days with ≥1 grade ≥3 treatment-related adverse event (TRAE). Results: At 42 months since randomization, 52% of nivolumab plus ipilimumab and 39% of sunitinib intermediate/poor-risk patients were alive; 18% and 5% surviving treatment-free, respectively. Among favorable-risk patients, 70% and 73% of nivolumab plus ipilimumab and sunitinib patients were alive; 20% and 9% treatment-free. Over the 42-month period, mean TFS was over twice as long after nivolumab plus ipilimumab than sunitinib for intermediate/poor-risk (6.9 vs. 3.1 months) and three times as long for favorable-risk patients (11.0 vs. 3.7 months). Mean TFS with grade ≥3 TRAEs was a small proportion of time for both treatments (0.6 vs. 0.3 months after nivolumab plus ipilimumab vs. sunitinib for intermediate/poor-risk, and 0.9 vs. 0.3 months for favorable-risk patients). Conclusions: Patients initiating first-line nivolumab plus ipilimumab for aRCC spent more survival time treatment-free without toxicity versus those on sunitinib, regardless of risk group.

Essentials Intracranial hemorrhage (ICH) is common in patients with brain tumors. We compared rates of ICH with DOACs and low molecular weight heparin. DOACs were associated with a lower incidence of ICH in primary brain tumors. DOACs appear safe to administer to patients with brain tumors. SUMMARY: Background Direct oral anticoagulants (DOACs) are efficacious in the treatment of cancer-associated thrombosis but are associated with an increased risk of hemorrhage compared with low-molecular-weight heparin in certain malignancies. Whether the DOACs increase the incidence of intracranial hemorrhage (ICH) in patients with brain tumors is not established. Objectives To determine the cumulative incidence of ICH in DOACs compared with Low-molecular-weight heparin (LMWH) in patients with brain tumors and venous thromboembolism. Patients and methods A retrospective comparative cohort study was performed. Radiographic images for all ICH events were reviewed and the primary endpoint was cumulative incidence of ICH at 12 months following initiation of anticoagulation. Results and conclusions A total of 172 patients with brain tumors were evaluated (42 DOAC and 131 LMWH). In the primary brain tumor cohort (n = 67), the cumulative incidence of any ICH was 0% in patients receiving DOACs vs. 36.8% (95% confidence interval [CI], 22.3-51.3%) in those treated with LMWH, with a major ICH incidence of 18.2% (95% CI, 8.4-31.0). In the brain metastases cohort (n = 105), DOACs did not increase the risk of any ICH relative to enoxaparin, with an incidence of 27.8% (95% CI, 5.5-56.7%) compared with 52.9% (95% CI, 37.4-66.2%). Similarly, DOAC did not increase the incidence of major ICH in brain metastases, with a cumulative incidence 11.1% (95% CI, 0.5-40.6%) vs. 17.8% (95% CI, 10.2-27.2%). We conclude that DOACs are not associated with an increased incidence of ICH relative to LMWH in patients with brain metastases or primary brain tumors.

4544 Background: The most commonly used prognostic models in aRCC, the Memorial Sloan-Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, were developed when cytokines and VEGF targeted monotherapies were standard of care, respectively. aRCC 1L treatment now includes combination therapy with 2 ICIs or ICI+VEGF receptor inhibitor. Re-evaluation of the MSKCC and IMDC prognostic models in the era of ICI therapy and identification of additional prognostic factors are overdue. Methods: Data from 1052 patients with aRCC treated on the CheckMate-214 (CM214) clinical trial with 1L nivolumab/ipilimumab (NIVO/IPI) or sunitinib (SUN) were analyzed retrospectively at median follow-up 5 yrs. For each treatment group, multivariable Cox model hazard ratios (HR) were compared to the published MSKCC and IMDC model HRs. Discrimination (c index) was assessed based upon the continuous scores obtained as the weighted combination of regression parameters from the published MSKCC & IMDC models. Results: KPS < 80% remained highly prognostic in both treatment groups (HRs > 2.5). With the exception of high calcium, the other factors of time from dx to treatment < 1 yr, hemoglobin < lower limit of normal (LLN), neutrophils > upper limit of normal (ULN), platelets > ULN and LDH > 1.5xULN consistently retained prognostic value for SUN (HRs ≥ published model HRs) but had diminished prognostic value for NIVO/IPI (each HR < published model HR). High calcium had diminished prognostic value for SUN and retained prognostic value for NIVO/IPI. The c-indices for discrimination were 0.61 and 0.64 for the MSKCC model in the NIVO/IPI and SUN treatment groups, respectively, and were 0.63 and 0.67 for the IMDC model in the NIVO/IPI and SUN treatment groups compared to reported IMDC c-index of 0.73 (Heng 2009). (Table) Conclusions: The prognostic ability of the MSKCC and IMDC risk models is reduced with combination ICI treatment. Evaluation of additional prognostic factors and development of new risk scores are needed and this work is ongoing. [Table: see text]

2501 Background: The immunoregulatory cytokine IL-27 upregulates inhibitory immune checkpoint receptors (eg, PD-L1, TIGIT) and downregulates proinflammatory cytokines (eg, IFNγ, TNFα). SRF388 is a fully human IgG1 blocking antibody to IL-27 with potential to promote immune activation in the tumor microenvironment. A phase 1 study was conducted to establish the preliminary safety of SRF388 and to identify recommended phase 2 doses (RP2D) suitable for monotherapy and combination expansions (NCT04374877). Methods: The dose-escalation study (accelerated single patient followed by standard 3+3) enrolled patients (pts) with advanced treatment-refractory solid tumors. Upon RP2D selection, monotherapy and combination expansions opened for treatment-refractory clear cell renal cell cancer (ccRCC), hepatocellular cancer (HCC), and non-small cell lung cancer. SRF388 was administered IV every 4 weeks (wks) as monotherapy and every 3 wks with pembrolizumab. Tumor response was assessed by RECIST1.1. Results: The monotherapy dose-escalation enrolled 29 pts with doses ranging from 0.003 to 20 mg/kg. Median age was 64 years. Most pts were female (62%) with ECOG PS of 1 (72%). Approximately 80% had prior PD-(L)1 blockade, and 48% had ≥4 prior therapies. Treatment-related adverse events (TRAEs) occurred in 21%, and all were low grade. Fatigue was the only TRAE reported in ≥10% (n = 3). No dose-limiting toxicities (DLTs) or Grade ≥3 TRAEs were observed. Median time on study was 9 wks (range 0–59). One patient with highly treatment-refractory NSCLC experienced a confirmed partial response (PR) at 8 wks that was durable for 20 wks. Nine pts (31%) experienced disease stabilization at 8 wks, with 6 of 9 exhibiting durable disease control at 6 months. Of the 7 pts with ccRCC in the dose-escalation portion of the trial, 3 (43%) experienced durable disease control for ≥20 wks (range: 20-32). With doses up to 20 mg/kg, SRF388 PK remain linear with an estimated T1/2 of 10-12 days. PK characteristics and safety profile support dosing every 3 or 4 wks. Based on safety, tolerability, PK, peripheral pSTAT1 inhibition, and preliminary efficacy, 10 mg/kg was selected as the RP2D. Both the pembrolizumab safety cohort (n = 10) and Stage 1 of the ccRCC monotherapy expansion (n = 17) have fully enrolled. Of the 10 evaluable pts with ccRCC, 1 confirmed monotherapy PR has been reported, enabling Stage 2 initiation. Changes in several serum cytokines and chemokines were observed after SRF388 administration, including expected increase in circulating IL-27 levels. Conclusions: Results of IL-27 pathway blockade with a first-in-class therapeutic demonstrates that SRF388 has good tolerability with encouraging preliminary antitumor activity as a monotherapy. Updated data, including safety and clinical outcomes as well as correlative biomarker analyses, will be presented. Clinical trial information: NCT04374877.

BackgroundCD73–adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5′-nucleotidase (NT5E), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)) and A2 adenosine receptor (A2AR;ADORA2A) transcript levels with markers of angiogenesis and antitumor immune response.MethodsPatients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73negative(CS=0), CD73lowor CD73high(< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and highNT5E,ENTPD1andADORA2Agene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared betweenNT5E,ENTPD1andADORA2Aexpression groups.ResultsAmong the 138 patients eligible for inclusion, ‘any’ CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73hightumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73negativegroup (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, highNT5Eexpression was associated with significantly worse 5-year OS (p=0.008).NT5EandENTPD1expression correlated with higher regulatory T cell (Treg) signature, whileADORA2Aexpression was associated with increased Treg and angiogenesis signatures.ConclusionsHigh CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73–adenosine pathway in RCC.

Background Intracranial hemorrhage (ICH) is a common and often devastating outcome in patients with brain tumors. Despite this, there is little evidence to guide anticoagulation management following an initial ICH event. Objectives To analyze the risk of recurrent hemorrhagic and thrombotic outcomes after an initial ICH event in patients with brain tumors and prior venous thromboembolism (VTE). Patients and Methods A retrospective cohort study was performed. Radiographic images obtained after initial ICH were reviewed for the primary outcomes of recurrent ICH and VTE. Results and Conclusions A total of 79 patients with brain tumors who developed ICH on anticoagulation for VTE were analyzed. Fifty‐four patients (68.4%) restarted anticoagulation following ICH. The cumulative incidence of recurrent ICH at 1 year was 6.1% (95% confidence interval [CI], 1.5‐15.3) following reinitiation of anticoagulation. Following a major ICH (defined as an ICH >10 mL in size, causing symptoms, or requiring intervention), the rate of recurrent ICH upon reexposure to anticoagulation was 14.5% (95% CI, 2.1‐38.35), whereas the rate of recurrent ICH following smaller ICH was 2.6% (95% CI, 0.2%‐12.0%). Mortality following a recurrent ICH on anticoagulation was 67% at 30 days. The cumulative incidence of recurrent VTE was significantly lower in the restart cohort compared to patients who did not restart anticoagulation (8.1% vs 35.3%; P = .003). We conclude that resumption of anticoagulation is lowest among patients with metastatic brain tumors with small initial ICH. Following an initial major ICH, resumption of anticoagulation was associated with a high rate of recurrent ICH.

485 Background: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. Angiotensin pathway inhibitors are postulated to favorably reprogram the stroma in part by inhibition of transforming growth factor-β, a major mechanism of resistance, and have been previously reported to be associated with improved outcomes in the setting of immune checkpoint inhibitors (ICIs) for metastatic urothelial carcinoma (Jain R, Clin Genitourin Cancer 2021). In this analysis, we examined the association of angiotensin inhibitors in the setting of NAC for MIBC preceding radical cystectomy (RC). Methods: Pts with MIBC who received NAC preceding radical cystectomy were assembled from 3 institutions: Dana-Farber Cancer Institute (DFCI), Moffitt Cancer Center (MCC) and McGill University Health Center (MUHC). Pts were retrospectively assessed for the association of concurrent ACEi/angiotensin receptor blockers (ARB) use at initiation of NAC on pathologic complete response (pCR), defined as pT0N0, and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected. The Kaplan-Meier method was used to estimate OS. Logistic and Cox regression were used to explore factors potentially prognostic for pCR and OS respectively. Results: 302 MIBC pts who received NAC preceding RC were available from 3 institutions: DFCI (n = 187), MCC (n = 50) and MUHC (n = 65). Overall, 141 pts (46.7%) received Cisplatin/Gemcitabine, 130 (43.1%) received dose dense MVAC and the remaining received other regimens. The overall pCR rate was 26.2%. The 5-year OS was 62%. 63 (20.9%) pts were receiving an ACEi and 41 (13.6%) were receiving an ARB. ACEi prior to NAC approached significance for association with pCR (odds ratio = 1.71 (95% CI = 0.94-3.11) p = 0.077). Pts with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% (8/26) vs 17.7% (14/98), p = 0.056) than those not on ACEi; no difference was observed for pts with cT2N0 tumors (31.1% vs 31.3%, p = 0.99). pCR, ECOG-PS and clinical stage were significantly associated with improved OS. ARB intake was not associated with pCR or OS. Conclusions: ACEi intake appeared potentially associated with increased pCR in pts with MIBC receiving NAC, which was more pronounced in those with higher clinical stages cT3/4N0-1. Given the association of pCR with OS, our data suggest the potential relevance of angiotensin as a therapeutic target in aggressive MIBC. Future prospective validation is warranted to repurpose angiotensin inhibitors in this setting, given their excellent toxicity profile and low costs.

558 Background: The AA profile may be altered in malignancies and provide insights into tumor biology and the immune state. We hypothesized that the longitudinal AA profiling of mUC pts receiving an immune checkpoint inhibitor (ICI) may provide insights into the immune response, which may be associated with immune events and help discover new therapeutic targets. Methods: We utilized serum from mUC pts receiving an ICI or platinum-based chemotherapy (PBC) at the Dana-Farber Cancer Institute. Age and sex matched healthy controls were also studied. The SeroTag immuno-oncology discovery array (Oncimmune) was utilized, with quantification of the AA reactivity towards 1150 antigens. Bound autoantibodies were detected using an anti-IgG-specific detection antibody conjugated to the fluorescent reporter dye phycoerythrin. The AA reactivity was reported as the median fluorescence intensity (MFI) for each color and sample using a Luminex FlexMAP3D analyzer. A significance analysis of microarrays was performed to identify AAs with elevated levels in bladder cancer compared to matched healthy controls (HCs). AAs with > 1.5 increase between pre- and post-treatment were reported. Scatter and box-whisker plots were reported for all pts and antigens, respectively. Results: Pre- (n = 66) and post treatment (n = 65) serum samples were available from mUC pts receiving pembrolizumab (n = 25), atezolizumab (n = 21), nivolumab (n = 5), avelumab (n = 1), durvalumab + tremelimumab (n = 1), nivolumab plus vaccine (n = 1), and 12 pts who received PBC (cisplatin n = 8, carboplatin n = 4). The median duration between the pre- and post-therapy samples was 6 months, median age was 67.7 years (range 40-91) with 51 men (77.3%). Overall, significant heterogeneity of AAs between pts was observed with 37 AAs showing higher reactivity in pre-treatment mUC pts vs. 47 HCs, notably anti-CTAG1 (NY-ESO-1), CTAG2 (NY-ESO-2), MAGE B-18, KRAS, GRB2, RARRES2, HSP72 and FGFR3 (all p < 0.05). Pre- and post-therapy AA profiles were similar with unique changes seen in each patient. Notably, 3 pts receiving an ICI developed AAs to NY-ESO-1. Pts receiving PBC less frequently developed new AAs, although pts treated with cisplatin appeared to develop AAs more frequently compared to carboplatin-treated pts. Conclusions: This is the first report of a comprehensive AA profile using a novel platform in mUC pts. The study identified multiple elevated AAs in mUC pts vs. HCs, most notably NY-ESO-1, which also developed in some pts following ICIs. Pts treated with PBC did not develop new AAs frequently, although there appeared to be a difference between cisplatin and carboplatin-based chemotherapy. Further development of this platform is warranted to provide data that is orthogonal to genomic/transcriptomic profiling and shed insights on potential therapeutically actionable antigens.

565 Background: Metabolomic profiling of plasma from mUC pts has not been comprehensively examined. Plasma metabolomics may capture the effects of interactions between the malignancy, host and therapy. We hypothesized that Identifying metabolites in plasma from patients with mUC receiving an ICI or PBC may shed valuable insights regarding tumor biology and mechanisms of resistance. Methods: We obtained 0.2 ml plasma before and after starting therapy from pts with mUC receiving an ICI or PBC at the Dana-Farber Cancer Institute. Plasma metabolomic profiling was conducted at the Broad Institute using 3 complementary liquid chromatography tandem mass spectrometry (LC-MS)-based metabolomics platforms. We measured 648 metabolites at baseline prior to starting ICI/PBC and at a second time point in each subject following initiation of ICI/PBC. Metabolite levels were assumed to be normally distributed with log transformation to transform distributions to be approximately symmetric. We performed Wilcoxon-rank sum test to compare the levels of metabolites before and after initiation of the ICI or PBC (significance at p < 0.05). Results: Plasma was available at baseline and during therapy in 53 mUC pts (ICI: n = 43; PBC: n = 10). The median age was 68 (range: 39-86) years and 42 (82.3%) were male. The median time from baseline to the second time point was 4.7 months (range: 0.7-90.2). The ICIs administered were atezolizumab (n = 20), pembrolizumab (n = 16), nivolumab (n = 5), and durvalumab + tremelimumab (n = 1). We identified 20 metabolites that were significantly increased in post-PBC plasma samples (vs. pre-PBC) and 19 metabolites increased in post-ICI (vs. pre-ICI) samples (p < 0.05). All altered metabolites except one (Uracil) were exclusive for each treatment group. The most significant metabolites that increased following initiation of the ICI and PBC are shown in the Table. Evaluation of the association of plasma metabolomics with clinical outcomes and toxicities is ongoing. Conclusions: This is the first report, to our knowledge, of comprehensive metabolomic plasma profiling of pre- and post-ICI and PBC pts with mUC. The metabolomic changes after ICI appear distinct from those seen after PBC. Furthermore, our study sheds insights on potential mechanisms of resistance and new therapeutic targets in pts with mUC.[Table: see text]

481 Background: EV is an anti-Nectin-4 antibody-drug conjugate that has been approved by the US FDA for mUC progressing on platinum and PD1/L1 inhibitor therapy and in cisplatin-ineligible pts following prior therapy. However, prognostic and predictive biomarkers in the setting of EV therapy are unclear. We aimed to investigate baseline and early changes in commonly available clinical and laboratory tests that could help predict survival and toxicities in patients with mUC treated with EV. Methods: Data from patients with mUC who were treated with EV at Dana Farber Cancer Institute between 2017 and 2021 were reviewed retrospectively. We assessed the association of demographic (age, sex), clinical (ECOG-performance status [PS], sites of metastasis) and laboratory variables (hemoglobin, RDW, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, platelet count and serum albumin) at baseline as well as after 4-7 weeks of treatment with Overall Survival (OS) by constructing univariate and multivariable Cox proportional-hazards models. Any variables significantly associated with OS at the univariate level (using an alpha-level of 0.1 to determine statistical significance) were then entered into the multivariable model. Predictors were eliminated from the final multivariable models by a backward selection process, retaining only those with a p-value of ≤ 0.05. Results: A total of 49 patients who received EV were included in the analysis. The median age was 72 years (range 48-88) and 36 (73.5%) were male. The median OS was 13.3 months (range: 2.7-38.7) and grade 3-4 toxicities were seen in 11 pts (22.4%). In the final multivariable models, lower serum albumin at 4-7 weeks (HR = 0.18; 95% CI = 0.05-0.71; p = 0.015), and baseline ECOG-PS of 1 vs. 0 (HR = 2.56; 95% CI = 1.05-6.21; p = 0.038) were significantly associated with worse OS (Table). Patients with higher serum albumin levels at 4-7 weeks also had significantly lower odds of experiencing grade 3-4 adverse events on EV (OR = 0.05; 95% CI = 0.002-0.52; p = 0.02). Conclusions: Lower serum albumin appeared to predict worse survival and severe toxicities in mUC pts receiving EV. This information may guide therapy and assist in the prevention of toxicities. Additionally, ECOG-PS was prognostic while the location of metastatic disease was not prognostic in the setting of EV.[Table: see text]

TPS588 Background: There have been multiple advances in therapy of advanced urothelial carcinoma following platinum and ICB; SG and EV are both FDA approved in this space though durations of response are short and overall survival limited at < 13 months. Given different mechanisms of action, non-overlapping toxicities and potential for synergy, EV and SG is hypothesized to have manageable toxicities and demonstrate additive anti-tumor activity. Methods: NCT04724018 is a single-center (Dana-Farber/Harvard Cancer Center), open-label, non-randomized phase I trial using a Bayesian Optimal Interval design. SG and EV agents are administered intravenously (IV) on days 1 and 8 every 3 weeks (1 cycle) until progression or intolerable toxicities. Laboratory evaluation is performed on days 1 and 8 every cycle with additional blood collected throughout treatment for pharmacokinetic and antidrug antibody studies. Imaging is performed at baseline and every 6 weeks for the first 4 cycles followed by every 9 weeks thereafter. Up to 4 dose levels of the combination of SG and EV are studied with a starting dose of SG of 8 mg/kg and EV of 1 mg/kg (dose level 1) with additional dose escalations outlined in table. Dose de-escalation of SG to 6 mg/kg with the starting dose of EV 1 mg/kg (dose level -1) is permitted. A total of 3 to 18 patients are expected to be enrolled in current dose level depending on dose limiting toxicities (DLTs). DLT is assessed during cycle 1 of therapy and toxicities are captured up to 4 weeks after the last dose of therapy and being defined by ≥1 of the following: neutropenic fever, thrombocytopenic bleeding, grade 3 neuropathy, of any duration and any other grade ≥3 non-hematologic toxicity to include hyperglycemia (except alopecia) lasting >1 week or requiring >3 weeks interruption of therapy or dose reduction. The first patient per 3-patient cohort is required to complete 1 full cycle (3 weeks) before additional patients can be enrolled in that cohort. Therefore, up to 24 patients may be accrued. Trial continues to enroll at dose level one. Clinical trial information: NCT04724018. [Table: see text]

To compare healthcare resource utilization (HRU) and costs associated with dose-dense methotrexate, vinblastine, doxorubicin, cisplatin (ddMVAC) and gemcitabine, cisplatin (GC) as neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC).Patient treated at Dana-Farber Cancer Institute from 2010 to 2019 were identified. HRU data on chemotherapy administered, supportive medications, patient monitoring, clinic, infusion, emergency department (ED) visits and hospitalization were collected retrospectively. Unit costs for HRU components were obtained from the Centers for Medicare and Medicaid Website and HRU was compared between groups using quantile regression analysis.137 patients were included; 51 received ddMVAC and 86 GC. Baseline characteristics were similar, except lower mean age (P0.001) and higher proportion of ECOG-PS = 0 (P0.001) for ddMVAC. ddMVAC required more granulocyte-colony stimulating factor support (P0.001), central line placement (P = 0.017), cardiac imaging (P0.001), and infusion visits (P0.001), whereas GC required more clinic visits. ED visits were higher for ddMVAC (P = 0.048), while chemotherapy cycle delays and hospitalization days were higher for GC (P = 0.008). After adjusting for ECOG-PS and age, the cost per patient was approximately 41% lower (95%CI: 28% to 52%; P0.001) for GC vs. ddMVAC, which translated to a median adjusted cost savings of $7,410 (95%CI: $5,474-$9,347) per patient.Although excess HRU did not clearly favor one regimen, adjusting for PS and age indicated lower costs with GC vs. ddMVAC. Given the similar cumulative cisplatin delivery with both regimens, the associated values and costs supports the preferential selection of GC in the neoadjuvant setting of MIBC.

BackgroundTreatment-free survival (TFS) characterizes disease control after discontinuation of immune checkpoint inhibitors (ICIs) until subsequent therapy or death. We previously evaluated TFS in a pooled analysis of the CheckMate 067 and CheckMate 069 trials of the ICIs nivolumab and ipilimumab, alone or in combination, in patients with advanced melanoma after minimum follow-up of 36 months. This analysis investigated TFS differences between treatments in CheckMate 067 after a minimum follow-up of 60 months, and their relation to overall survival (OS) differences.MethodsData were from 937 patients who initiated treatment (nivolumab plus ipilimumab, nivolumab, or ipilimumab) in CheckMate 067 (NCT01844505). TFS was defined as the area between the Kaplan-Meier curves for time to protocol therapy cessation and time to subsequent systemic therapy initiation or death, each measured from randomization. TFS was partitioned as time with and without toxicity. Toxicity included persistent and late-onset grade ≥2 select treatment-related adverse events (ie, those of potential immunologic etiology). The area between Kaplan-Meier curves was estimated by the difference in 60-month restricted-mean times of the endpoints. Between-group differences were estimated with bootstrapped 95% CIs.ResultsAt 60 months from randomization, 39%, 24%, and 11% of patients assigned to treatment with nivolumab plus ipilimumab, nivolumab, and ipilimumab, respectively, had survived and were treatment-free. The 60-month mean TFS was approximately twice as long with the combination (19.7 months) than with nivolumab (9.9 months; absolute difference, 9.8 (95% CI 6.7 to 12.8)) or ipilimumab (11.9 months; absolute difference, 7.8 (95% CI 4.6 to 11.0)). In the respective groups, mean TFS represented 33% (8% with and 25% without toxicity), 17% (2% and 14%), and 20% (3% and 17%) of the 60-month period. Compared with 36-month estimates, mean TFS over the 60-month period represented slightly greater percentages of time in the nivolumab-containing regimen groups and a lesser percentage in the ipilimumab group. TFS differences between the combination and either monotherapy increased with longer follow-up.ConclusionsAlong with improved long-term OS with the nivolumab-containing regimens versus ipilimumab, TFS without toxicity was sustained with nivolumab plus ipilimumab versus either monotherapy, demonstrating larger between-group differences with extended follow-up.

Introduction Nous avons precedemment defini une nouvelle mesure de resultat, la SST (ou TFS en anglais pour Treatment Free Survival) qui designe le delai ecoule entre l’arret des CPI et l’instauration d’un traitement ulterieur ou le deces. La SST fait partie d’une analyse integree permettant de decrire de facon complete comment les pts passent le temps de survie globale (SG), sous et sans traitement, avec/sans toxicite liee au traitement. Nous avons rapporte des donnees de survie, y compris la SST, chez les pts traites par CPI atteints d’un MEL dans l’essai de phase 3 CheckMate 067 ( NCT01844505 ) durant la periode de 36 mois apres la randomisation (Regan. J Clin Oncol.2019) ; Les resultats a 60 mois sont presentes ici. Materiel et methodes Les donnees ont ete analysees chez 937 pts atteint d’un MEL qui ont debute un traitement avec nivolumab (NIVO) plus ipilimumab (IPI), NIVO, ou IPI dans la CheckMate 067. La SST a ete definie comme la zone situee entre les courbes de Kaplan–Meier (KM) pour 2 criteres d’evaluation conventionnels definis a partir de la randomisation : le delai jusqu’a l’arret du traitement de l’etude et le delai jusqu’au traitement ulterieur ou le deces. La SST a egalement ete divisee en SST avec ou sans evenements indesirables lies au traitement (EILT) de grade ≥ 3 et la SG a ete estimee. L’aire sous chaque courbe de KM a ete estimee par le delai moyen restreint a 60 mois jusqu’a l’evenement restreint a 60 mois et exprimee comme un pourcentage de la periode de 60 mois. Des intervalles de confiance a 95 % ont ete calcules pour les differences. Resultats Sur la periode de 60 mois, les pts ont passe en moyenne 33 %, 17 % et 20 % du temps sans traitement apres avoir recu NIVO + IPI, NIVO, et IPI, respectivement (SST moyenne restreinte a 60 mois : 19,7, 9,9 et 11,9 mo). La SST moyenne restreinte a 60 mois des pts traites par NIVO + IPI etait superieure a celle des pts traites par NIVO de 9,8 mois (IC a 95 %, 6,7–12,8) et superieure a celle des pts traites par IPI de 7,8 mois (IC a 95 %, 4,6–11,0). La SST moyenne avec des EILT de grade ≥ 3 correspondait a une faible proportion de la periode de 60 mois : 3 %, 2 % et Discussion Avec un suivi prolonge, la SST moyenne avec ou sans toxicite correspondait a des proportions plus elevees de la periode de 60 mois vs 3 mois pour NIVO + IPI, et NIVO, mais pas pour IPI. Les pts traites avec NIVO + IPI ont continue a avoir une SST deux fois plus longue que celle des patients traites par NIVO seul, en raison de l’arret precoce du traitement pour toxicite sans progression de la maladie et avec une resolution ulterieure d’un grand nombre de ces toxicites. La majeure partie du temps de SST a ete passee sans EILT de grade ≥ 3 dans tous les bras.

Venous thromboembolism is commonly diagnosed in patients with primary and secondary brain tumors. Anticoagulation management in the setting of brain tumors is complicated by the high background rate of spontaneous intracranial hemorrhage. Until recently, there was limited evidence to support the decision to administer therapeutic anticoagulation in the setting of brain metastases or primary brain tumors. The current evidence suggests that the safety profile of therapeutic low molecular weight heparin for the treatment of venous thromboembolism is contingent on whether the origin of brain tumor is primary (i.e., glioma) versus secondary. In patients with brain metastases, the rate of intracranial hemorrhage often exceeds 20% but is not influenced by the administration of low molecular weight heparin. In contrast, in primary brain tumors such as glioma, therapeutic anticoagulation is associated with an increased risk of intracranial hemorrhage that can negatively impact survival. This chapter reviews the underlying mechanisms contributing to thrombosis and hemorrhage in brain tumors and summarizes the current evidence and approaches in anticoagulation to treat venous thromboembolism.

Venous thromboembolism is commonly diagnosed in patients with primary and secondary brain tumors. Anticoagulation management in the setting of brain tumors is complicated by the high background rate of spontaneous intracranial hemorrhage. Until recently, there was limited evidence to support the decision to administer therapeutic anticoagulation in the setting of brain metastases or primary brain tumors. The current evidence suggests that the safety profile of therapeutic low molecular weight heparin for the treatment of venous thromboembolism is contingent on whether the origin of brain tumor is primary (i.e., glioma) versus secondary. In patients with brain metastases, the rate of intracranial hemorrhage often exceeds 20% but is not influenced by the administration of low molecular weight heparin. In contrast, in primary brain tumors such as glioma, therapeutic anticoagulation is associated with an increased risk of intracranial hemorrhage that can negatively impact survival. This chapter reviews the underlying mechanisms contributing to thrombosis and hemorrhage in brain tumors and summarizes the current evidence and approaches in anticoagulation to treat venous thromboembolism.

2551 Background: IL-27 is an immunosuppressive cytokine, consisting of two subunits p28 and EBI3, that upregulates immune checkpoint receptors (eg, PD-L1, TIGIT) and downregulates proinflammatory cytokines such as IFNγ, TNFα, and IL-17. SRF388 is a first-in-class, fully human IgG1 antibody to IL-27 that blocks the interaction between IL-27 and its receptor, thereby promoting immune activation in the tumor microenvironment. The IL-27 pathway is activated in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), and high circulating levels of EBI3 are associated with inferior outcomes in both. Circulating EBI3 levels may serve as a predictive biomarker of SRF388 activity. Methods: Patients with advanced solid tumors refractory to standard therapy were enrolled in a phase 1 dose-escalation study (accelerated single patient followed by standard 3+3) to establish the preliminary safety of SRF388 as a monotherapy and to identify a dose suitable for expansion (NCT04374877). SRF388 was administered intravenously every 4 weeks. Tumor response was assessed by RECIST v1.1. SRF388 pharmacokinetic (PK) and pharmacodynamic (PD) [phospho-STAT (pSTAT) inhibition] analyses were performed. Results: As of January 26, 2021, 12 patients have received SRF388 at doses ranging from 0.003 to 10 mg/kg with 2 patients undergoing intra-patient dose escalation. Median age was 68 years, 67% were female, and ECOG PS was 0/1 (42%/58%). Median number of prior therapies was 2 (range 1–9), and 75% were anti-PD-(L)1 experienced (n = 9). The only treatment-related adverse events observed across dose levels were low-grade fatigue (n = 1, 8%), nausea (n = 1, 8%) and excess salivation (n = 1, 8%). No dose-limiting toxicities (DLTs) or ≥ Grade 3 related toxicity have occurred. Mean time on study is 12.5 weeks (range 4–40). One patient with RCC who received prior anti-PD-1 has prolonged stable disease for > 9 months. SRF388 PK are linear with estimated T1/2 ranging from 6–19 days. There is evidence of accumulation and no anti-drug antibody development to date. Maximal inhibition of the IL-27 signaling pathway as measured by > 90% pSTAT inhibition in whole blood was achieved starting at 0.3 mg/kg. Given combined evidence of near-complete pathway inhibition and preclinical human equivalent dose modeling projecting biologically active doses, additional slots were opened for RCC and HCC starting at 1 mg/kg. Conclusions: Preliminary results of IL-27 pathway blockade with a first-in-class therapeutic demonstrates that SRF388 is well tolerated at doses that achieve maximal inhibition of downstream pSTAT signaling through the dosing period. Expansions are planned in HCC and RCC. Updated data including the recommended phase 2 dose, clinical outcomes, PK/PD and correlative analyses will be presented. Clinical trial information: NCT04374877.

472 Background: Enfortumab Vedotin (EV), an antibody-drug conjugate that targets nectin-4, is approved for metastatic urothelial carcinoma (mUC) progressing post-platinum and PD1/L1 inhibitor therapy. Erdafitinib is approved in patients for post-platinum mUC with activating genomic alterations in FGFR2/3, but the activity of EV in this subset is unclear. We investigated the activity of EV in patients (pts) with mUC based on FGFR2/3 genotype to inform management. Methods: In this multi-center, retrospective analysis, we assessed the objective response rate (ORR) to EV in mUC pts with and without FGFR2/3 genomic alterations detected by targeted panel next-generation sequencing. Activating gene fusions and known hotspots mutations in the two genes were considered. Descriptive analysis of ORR and patient characteristics was performed. Fisher’s exact test and binomial test with two-tailed p-value were used. Results: 40 pts were available from 4 institutions. Most pts were male (31/40, 78%) and the median age at start of EV was 74.1 (range 49 – 90) years. Ten patients (25%) had upper tract urothelial carcinoma (UTUC), and 33 (82%) had baseline ECOG performance status of 0-1. 31 of 39 patients had received both platinum-based chemotherapy and PD1/L1 inhibitors. Seven patients had confirmed activating hotspot FGFR3 mutations (p.S249C or p.Y373C). One pt had FGFR2 high-level amplification (HA), and one had FGFR3 HA. Of 36 patients evaluable for ORR, 18 had partial response (PR), 12 had stable disease (SD) and 6 had progressive disease (PD). Patients with FGFR2/3 activating mutations exhibited an ORR that was not statistically different compared to patients without no mutations: 2/7 (29%; 90% CI: 5 – 66%) vs. 16/29 (55%; 90% CI: 38 – 71%) respectively ( p-value = 0.4). 3/7 patients with FGFR3 hotspot mutations received an FGFR2/3 inhibitor and none responded; one of them had a sequential response to EV. Conclusions: In this multi-center retrospective cohort, FGFR2/3 activating genomic alterations did not appear to compromise response to EV in mUC. Larger studies are required to confirm our findings and optimal sequencing of EV and erdafitinib in mUC pts with FGFR2/3 genomic alterations requires further assessment.

489 Background: Immune checkpoint inhibition (ICI) has greatly improved clinical outcomes for pts with mUC and other cancers. ICI is associated with a class of AEs, deemed irAEs due to immune activation. Nonetheless, biomarkers associated with irAE are still lacking. We hypothesized that the immune response against neoantigens is partly responsible for irAEs and investigated the association between irAEs, TMB and response to ICI. Methods: We identified patients with mUC at Dana Farber Cancer Institute who were treated with ICI (monotherapy or combination) and had available tumor sequencing data through Oncopanel. TMB was calculated using the number of non-synonymous exonic mutations per megabase. The severity of irAEs was graded using CTCAE v.5.0. Mann-Whitney U test was performed to identify association between TMB, incidence and grade of irAEs. A cut-off of 10/mb was assigned for TMB. Fisher’s exact test was used to evaluate the radiologic response between pts with and without irAEs and low vs. high TMB. Multivariable linear regression was used to assess the relationship between TMB, irAEs and response. p-values were adjusted using Benjamini-Hochberg method. Results: Of 101 pts with mUC who met the inclusion criteria, 32 (32%) reported irAEs. 6 (6%) were grade (G)1, 20 (20%) were G2, and 6 (6%) were G3. Median(m) time on therapy was 84 days for pts without irAEs and 88 days for pts with irAEs. Pts with irAEs had higher mTMB (15.4/mb) compared to pts with no irAEs (9.8) ( p = 0.01). In pts on monotherapy (93), those with irAEs (n=27) had a higher mTMB (15.13/mb) compared to pts with no irAEs (n=66) (mTMB = 10.20/mb) ( p = 0.01). Out of 94 pts with radiological data, response was achieved in 16 (50%) pts with irAE vs 10 (16%) pts with no irAE ( p < 0.001). When both irAE and response were included in a multivariable regression, the association between irAE and TMB was not significant ( p = 0.4). Pts with both irAE and high TMB had a response rate of 56% which was significantly higher than those with either irAE but low TMB (28.6%) or high TMB but no irAE (21.2 %) or low TMB and no irAE (10.3%) (Chi-square test p = 0.002; FDR corrected p-values for individual comparisons in Table). There was no association between TMB and irAE grade. Conclusions: Higher TMB was associated with higher incidence of irAEs in pts with mUC on ICIs. Moreover, pts with both high TMB and irAEs exhibited better response rates than those with only high TMB or irAEs, suggesting that they may provide complementary tumor and host characteristics. Further evaluation in mUC is needed to confirm this relationship between TMB, irAEs and response in a larger cohort and explore specific mutational signatures that may be associated with irAEs. [Table: see text]

467 Background: The genetics of urothelial carcinoma (UC), the most common histology of urinary tract (UT) tumors, is well characterized; much less is known about the genomic features of rare histologic variants of UT tumors. We aim to compare the genomic alterations (GA) of UT tumors with adenocarcinoma (AD), small cell (SC), squamous cell (SQ), or plasmacytoid (PC) histologies, to UC tumors. Methods: We identified patients with pure variant (AD, SC, SQ, PC) or UC histology with genetic characterization through the GENIE registry. Patient tumor genomic data were captured by Memorial Sloan Kettering Cancer Center (MSK)-IMPACT and Dana-Farber Cancer Institute (DFCI)-Oncopanel NGS initiatives. Tumors with mixed histology were excluded. We limited our analysis to genes tested >1000 times (N=211). Mutation frequencies and copy number variants (CNVs), collectively called GAs, were determined for AD, SC, SQ, PC, and UC, and were compared using the Fisher’s Exact test and Kruskall Wallis test. Nominal p values were obtained, and FDR correction was employed (q < 0.1). Results: We identified 1199 patients with available genomic data who met the inclusion criteria. Histologic distribution was: 32 AD, 13 SC, 15 SQ, 11 PC, and 1128 UC tumors. The median age was 68 years and 77% of patients were male. Statistically significant differences in genetic alterations by subtype are shown in the table below. ARID1A and KDM6A GAs were higher in UC; PC and SC; CDH1 GAs higher in PC; RB1 and TP53 GAs higher in SC; SMAD4 GAs higher in AD; and NFE2L2 GAs higher in SQ. Conclusions: Variant UT histologies exhibit a distinct pattern of alterations compared to UC, consistent with their divergent clinical behavior. This suggests different biological origins for these variant histologies and possibly different therapeutic vulnerabilities. Exploring the GAs of these UT tumors in larger datasets is warranted. [Table: see text]

432 Background: The renin-angiotensin system (RAS) is involved in regulation of angiogenesis, cell proliferation, desmoplasia and immunosuppression. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) may have antitumor effects partly by inhibiting transforming growth factor (TGF)-β, a major resistance mechanism in bladder cancer. Methods: Patients (pts) with muscle invasive bladder cancer (MIBC) treated or not treated with ACEi/ARB while receiving preceding radical cystectomy (RC) were assessed for pathologic complete response (pCR) defined as pT0N0 and overall survival (OS). Pathologic features, performance status, clinical stage, type and number of cycles of NAC, and presence of grade ≥3 toxicities were collected retrospectively. The Kaplan-Meier method was used to estimate overall survival (OS). Logistic and Cox regression was used to explore factors potentially prognostic for pCR and OS respectively. Results: 187 patients received NAC followed by RC. The mean age at the time of NAC was 65. 71% were male and 29% were female. Of the 187 patients, 61% received Cisplatin/Gemcitabine and 28.3% received dose dense MVAC. Of patients receiving NAC, 53 (28%) had a pCR. The 5-year OS was 64%. There were 41 (21.9%) patients taking an ACEi and 24 (12.8%) patients taking an ARB at the start of NAC. Of the 41 patients who took an ACEi, 17 (41.5%) had a pCR; of the 146 patients who did not take an ACEi, 36 (24.7%) had a pCR. ACEi intake during NAC was the only factor associated with pCR on multivariable analysis (odds ratio of 2.17 [95% CI 1.05-4.48] p = 0.037). pCR was the only factor shown to be associated with significantly improved OS (Hazard Ratio 0.18 [95% CI 0.07-0.45] p = < 0.001). After adjusting for pCR, ACEi was not significantly prognostic of OS (HR = 1.12, 95% CI = 0.60 to 2.09, p = 0.72). ARB intake while receiving NAC was not associated with pCR or OS. Conclusions: ACEi intake was associated with significantly increased pCR in patients with MIBC receiving NAC, and pCR was the only significant factor associated with OS. We hypothesize that ACEi may augment the activity of NAC and increase pCR, which translates to improved OS. ACEi intake was not associated with improvement in OS potentially due to competing causes of mortality in patients requiring ACEi. Our data requires validation.

10043 Background: We previously defined a novel outcome, TFS, to characterize the time between ICI therapy cessation and subsequent therapy initiation/death. TFS is part of an integrated analysis to comprehensively describe how pts spend overall survival (OS) time, on and off treatment, with/without treatment-related toxicity. We reported survival states, including TFS, in ICI-treated pts with MEL in the phase 3 CheckMate 067 trial (NCT01844505) over the 36-mo period since randomization (Regan. J Clin Oncol. 2019); 60-mo results are presented here. Methods: Data were analyzed for 937 pts with MEL who started treatment with nivolumab (NIVO) plus ipilimumab (IPI), NIVO, or IPI in CheckMate 067. TFS was defined as the area between the Kaplan–Meier (KM) curves for 2 conventional time-to-event endpoints defined from randomization: time to protocol therapy cessation and time to subsequent therapy/death. TFS was also divided into TFS with/without grade ≥3 treatment-related adverse events (TRAEs), and OS was estimated. The area under each KM curve was estimated by the 60-mo restricted mean (r-mean) time to event and expressed as a percentage of the 60-mo period. Bootstrapped 95% CIs were calculated for differences. Results: Over the 60-mo period, pts spent an average of 33%, 17%, and 20% of time free of treatment after receiving NIVO+IPI, NIVO, and IPI, respectively (r-mean TFS, 19.7, 9.9, and 11.9 mo; Table). NIVO+IPI-treated pts had r-mean TFS that was 9.8 mo longer than NIVO-treated pts (95% CI, 6.7–12.8) and 7.8 mo longer than IPI-treated pts (95% CI, 4.6–11.0). Mean TFS with grade ≥3 TRAEs remained a small proportion of the 60-mo period at 3%, 2%, and < 1% with NIVO+IPI, NIVO, and IPI, respectively. Conclusions: With extended follow-up, average TFS with/without toxicity represented greater percentages of the 60-mo vs 36-mo period for NIVO+IPI and NIVO, but not for IPI. Pts treated with NIVO+IPI continued to have TFS twice as long as those treated with NIVO alone, due to earlier therapy cessation for toxicity without disease progression and subsequent resolution of many of those toxicities. The majority of TFS time was spent without grade ≥3 TRAEs across all arms. [Table: see text]

Background Conventional measures such as median progression-free survival may suboptimally characterize the full impact of immuno-oncology (I-O) agents vs other systemic anticancer therapies. Patients discontinuing I-O agents may experience periods of disease control without needing subsequent systemic anticancer therapy (Rx) but may still experience toxicity (TOX). Treatment-free survival (TFS) ± TOX can simultaneously characterize disease control and TOX for this off-treatment period. Methods Data were analyzed from all 1082 patients initiating Rx on the randomized phase 3 CheckMate 214 trial of nivolumab + ipilimumab (NIVO+IPI) vs sunitinib (SUN) for treatment-naive predominantly clear cell advanced renal cell carcinoma. TFS is defined as the area between Kaplan–Meier (KM) curves for 2 conventional time-to-event endpoints defined from randomization: time to protocol Rx cessation and time to subsequent Rx or death. TFS was subdivided as TFS with and without TOX by defining a third endpoint: time to cessation of Rx and TOX. TOX was defined as grade ≥3 Rx-related adverse events. Area under each KM curve was estimated by the 36-month restricted mean time to event. Results At 36 months, 60% of NIVO+IPI and 51% of SUN patients were alive, 15% NIVO+IPI and 9% SUN remained on original Rx, and 34% NIVO+IPI and 19% SUN patients were surviving free of subsequent Rx. The 36-month restricted mean TFS was 6.7 and 2.9 months for all NIVO+IPI and SUN patients, respectively (6.4 vs 2.8 months TFS without TOX). The table shows time by TFS subdivision and IMDC risk. Table . 971P IMDC risk group All Favorable Intermediate/Poor N = 547 N = 535 N = 124 N = 119 N = 423 N = 416 Restricted mean time NIVO+IPI SUN Difference NIVO+IPI SUN Difference NIVO+IPI SUN Difference OS, months 28.0 25.6 32.0 32.9 26.9 23.5 Time on protocol Rx, months 13.4 12.7 13.5 20.1 13.4 10.6 TFS, months (95% CI) 6.7 2.9 3.8 (2.4–5.3) 9.8 2.7 7.2 (4.4–10.0) 5.8 3.0 2.8 (1.7–4.0) TFS with TOX 0.4 0.1 0.2 (0.05–0.4) 0.5 0.1 0.4 (0.2–0.6) 0.3 0.2 –0.1 (–0.03–0.3) TFS without TOX 6.4 2.8 3.6 (2.3–5.0) 9.4 2.6 6.8 (4.1–9.5) 5.5 2.8 2.7 (1.6–3.8) Survival after subsequent Rx initiation, months 7.9 10.0 8.7 10.2 7.7 10.0 IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; OS, overall survival. Conclusions NIVO+IPI provides longer survival and delayed time to subsequent Rx vs SUN. More importantly, NIVO+IPI provides longer TFS without TOX, during which patients do not require Rx and are free from TOX. Given the durability of I-O responses relative to SUN after Rx cessation, it will be of interest to measure TFS over time. Clinical trial identification NCT02231749. Editorial acknowledgement Nicolette Belletier, PhD, and Lawrence Hargett of Parexel. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb and ONO Pharmaceutical Company Limited. Disclosure M.M. Regan: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): IPSEN; Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution): Veridex; Research grant / Funding (institution): OncoGenex; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ferring; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pierre Fabre; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Millennium Pharmaceuticals; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Sotio; Research grant / Funding (institution): Dendreon; Research grant / Funding (institution): Medivation. M.B. Atkins: Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: Genentech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: X4 Pharma; Advisory / Consultancy: Merck; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Acceleron; Advisory / Consultancy: Eisai; Advisory / Consultancy: Glactone Pharma; Advisory / Consultancy: Agenus; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Aduro Biotech; Advisory / Consultancy: Newlink Genetics/Pharmatech; Advisory / Consultancy: Arrowhead Pharmaceuticals; Advisory / Consultancy: Werewolf Pharma; Advisory / Consultancy: Oncolys BioPharma; Advisory / Consultancy: Surface; Advisory / Consultancy: Iovance Biotherapeutics. T. Powles: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self): Merck; Honoraria (self): BMS; Honoraria (self): Pfizer; Honoraria (self): IPSEN; Honoraria (self): Novartis; Honoraria (self): Exelixis. S. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS. J.L. Johansen: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS. S. Rao: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS. K.M. Gooden: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS. D.F. McDermott: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: X4 Pharma; Advisory / Consultancy: Array Biophrama; Advisory / Consultancy, Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Jounce Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Alkermes; Advisory / Consultancy: Lilly; Full / Part-time employment: BIDMC; Research grant / Funding (institution): Promethus Laboratories. All other authors have declared no conflicts of interest.

Introduction Both venous thromboembolism (VTE) and intracranial hemorrhage (ICH) are common potentially life-threatening complications of primary and metastatic brain tumors. Despite emerging evidence regarding the safety of anticoagulation in patients with brain tumors, there is little evidence on appropriate management of VTE following an ICH. Potential management options after an ICH in patients with brain tumors include resumption of full or modified dose anticoagulation or cessation of anticoagulant therapy with or without placement of an inferior vena cava (IVC) filter. We evaluated rates of recurrent VTE and ICH following an initial ICH occurring on anticoagulant therapy. Methods A retrospective cohort study was performed using a hospital-based online medical record database (CQ2) which links ICD-9 and ICD-10 codes with prescription medication records. Cases were identified based on coding for primary brain tumors or brain metastases, after which charts were manually reviewed for a diagnosis of ICH. A blinded review of radiographic imaging was performed, and the initial ICH was categorized as either trace, measurable, or major. Measurable intracranial hemorrhages were those defined as greater than 1 mL in volume and major intracranial hemorrhages were defined as greater than 10 mL in volume, symptomatic, or requiring surgical intervention. The electronic medical record was reviewed to ascertain longitudinal anticoagulation status after the initial ICH. The primary endpoints of the study were recurrent ICH and venous thromboembolism (VTE) within 12 months from the initial ICH. Gray's test was used to compare the cumulative incidence of recurrent ICH and VTE between the groups, with death as a competing risk. Results A total of 79 patients with primary brain tumors or brain metastases and confirmed ICH were included in the study. Fifty-four patients (68.4%) restarted anticoagulation after ICH and 25 patients discontinued anticoagulation entirely. The cohorts were well-matched for tumor diagnosis, age, and comorbidities that portend an increased risk of ICH such as hypertension, chronic kidney disease, and concomitant aspirin use (Table 1). The cumulative incidence of recurrent ICH (95% CI) at one year was 6.1% (1.5 - 15.3) in the restart cohort compared to 4.2% (0.3 - 18.3) in patients who did not restart anticoagulation. Median time from anticoagulation restart to recurrent ICH was 36 days. A total of 16 of 31 patients with major ICH restarted anticoagulation and among these patients two developed subsequent ICH (cumulative incidence 14.5%, 95% CI 2.1 - 38.3). Among the 15 patients with a major ICH who did not restart anticoagulation, the cumulative incidence was 6.7% (0.3 - 27.5). Eleven of 15 patients with measurable ICH restarted anticoagulation and among these patients one subsequently developed ICH (cumulative incidence 0.1%, 95% CI 0.0 - 0.3). No recurrent ICH events were observed in 33 patients with trace initial hemorrhages regardless of restart status. All recurrent ICH events met criteria for classification as a major hemorrhage on the basis of clinical symptoms, and 30-day mortality after recurrent ICH was 100%. The cumulative incidence of recurrent VTE was significantly lower in the restart cohort compared to cohort of patients who did not restart anticoagulation (8.1 vs. 35.3, P=0.003, Figure 1). There were a total of five VTE events in the restart cohort, three deep vein thrombi (DVT) and two pulmonary emboli (PE). Two of the DVT were associated with an IVC filter. There were a total of nine VTE events in patients who did not restart anticoagulation, seven DVT and two PE. Five of the DVT were associated with an IVC filter. The two PE were both submassive events requiring ICU admission. Conclusions Recurrent VTE events are less frequent and less severe in patients who restart anticoagulation following ICH in patients with brain tumors on anticoagulation. Restarting anticoagulation after smaller ICH (trace or measurable) appears safe. However, approximately 1 in 7 patients with major initial ICH who restarted anticoagulation subsequently developed recurrent major ICH that was associated with a very high mortality rate. This raises serious questions as to the safety of restarting therapeutic anticoagulation following major hemorrhage in the setting of brain tumors. Disclosures Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Zwicker:Quercegen: Research Funding; Daiichi: Consultancy; Seattle Genetics: Consultancy; Parexel: Consultancy; Incyte: Research Funding; Bayer: Consultancy; Portola: Consultancy.

9550 Background: Many pts treated with ICIs can discontinue treatment and experience ongoing disease control and toxicity. We previously proposed a novel outcome, TFS, as the time between ICI therapy cessation and subsequent therapy initiation or death, with integrated graphical analysis to better characterize the unique effects of ICIs (ASCO 2018 #9531). In the CheckMate 067 and 069 trials of ipilimumab (IPI) and nivolumab (NIVO) alone or in combination (NIVO+IPI) in pts with MEL, the 36-month restricted mean TFS was 8.7, 4.6 and 11.1 mo, respectively. We explored the sensitivity of TFS to be informative of overall survival (OS) differences through subgroup analysis. Methods: Data from MEL pts in the CheckMate 067 and 069 trials were pooled and analyzed. TFS was defined as the area between the Kaplan-Meier curves for two endpoints, from randomization: (A) time to ICI therapy cessation; and (B) time to subsequent therapy initiation or death. TFS was estimated by restricted mean survival time until 36 mo since randomization. Differences in restricted mean TFS between subgroups of pts (such as PD-L1 status, lactate dehydrogenase [LDH], performance status [PS], gender) were calculated with bootstrapped 95% CIs. OS from randomization was also estimated. Results: Among 407 pts treated with NIVO+IPI, restricted mean TFS ranged from 8-13 mo across subgroups (Table). Subgroup differences in mean TFS were larger for prognostic factors LDH and PS and smaller in non-prognostic PD-L1 status and gender subgroups. Conclusions: Clinically meaningful TFS was seen across all subgroups. TFS was sensitive to prognostic subgroup differences. These results provide further support for TFS as a relevant clinical endpoint. Additional subgroups and comparisons with single agent NIVO and IPI arms will be presented at the meeting. [Table: see text]

4582 Background: CD73 or ecto-5'-nucleotidase mediates the de-phosphorylation of adenosine monophosphate to adenosine which promotes immunosuppression in the tumor microenvironment. Its prognostic significance in localized RCC has not been well characterized. Methods: We assessed CD73 protein expression using immunohistochemistry (Cell Signaling Technology, D7F9A, 1:25) on tissue microarrays (TMAs) containing tumor tissue from patients with pT1-4,N0-1, M0 RCC who underwent nephrectomy.CD73 expression was quantified using a combined score (CS: intensity x percentage of cells staining positive). CD73 positivity was defined as any CD73 expression on tumor cells (CS > 0). Patients were categorized into CD73 negative (CS = 0), low ( < median CS) and high (≥ median CS) groups. Clinical data was collected retrospectively.Baseline patient characteristics were compared between CD73 negative and positive (high + low) groups using the Cochran-Armitage trend test. Multivariable Cox regression evaluated associations of CD73 expression with disease-free and overall survival (DFS, OS) after adjusting for other baseline prognostic variables. Results: Of the 112 patients included, clear cell was the most common histology (70%) followed by chromophobe (12.5%), and papillary (12%) RCC. CD73 expression (CS > 0) was noted in 22% (n = 25) of tumors and was associated with more advanced stage (T3-4/N+: 37.5% vs. 25%; p = 0.02) and a trend towards higher nuclear grade (≥3: 48% vs. 35%; p = 0.07). Median follow-up from nephrectomy was 9.7 yrs. In multivariable analysis adjusting for nuclear grade ( < 3 vs. ≥3) and stage (T1-2, N0 vs. T3-4/N+), tumors with high CD73 expression had significantly worse DFS and OS (Table). Conclusions: CD73 expression was found in 22% of RCC patients and was associated with adverse pathologic features and poor prognosis independent of tumor stage and histologic grade. Our results provide strong rationale for further investigation of the CD73/adenosine pathway as a therapeutic target in RCC. [Table: see text]

Introduction Venous thromboembolism (VTE) is a common complication of cancer. Patients with primary brain tumors and brain metastases are at particularly high risk, with about 20-30% suffering a VTE event. The administration of enoxaparin appears to be safe in patients with brain metastases but confers an increased risk of intracranial hemorrhage (ICH) in patients with primary brain tumors. Direct-acting oral anticoagulants (DOACs) have demonstrated efficacy in the treatment of cancer-associated thrombosis with an increased risk of hemorrhage compared to low molecular weight heparin (LMWH). There are limited data on the safety of DOACs in patients with brain tumors. As the risk of ICH associated with parenteral anticoagulants differs for primary versus secondary brain tumors, we analyzed ICH outcomes for patients with VTE receiving enoxaparin or a DOAC. Methods A retrospective cohort study was performed using a hospital-based online medical record database (CQ2) linking ICD-9 and ICD-10 codes with prescription medication records. Cases were identified based on coding for primary brain tumors or brain metastases and prescription of either a DOAC or enoxaparin. A blinded review of radiographic imaging was performed, and intracranial hemorrhages were categorized as either trace, measurable, and major. Measurable intracranial hemorrhages were those defined as greater than 1 mL in volume and major intracranial hemorrhages were defined as greater than 10 mL in volume, symptomatic (defined as focal deficit, headache, nausea, or a change in cognitive function), or required surgical intervention. Gray's test was used to compare the cumulative incidence of ICH between the groups, with death as a competing risk. Results A total of 170 patients with primary brain tumors and brain metastases were included in the study. In the primary brain tumor cohort (N=65), 18 patients received a DOAC while 47 received enoxaparin. The cumulative incidence of any ICH at 12 months was 0% in patients receiving a DOAC compared to 36.8% (95% confidence interval 22.3-51.3%) in those receiving enoxaparin (P=0.012). There were no major ICH events in the DOAC group and 8 and in the LMWH group (12-month cumulative incidence of 0% versus 18.2%, 95% CI 8.4-31.0, P=0.062). In the brain metastases cohort (N=105), 21 patients received a DOAC while 84 received enoxaparin. The DOAC and enoxaparin groups were well-matched for tumor diagnosis (non-small lung cancer 52% and 51%, respectively) including those tumor types with a high incidence of ICH (i.e. melanoma 5% and 7% and renal cell carcinoma 14% and 11%, respectively). In patients with brain metastases, DOACs did not increase the risk of any ICH relative to enoxaparin (12-month cumulative incidence 27.8% versus 52.9%, P=0.15) nor major ICH (12-month cumulative incidence 11.1% vs 17.8%, P=0.38). Conclusions DOACs can be safely administered to patients with brain tumors. In patients with primary brain tumors (i.e. glioma), DOACs appear to be safer than LMWH and should be considered for this indication. Figure. Figure. Disclosures Zwicker: Incyte: Research Funding; Parexel: Consultancy; Quercegen: Research Funding; Daiichi: Honoraria.

299 Background: Advance care planning is an important aspect of providing high quality care to oncology patients. ASCO Quality Oncology Practice Initiative (QOPI) recognizes the importance of advance directive documentation as a quality measure. MOLST forms are often completed to document a patient’s preferences for medical care at the end of life. The primary objective of this study was to improve the MOLST form documentation process in an outpatient solid tumor oncology clinic. Methods: We conducted a survey to identify areas for improvement and created a process map illustrating the complexities of the current MOLST form documentation process. A multidisciplinary team comprised of physicians, nurses, administrative staff, a quality improvement leader and a palliative care expert was created to focus on this initiative. We developed a new process whereby completed MOLST forms were uploaded into the electronic medical record (EMR) system. We implemented the following interventions: 1) made MOLST forms accessible to clinicians; 2) created a centralized location to place MOLST forms; 3) educated oncology staff about the new process; and 4) streamlined the MOLST form scanning process into the EMR. This process was studied during a pilot between January 22, 2018-February 2, 2018. A pre-pilot convenience sample was compared to pilot data. Results: Oncologists identified the need to improve the MOLST form documentation process on the pre-pilot survey. The percentage of completed MOLST forms scanned into the EMR increased from 44.4% (4 out of 9 forms) pre-pilot to 87.5% (7 out of 8 forms) during the pilot (p = 0.06). All of the MOLST forms completed using the new process were scanned into the EMR. Physician satisfaction with the MOLST process increased from 7.1% (2 out of 28 survey respondents) pre-pilot to 87.5% (14 out of 16 survey respondents) post-pilot (p < 0.01). Conclusions: A targeted process to enhance the documentation of completed MOLST forms succeeded and increased physician satisfaction. Further work will need to be performed to better identify oncology patients appropriate for MOLST form discussions.

BACKGROUND Venous thromboembolism occurs in approximately 15-30% of individuals with primary brain tumors (e.g. glioblastoma, astrocytoma, and oligodendroglioma). Spontaneous intracranial hemorrhage (ICH) is also a frequent complication of primary brain tumors thus complicating the decision to administer therapeutic anticoagulation. Therapeutic anticoagulation does not appear to increase the risk of intracranial hemorrhage among patients with solid tumor brain metastases but whether anticoagulation is safe to administer to patients with primary brain tumors is less clear. The aim of this study was to determine the rate of intracranial hemorrhage associated with therapeutic enoxaparin for treatment of venous thromboembolism in patients with primary brain tumors compared to those patients with brain tumors not exposed to therapeutic anticoagulation. METHODS A 1:1 matched, cohort study was performed using a large hospital-based online medical record database (CQ2) linking ICD-9 codes with prescription medication records, cases were initially identified based on coding for primary brain tumors, venous thromboembolism, and prescription of enoxaparin. Matched controls were identified using a "round-robin" algorithm that ranked controls according to a scoring formula based on successful match for year of diagnosis, age, and gender. A blinded review of radiographic imaging was performed and intracranial hemorrhages were categorized as trace, measurable, and significant. Measurable intracranial hemorrhages were those defined as greater than 1 mL in volume and "significant" intracranial hemorrhages were defined as greater than 10 mL in volume, symptomatic (defined as focal neurologic deficit, headache, nausea, or change in cognitive function), or required surgical intervention. Time-to-event statistical analysis was performed using a competing risk analysis to account for death from any cause as an absorbing competing risk. Statistical comparison of event rates between cases and controls was performed using Fine and Gray competing risk regression. RESULTS A total of 100 patients with primary brain tumors were included in the study. The most common diagnosis was glioblastoma (85%), followed by anaplastic oligodendroglioma (8%), and anaplastic astrocytoma (7%). The two cohorts were well matched for age (60 years old), gender (65% male), and types of treatment received (99% radiation, 34% stereotactic radiosurgery, and 71% surgical resection). There was no statistical difference in the rate of measurable intracranial hemorrhage for the group of patients who received therapeutic enoxaparin at any point following the diagnosis of glioma compared to those who did not receive anticoagulation (subdistribution ratio hazard ratio 1.09, 95% CI 0.53-2.22). The 1-year cumulative incidence of measurable hemorrhage among those who were treated with enoxaparin was 23.6% compared with 20.0% in the control group (Gray's test P=0.48). The 1-year cumulative incidence of significant hemorrhage was 13.1% in those receiving enoxaparin compared with 6.0% in controls (sHR 1.45, 95% CI .47-4.65, P=0.68). The median survival was similar for the enoxaparin (1.56 years) and controls (1.63 years, Log rank P=0.81). CONCLUSION Intracranial hemorrhage is common in patients with primary brain tumors. In this matched cohort analysis utilizing a blinded radiologic review, the administration of therapeutic low molecular weight heparin did not significantly increase the risk of intracranial hemorrhage in the setting of glioma and venous thromboembolism. In patients with primary brain tumors, the diagnosis of venous thromboembolism treated with therapeutic enoxaparin did not impact overall survival. Disclosures Zwicker: Quercegen Pharma: Research Funding.