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PURPOSE We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances. PATIENTS AND METHODS Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). RESULTS Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC. CONCLUSION CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.

674 Background: Metastasis directed therapy (MDT) is associated with improved cancer-specific survival and delay in use of systemic therapy for metastatic clear cell RCC (mccRCC). Although the benefits of MDT may differ based on organ site of metastasis due to differences in disease biology, survival based on site of metastasis remain underexplored. We aim to evaluate survival outcomes of patients who underwent MDT for solitary sites of mccRCC. Methods: The Mayo Clinic Nephrectomy Registry was queried to identify adults undergoing radical or partial nephrectomy for unilateral, sporadic ccRCC from 2000 to 2019 with a single site of metastasis treated with MDT including complete metastasectomy or radiation, in lieu of systemic therapy. Overall and cancer-specific survival were estimated using the Kaplan-Meier method, with the duration of follow-up calculated from the date of metastasis to the date of death or last follow-up. Associations with time to death from RCC were evaluated using Cox proportional hazards regression models and summarized with hazard ratios and 95% confidence intervals (CIs). Results: In this cohort of 207 mccRCC patients, 152 underwent complete metastasectomy and 55 underwent radiation. 133 died at a median of 2.7 years (IQR 1.2-4.7) following metastasis, including 105 who died from RCC at a median of 2.2 years (IQR 1.0-3.9). The median duration of follow-up for the 74 patients who were still alive at last follow-up was 8.1 years (IQR 3.7-12.1). Overall survival rates (95% CI) at 2, 4, 6, 8, and 10 years following metastasis were 73% (69-79), 54% (48-62), 45% (38-52), 37% (30-44), and 32% (26-40), respectively; cancer-specific survival rates were 75% (69-81), 56% (50-64), 47% (41-55), 44% (37-52), and 42% (35-50), respectively. Age, poor performance status, presence of synchronous metastasis and asynchronous metastasis

548 Background: PD-L1 and B7-H3 have been found to be overexpressed in urothelial carcinoma (UC) of the urinary bladder. Recent studies have also demonstrated that B7-H3 and PD-L1 can promote resistance to platinum-based drugs but the predictive value of B7-H3 expression in patients treated with platinum-based chemotherapy is unknown. This study aims to investigate the association of PD-L1 and B7-H3 tumor expression with oncological outcomes in patients who underwent radical cystectomy (RC) and received subsequent adjuvant chemotherapy. Methods: Immunohistochemistry was performed on paraffin-embedded sections from bladder and lymph node specimens of 81 patients who had RC for bladder cancer. PD-L1 and B7-H3 expression on tumor cells was assessed by immunohistochemistry in both primary tumors and lymph node specimens. Association with clinicopathologic outcomes was determined using Fisher’s exact test and postoperative survival using Kaplan–Meier survival curves and Cox regression model. Results: B7-H3 expression in cystectomy specimens was more common than PD-L1 expression (72.8% vs. 35.8%). For both markers, no association was found with pathologic tumor stage, lymph node (LN) status, and histological subtype. Similar findings were observed for double-positive tumors (PD-L1+B7-H3+). Concordance between the primary tumor and patient-matched lymph nodes was found in 76.2% and 54.1% of patients for PD-L1 and B7-H3, respectively. PD-L1 tumor expression was not associated with oncologic outcomes. However, B7-H3 expression was associated with recurrence-free survival (HR: 2.38, 95% CI 1.06–5.31, p = 0.035) and cancer-specific survival (HR: 2.67, 95% CI 1.18–6.04, p = 0.019). Conclusions: In our single institutional study, B7-H3 is highly expressed in patients with UC treated with adjuvant chemotherapy and it was associated with decreased recurrence-free survival and cancer-specific survival. Pending further validation in larger cohorts, B7-H3 expression may function as a predictor of response to adjuvant chemotherapy and thus be useful in patient and regimen selection.

TPS739 Background: The landscape for treatment of metastatic renal cell carcinoma (mRCC) has changed dramatically over the past 7 years with the approvals of tyrosine kinase inhibitors and immune-oncology (IO) agents alone or in combination for untreated mRCC. However, multiple knowledge gaps remain. While active surveillance remains an option for selected pts, prospective evidence on selection of and outcomes for pts is limited. Recent phase III trials all used a common comparator, sunitinib, so no comparative effectiveness data on the new IO-based regimens exists. There are also no routinely used predictive biomarkers in mRCC pt management. Therefore, a better understanding of the biologic determinants associated with cancer heterogeneity and clinical outcomes through blood, tumor, and radiographic based assessments is needed. Importantly, longitudinal changes in health-related quality of life (QOL) and symptom burden of patients with mRCC initiated on new IO–based regimens outside of an interventional clinical trial are poorly understood. Pt reported outcomes (PRO) are rarely captured in a systematic manner. Addressing the evidence gap for how real world pts symptomatically change with treatment combinations and sequences over time is a pressing unmet need. Methods: This is a prospective, observational cohort, phase IV study of 800 mRCC pts in the US. Pts must: be age ≥19 at informed consent; have a diagnosis of mRCC (any histology) with no prior systemic therapy for mRCC (surgery and radiation therapy, prior neoadjuvant/adjuvant therapy for non-mRCC, and pts currently not on systemic therapy and being observed are all permitted); and be able to comply with completion of PROs. Those being treated for active malignancies other than mRCC or not intending to undergo follow up care at a study site within PCORnet are excluded. Pts will undergo consent and baseline assessments, including research blood collection and processing, by the study site team. A novel aspect of this study is the use of PCORnet and Medicare data to minimize data collection burden on sites. PCORnet, the National Patient-Centered Clinical Research Network, is a network of networks that curates EHR data from multiple health systems using a common data model. This allows subsequent follow up to be centrally coordinated by the coordinating center. PRO will be collected at baseline (pre-treatment), every 3 mos for 2 yrs, and then every 6 mos until end of follow up (minimum 18 mos follow-up; maximum 36 mos follow-up). The primary objective is to determine distinct patterns of change in QOL and symptom burden of mRCC pts receiving therapy. Secondary objectives include quantifying the time to treatment discontinuation of pts, identifying patterns of clinical management in the real world setting of mRCC pts on various treatment regimens, and evaluating overall survival of mRCC pts. ClinicalTrials.gov Identifier: NCT04919122 Clinical trial information: NCT04919122 .

201 Background: Previous studies have evaluated peripheral whole blood mRNA to identify prognostic biomarkers in metastatic prostate cancer, with no consistent genes of prognostic significance between studies and sample collection done at various points of therapy. We aim to identify the prognostic value of 20 previously identified genes in patients mCRPC from a prospective clinical trial. Methods: Between June 2013 and August 2015, whole blood was prospectively collected in PAXgene RNA tubes from 92 men with mCRPC (NCT01953640). Gene expression from samples with RIN > 4.0 were quantified using a customized NanoString CodeSet of 20 candidate genes (C1QA, MCM2, STOM, GABARAPL2, R10K3, HMBS, TFDP1, CDKN1A, ITGAL, TMCC2, TERF2IP, MMP9, SNCA, TIMP1, SLC4A1, SELENBP1, TMEM66, SEMA4D, PROS1, CD22). The raw data from the nCounter Analysis system were normalized to the positive controls and log2 transformed. Univariable Cox proportional hazards models were performed on each target gene sufficiently above negative control (5 times the maximum value of the negative control) to evaluate associations with overall survival (OS). For each gene we considered a linear, quadratic, or categorical model with quantile cutpoints. Categorical models with cutpoints at the 25th percentile for the genes CD22, GABARAPL2, R10K3, and STOM were used as there was a nonlinear relationship between gene expression and death hazard. The remaining genes were modeled with a linear model. Findings were considered statistically significant based on p-values adjusted using the Holm-Bonferroni correction. Results: 18/20 genes were identified and passed quality control (QC) measures, which excluded C1QA and MCM2. 72/92 men had an evaluable pretreatment specimen that passed QC. The median age was 72 years. The study cohort was evenly balanced in terms of Gleason score ( < = 7 v. > 7) and 60% had high volume disease. The median follow-up time was 5.73 years (IQR: 5.39, 6.49) and 58 patients had died. Of the 18 genes evaluated, STOM (Stomatin) [hazard ratio (HR) 3.00, adjusted p = 0.007] and GABARAPL2 (GABA Type A Receptor Associated Protein Like 2) [HR 2.62, adjusted p = 0.033] were significantly associated with overall survival in univariate analysis. In multivariate analysis, after adjusting for volume of metastatic disease and Gleason score, STOM [HR 2.89, adjusted p = 0.014] was significantly associated with overall survival. Conclusions: Elevated whole blood mRNA expression of STOM is adversely associated with OS in mCRPC. Further studies investigating elucidating the molecular significance of STOM in mCRPC are planned. Clinical trial information: NCT01953640 .

362 Background: Despite current guidelines, less than 50% of patients with metastatic (m) non-squamous (NSq) NSCLC undergo comprehensive molecular genotyping. At our institution, based on improved comprehensiveness of genotyping with use of concurrent tissue (T) and plasma (P) next generation sequencing (NGS), we designed an electronic medical record (EMR)-based “nudge intervention” to auto-generate an order for P NGS at the time of initial consultation, while T NGS was carried out reflexively based on institutional pathways. Methods: A prospective study was conducted at the Abramson Cancer Center and 2 community sites within the University of Pennsylvania Health System after IRB approval. A provider team-focused EMR-based “nudge intervention” was designed to order P NGS at the time of new patient consultation. Eligible patients for the nudge were identified using an EMR based checklist, that included 3 criteria i. newly diagnosed, ii. treatment naïve, iii. mNSq NSCLC. Results from the intervention period (4/2021-12/2021) were compared to baseline data from similar patients treated at our institution between 01/2019 and 03/2021. Categories of NCCN guideline recommended molecular genotyping were defined as: i) comprehensive: EGFR, ALK, BRAF, ROS1, MET, RET, NTRK testing, and ii) incomplete or no testing performed. The proportion of patients with comprehensive molecular genotyping prior to 1st-line therapy were compared in the pre- and post-intervention groups using the chi-square test. Results: 526 patients with mNSq NSCLC were included in this analysis: 381 in the pre-intervention cohort, 145 in the post-intervention cohort. After implementation of the EMR-based nudge, a higher proportion of patients underwent concurrent T+P testing resulting in improved comprehensive molecular genotyping. In addition, a greater proportion of patients had comprehensive genotyping available prior to 1st-line therapy in the post-intervention vs pre-intervention cohort (Table). Conclusions: Across 3 practice sites, a provider team-focused EMR-based nudge intervention was associated with a significantly higher proportion of patients with mNSq NSCLC undergoing comprehensive molecular genotyping, both overall and prior to 1st-line therapy. These findings demonstrate that behavioral, EMR-based nudges can promote guideline concordant diagnostic testing at both community and academic sites and should be studied further as a tool to improve rates of molecular testing in NSCLC.[Table: see text]

7527 Background: Pts with R/R DLBCL who fail or are ineligible for ASCT have very poor outcomes with standard palliative chemotherapy. Rituximab + GemOx had a complete response rate of 33% (Cazelles et al, Leuk Lymphoma 2021); novel approaches are needed. Epco is a subcutaneously administered bispecific antibody targeting CD3 on T cells and CD20 on B cells. In the EPCORE NHL-1 dose-escalation trial, epco had manageable safety and antitumor activity in heavily pretreated B-cell NHL including DLBCL. EPCORE NHL-2 is a phase 1/2 trial evaluating epco + standard B-cell NHL therapies; shown here are results from arm 5 (NCT04663347). Methods: Adults with R/R CD20+ DLBCL who failed or were ineligible for ASCT received epco (QW, cycle [C] 1–3; Q2W, C4–9; Q4W, C≥10) and GemOx (Q2W, C1–4) until disease progression or unacceptable toxicity (28 d/C). Step-up epco dosing and prophylactic corticosteroids were required in C1 to mitigate CRS. Response was assessed by PET-CT per Lugano 2014 criteria. Results: As of Dec 1, 2021, 27 pts (median age, 71 y; range, 47–87 y) had received epco + GemOx (epco 24 mg, n=3; 48 mg, n=24). Most were stage IV (56%), primary refractory (56%), and refractory to last therapy (70%). Median number of prior therapies was 2 (range, 1–13). Median follow-up was 6.0 mo (range, 1.0–11.1), with treatment (Tx) ongoing in 16 pts (59%). The most common Tx-emergent AEs were CRS (70%), thrombocytopenia (70%), neutropenia (56%), anemia (52%), and infections (52%). CRS events were all grade (G) 1/2, with most cases occurring in C1; all cases resolved. One pt had ICANS (G3); 1 pt had tumor lysis syndrome (G3). Six pts (22%) had G5 AEs; investigator could not rule out contribution of epco in 2 pts: small bowel perforation in pt (72 y) with transformed DLBCL and extensive gastrointestinal involvement (had complete metabolic response [CMR]); acute hepatitis/multiorgan failure in pt (68 y) with transformed DLBCL and liver involvement (had CMR). Of 4 pts with fatal AEs unrelated to epcoritamab by investigator, 2 (87 y) had primary refractory disease and 2 (74 y) had multiple comorbidities. Response is shown in the Table. At the time of data cut, 65% of responders remained in response with the longest duration of response 6.9 mo. All 3 pts with prior CAR T remained on Tx and in response (2 CMR and 1 partial metabolic response [PMR]). Conclusions: When considering individual safety profiles of epco or GemOx, no unexpected safety findings were observed for epco + GemOx. In this R/R population with high unmet need, these initial data are encouraging and warrant further clinical evaluation. Clinical trial information: NCT04663347. [Table: see text]

9022 Background: Current guidelines recommend comprehensive molecular genotyping for newly diagnosed patients (pts) with metastatic non-squamous (non-Sq) NSCLC. We have previously demonstrated that concurrent plasma (P) and tissue (T) based next-generation sequencing (NGS) improves detection of clinically actionable mutations in pts with advanced NSCLC. We analyzed the impact of concurrent T+P NGS on comprehensiveness of molecular genotyping and on overall survival (OS). Methods: A retrospective cohort study of pts with newly diagnosed stage IV non-Sq NSCLC who received therapy at our institution between 01/2019 and 12/2020 was performed. Categories of NCCN guideline testing were defined, i) comprehensive: EGFR, ALK, BRAF, ROS1, MET, RET, and NTRK testing, ii) incomplete: 2-6 genes tested, and iii) no testing performed. The proportion of pts with comprehensive molecular testing performed, prior to 1st-line therapy and by detection modality (T NGS vs. T+P NGS), were compared using Fisher’s exact test. Median OS was estimated using Kaplan-Meier methodology from diagnosis to death or censored at most recent follow-up. Results: 335 patients were included in this analysis, 98.5% (330/335) underwent molecular testing: either comprehensive: n = 291 (86.9%), incomplete testing: n = 39 (11.6%); or no testing n = 5 (1.5%). Testing with T NGS was completed in 32.7% (108/330); 67.2% (222/330) underwent concurrent T+P NGS. These groups were well balanced for baseline characteristics, with the exception of a higher number of never smokers in T+P vs. T NGS (30.2% vs. 14.8%, p < 0.0001). Proportion of pts with comprehensive molecular testing was higher among pts with T+P NGS: 99.5% (221/222) vs. T NGS: 64.8% (70/108), p < 0.0001. All pts with T+P NGS testing had results available prior to 1st line therapy; 100% (204/204) compared to 60.7% (51/84) for T NGS, p < 0.0001. With median follow up of 20.5 months (mos, range 0.3 - 33.1), median OS was 18.6 mos. Median OS for pts tested with T+P NGS vs T alone was numerically longer at 23.2 vs. 14.1 mos, but not statistically significant (p = 0.078). However, regardless of testing modality, patients with comprehensive molecular genotyping had superior OS compared to those with incomplete or no testing (22.1 mos vs. 11.6 mos, p = 0.017). The institution of oral targeted therapy had no bearing on this difference in OS (test for interaction, p = 0.6509). Conclusions: Performance of concurrent T+P NGS testing was associated with a higher likelihood of comprehensive molecular genotyping, as well as improved availability of results, including prior to first line therapy. Patients with comprehensive genotyping have improved OS compared to patients with incomplete or no testing. These results support implementation of a concurrent T+P NGS approach upon initial diagnosis of metastatic non-Sq NSCLC.

TPS4184 Background: While treatment of pancreatic cancer has advanced, survival rates remain low. Stereotactic body radiotherapy (SBRT; high dose per fraction radiation) may exhibit improved clinical outcomes in locally advanced pancreatic cancer but carries potential gastrointestinal toxicity risks (Zhong 2017). Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically converts superoxide to hydrogen peroxide (Riley 2006). Studies have shown that normal cells tolerate hydrogen peroxide fluxes better than cancer cells (Doskey 2016). As radiation response modifiers, dismutase mimetics have the potential to increase tumor control of SBRT without compromising radiation safety (El-Mahdy 2020, Sishc 2021). In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT. Improvements versus placebo were also observed in local tumor control, time to metastases, and progression-free survival. Altogether, these data support the hypothesis that rucosopasem may improve survival and the benefit-risk ratio of SBRT by improving efficacy without increasing gastrointestinal toxicity. Materials/Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet. Approximately 160 patients will be randomized (approximately 35 sites) to receive rucosopasem 100 mg or placebo via IV infusion over 15 minutes, prior to each SBRT fraction (5 x 10 Gy). Patients judged to be resectable will undergo surgical exploration within 8 weeks after SBRT. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, locoregional control, time to metastasis, surgical resection rate, RO resection rate, best overall response, in-field local response, and safety (acute and late toxicities). Exploratory endpoints include PRO-CTCAE and CA19-9 normalization. This trial is now enrolling. Clinical trial information: NCT04698915.

8014 Background: Elranatamab (PF-06863135) is a bispecific molecule that activates and redirects the T-cell mediated immune response against multiple myeloma (MM), a plasma cell dyscrasia characterized by expression of B-cell maturation antigen (BCMA). MagnetisMM-1 (NCT03269136), the ongoing Phase 1 first-in-human study for elranatamab, was designed to characterize safety, pharmacokinetics (PK), pharmacodynamics, and efficacy for patients (pts) with relapsed or refractory MM. Methods: Elranatamab was given subcutaneously (SC) at doses from 80 to 1000µg/kg either weekly or every 2 weeks (Q2W). Treatment-emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events (v4.03) and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria. PK, cytokine and soluble BCMA profiling, and lymphocyte subset analyses were performed. Response was assessed by International Myeloma Working Group (IMWG) criteria. Minimal residual disease (MRD) was assessed by next generation sequencing at a sensitivity of 1×10-5 in accordance with IMWG criteria. Results: A total of 55 pts received single-agent elranatamab SC at a dose ≥215μg/kg as of 1-Nov-2021. Median age was 64 (range 42-80) years, and 27% of pts were Black/African American or Asian. Median number of prior regimens was 6 (range 2-15), 91% were triple-class refractory, 56% had prior stem cell transplantation, 27% had high cytogenetic risk, and 22% received prior BCMA-targeted therapy. The most common TEAEs regardless of causality included CRS, neutropenia, anemia, injection site reaction, and lymphopenia. With pre-medication and a single priming dose (600µg/kg or 44mg), the overall incidence of CRS at the recommended dose (1000µg/kg or 76mg) was 67% and limited to Grade 1 (33%) or Grade 2 (33%), with no events Grade 3 or higher. Exposure was dose dependent and Q2W dosing achieved exposure associated with anti-myeloma efficacy. Cytokine increases occurred with the first dose and were reduced by pre-medication. Soluble BCMA decreased with disease response, elranatamab therapy was associated with increased peripheral T cell proliferation, and median time to response was 36 days (range 7-73). With a median follow-up of 8.1 months (range 0.3-21) and including only IMWG confirmed responses, 31% of pts achieved complete response or better and the overall response rate was 64% (95% CI 50-75%). For responders (n = 35), median duration of response was not yet reached, but the probability of being event-free at 6 months was 91% (95% CI 73-97%). Single-agent elranatamab induces durable clinical and molecular responses, and updated data including MRD assessment will be presented. Conclusions: Elranatamab shows a manageable safety profile and achieves durable clinical and molecular responses for pts with relapsed or refractory MM. Clinical trial information: NCT03269136.

e17036 Background: Elevated serum CGA is associated with an intrinsic or treatment-related neuroendocrine differentiation in men with mCRPC. We previously demonstrated that elevated serum CGA was negatively associated with OS in men with mCRPC. Fluctuations in serum CGA during mCRPC therapy is not well known. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with AA therapy. Methods: Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial (“PROMOTE”; NCT#01953640) with uniform serum processing performed prior to initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients (pts) receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded). All patients underwent a composite response assessment at 12-weeks with imaging/PSA/QOL questionnaires. Kaplan Meier estimates, and Cox Regression models were used to calculate association with time-to-treatment failure (TTF) analyses, defined as time from treatment initiation to AA/P discontinuation based on disease progression (BlueSky Statistics, Chicago, IL, USA). Results: Of the 71 eligible pts, 67/71 had paired baseline and 12-week CGA and 70/71 pts had a baseline and a 12-week PSA available. The median baseline CGA was 83.0ng/ml (range: 53.0 - 127.0 ng/ml), median baseline PSA was 14.4 ng/ml (range: 6.4-40.2 ng/ml), and the median TTF was 10 months (range: 6-25 months). The median CGA after 12 weeks of AA/P was 98.0 ng/ml (58.0 -148.0 ng/ml) and we observed a CGA rise in 41/67 (61.2%) pts. An increase in chromogranin was associated with a lower risk of treatment failure (HR: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6 -16.0). An elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). Conclusions: We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in pts with mCRPC were associated with a favorable response to AA/P. Further studies are needed to assess if rising CGA during therapy reflects neuroendocrine differentiation and may indicate a sign of treatment effect targeting the androgen susceptible cells. Clinical trial information: NCT#01953640.

8041 Background: The combination of daratumumab (Dara), pomalidomide (POM), and dexamethasone (dex) (DPd) has previously demonstrated deep and durable responses including high rates of minimal residual disease (MRD) negativity, in patients with relapsed/refractory (R/R) MM. Quadruplet regimens may further improve results. We report updated findings from a phase 2 multicenter trial of the addition of ixazomib to DPd (DIPd) in patients with early R/R MM. Methods: This is a prospective, multi-center, open-label, single arm phase II trial with a primary objective to evaluate the overall response rate (ORR), safety, and efficacy of DIPd. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and MRD-negativity rate. A Simon’s optimal 2-stage design was used, with 14 subjects in stage 1 to assess response and 32 patients for stage 2. Eligible patients may not have had exposure Dara or ixazomib, may not have progressed on POM, and may have received ≥1 and ≤3 prior lines of therapy. The first six patients in the safety run-in received Dara 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, POM 4mg orally on days 1-21 of a 28-day cycle, ixazomib 4mg orally on days 1,8,15 every 28 days, and dex 20-40mg weekly. Grade 3-4 neutropenia was observed in 100% of patients, prompting dose reduction to ixazomib 3 mg and POM 3 mg by the DSMB. An amendment allowed subcutaneous Dara administration. MRD assessments are being performed by EuroFlow for patients in VGPR or suspected CR. Pharmacodynamic changes in patients’ tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Results: To date, 14 subjects have been treated in stage 1, and 18 patients in stage 2. Median age was 61.5 (range 41-87) years, 50% were female and 72% white. Median number of prior regimens was 1 (range 1-3), all patients were lenalidomide-exposed, and 47% (11/23) had high-risk cytogenetic features. The most common grade 3-4 treatment emergent adverse events included neutropenia (78%), infection (30%), leukopenia (11%), respiratory conditions (7%), psychiatric disturbance (4%), and thrombosis (4%). Median time on treatment was 4 months (1-29), with 11 patients remaining on DIPd and 5 deaths (4 due to progressive disease and 1 due to sepsis). ORR to date was 84% (16/19), and the best responses included: 5 (26%) sCR; 4 (21%) VGPR; 7 (37%) PR. After a median follow up of 12 months, the median OS was 39 months and PFS was 9.5 months. Conclusions: The quadruplet regimen DIPd is a well-tolerated combination that has shown early safety, efficacy, and ORR in early R/R myeloma, including patients with high-risk genetic abnormalities. Clinical trial information: NCT03590652.

e12506 Background: Breast cancer accounts for a million new cases annually worldwide with 40,000 deaths reported in 2020 in the United States. Treatment includes surgery, adjuvant chemotherapy, radiotherapy and endocrine therapy. Oncotype recurrence score (RS), a 21-gene expression assay, is a tool to predict the benefit of adjuvant chemotherapy in hormone receptor (HR) positive breast cancer. High RS suggests benefit with chemotherapy. The goal of this study is to evaluate the relationship of the Oncotype RS with traditional prognostic/predictive factors. Methods: Retrospective IRB approved study of all patients from January 1, 2017, to December 31, 2019 with invasive breast cancer and an Oncotype RS in a community hospital setting. Study parameters included patient age, grade, tumor size, histologic subtype, HR status, number positive (0-4) lymph nodes (LN), extra nodal extension (ENE), lymphovascular invasion (LVI), and RS. Statistical analysis was done using linear regression and one-way ANOVA followed up with Tukey’s procedure. Results: A total of 470 patient charts evaluated and 22 patients excluded due to incomplete data with the following breakdown. LN positive = 14% (61/450). Oncotype score low (RS < 11) = 25% (114/448), intermediate (RS 11-25) = 59% (265/448) and high (RS > 25) = 15% (69/448). Grade 1 = 34% (153/448), Grade 2 = 50% (225/448) and Grade 3 = 15% (70/448). There was statistical significance in the mean difference in RS between the levels of grade and the levels of HR. The mean differences in RS between Grades 3 versus 1 was 10.9 (p < 0.001); between Grades 3 versus 2 was 8.3 (p < 0.001); and between Grades 2 versus 1 was 2.6 (p = 0.026). The mean Oncotype RS for grades 1,2,3 was 13.87 vs 16.33 vs 28.24 respectively. HR status was categorized as 51-100% (strong HR+), 11-50% (intermediate), or 1-10% (weak). Comparing strong HR+ versus intermediate/weak, the mean differences in RS were -41.4 and -35.7, respectively (p < 0.001). There were no significant differences in RS evaluated against the following parameters, patient age, tumor size, number of positive lymph nodes (0-4), LVI, or ENE. Conclusions: Tumor grade and HR status had strong association with the Oncotype RS as expected. Grade 3 tumor associated with high RS (mean 28). Intermediate HR (11-50%) associated with much higher RS = 52 similar to weak HR (1-10%) = 58. We report that RS had no correlation to patient age, tumor size or even LN status. The LN and RS association may have been impacted by low (14%) LN positive status (reportable in the modern era). Our study adds to the data that biology trumps size (traditional risk factors) while posing the question does intermediate HR status (11-50%) deserve recognition as a more substantial risk factor than previously considered.

321 Background: KEYNOTE-564 demonstrated that adjuvant pembrolizumab after nephrectomy for high-risk clear cell renal cell carcinoma (RCC) decreased the risk of disease progression and – albeit with immature follow-up (2 years) – found a signal of improved overall survival as well. Herein, we used extrapolations from a Markov-model, accounting for the costs and toxicities of pembrolizumab relative to its efficacy, to investigate its utility at a population level. Methods: A decision-analytic Markov Model was used to conduct a cost-utility analysis of adjuvant pembrolizumab versus placebo after nephrectomy for high risk RCC, using data from KEYNOTE-564 to inform model probabilities. Transition probabilities not found in KEYNOTE-564, in addition to utility values, were extracted from the literature. Base case analyses were conducted with 5-year and 15-year time horizons (using extrapolations from 2-year outcomes), and 3-week time cycles. Primary outcomes were Quality-adjusted life years (QALYs), 2021 US Medicare costs, and Incremental cost-effectiveness ratios (ICERs). The willingness-to-pay threshold was set at $100,000/QALY. One-way sensitivity analyses were used to identify cost-effectiveness thresholds of individual parameters while probabilistic sensitivity analyses with 100,000 Monte-Carlo simulations were used to simultaneously vary all model inputs. Results: Pembrolizumab was associated with higher QALYs and costs relative to placebo (Table). Pembrolizumab was not cost-effective at a 5-year time horizon but was cost-effective at 15 years and beyond. One-way sensitivity analysis noted that pembrolizumab became cost-effective at 5-years if: 1) its administration cost was less than $5,064 (base = $10,278) or 2) if the 5-year risk of progression was 18.8% higher in placebo vs pembrolizumab (base = 9%). Using pembrolizumab’s reported hazard ratio of 0.68 for progression from KEYNOTE-564, we estimated that pembrolizumab would be cost-effective at 5-years for all patients with a Mayo Progression Free Survival Score of 10 or higher. Probabilistic sensitivity analysis found that pembrolizumab was cost-effective for 29% and 58% of microsimulations at 5 and 15 years, respectively. Conclusions: At current prices, adjuvant pembrolizumab was not cost-effective for all trial patients at a population level at 5-years after treatment but may be cost-effective for time horizons over 15 years. Instead, adjuvant pembrolizumab was found to be cost-effective only for the highest risk subsets of RCC at 5-years. Longer term trial data of progression-free survival and overall survival are necessary to confirm these extrapolations.[Table: see text]