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PURPOSE Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. “Switch maintenance” therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons. PATIENTS AND METHODS Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS). RESULTS Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival. CONCLUSION Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

499 Background: In EV-103 Cohort K (NCT03288545), EV and P in combination (EV+P) showed encouraging antitumor activity and a manageable safety profile when used as 1L therapy in patients (pts) w/ la/mUC who are ineligible for cisplatin, a population w/ high unmet need. Here we report results of an analysis of prespecified Cohort K subgroups known to be associated w/ poor outcomes. Methods: Pts who are cisplatin-ineligible w/ previously untreated la/mUC were randomized 1:1 to EV (1.25 mg/kg) as monotherapy on Days 1 and 8 or in combination w/ P (200 mg) on Day 1 of 3-week cycles. Primary endpoint is cORR per RECIST v1.1 by blinded independent central review w/ no formal statistical comparison between arms. Secondary endpoints included duration of response and safety (e.g. treatment-related adverse events, TRAEs). The cORR analysis was performed in prespecified subgroups including age, ECOG PS, liver metastasis, PD-L1 expression status, metastatic disease site at baseline, and primary disease site of origin. Results: 149 pts were treated: EV+P n=76; EV n=73; cORRs across key subgroups for both EV+P and EV monotherapy are shown in the table. For EV+P overall cohort, cORR (95%CI): 64.5% (52.7, 75.1); median DOR was not reached. cORRs were consistent across subgroups for EV+P including those w/ ECOG PS score of 1-2: 62.8% (46.7, 77.0) and presence of liver metastasis: 53.8% (25.1, 80.8). Among TRAEs of special interest in the EV+P arm, skin reactions occurred in n=51 (67.1%); peripheral neuropathy occurred in n=46 (60.5%). For EV+P, 68.4% of pts had TRAEs leading to interruption of either EV or P; 48.7% of pts had TRAEs leading to EV dose reduction. Median duration of EV+P treatment was 11 cycles. Conclusions: EV+P showed promising cORR in 1L cisplatin-ineligible pts w/ la/mUC; activity was consistently observed across a range of pre-specified subgroups including those with poor prognosis. EV+P TRAEs were manageable w/ close monitoring and appropriate dose modifications w/ a meaningful duration of treatment. EV+P has the potential to address high unmet needs in 1L la/mUC and MIBC and is being further evaluated in 3 Phase 3 trials (NCT04223856, NCT04700124, NCT03924895). Clinical trial information: NCT03288545 . [Table: see text]

438 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy or chemoradiation is the standard of care for urothelial carcinoma (UC) patients with MIBC. Both cystectomy and chemoradiation have short and long-term toxicity and QOL implications. Mutations in DNA damage repair/response genes are associated with pathologic downstaging after NAC. We hypothesized that a combination of biomarker selection and clinical staging would identify patients prospectively for a cystectomy or chemoradiation avoidance algorithm. Methods: We conducted a single-arm, phase II, non-inferiority trial (NCT02710734) to evaluate a risk-adapted approach for MIBC. Patients with cT2-T3N0M0 UC underwent NAC with accelerated MVAC. Pre-NAC TURBT specimens were sequenced (Caris) for mutations in ATM, ERCC2, FANCC or RB1. Patients with ≥ 1 mutations and no clinical evidence of disease by restaging TUR, urine cytology and imaging post-NAC began pre-defined active surveillance (AS). Remaining patients underwent bladder-directed therapy. The primary endpoint was metastasis-free survival (MFS) at 2 years for the entire cohort. The risk-adapted approach would be declared non-inferior to the standard of care if the lower bound of an exact 1-sided 95% CI for MFS was > 64%. The study required 70 patients with a 4.5% type I error and 81.6% power. Results: 71 (ITT) patients were enrolled over 33 months at four academic centers. Median age was 70 years (47-83), 74% were male, 92% Caucasian, 81% ECOG PS 0 and 79% cT2. 90% completed 3 cycles of MVAC with 17% grade 3-4 TRAEs. In the ITT population, 33 (46%) had a relevant mutation and 26 (37%) began AS. With a median follow-up of 41 months, 47 patients (66%) are metastasis-free (CI 54%-77%). The 2-year MFS for the ITT patients (primary endpoint) was 72% (lower bound exact 1-sided 95% CI=62%). On post hoc analysis, the 2-year MFS was 65% in the AS group (CI 44%-83%) and 76% (CI 60%-87%) in the remaining patients (P=0.42). In the AS group, 18 patients (69%) had some UC recurrence, 8 had a cystectomy, 2 chemoradiation, and 13 (50%) are metastasis-free with an intact bladder. Of the 10 patients (38%) on AS who developed metastatic disease, 9 recurred with localized disease first. The 2-year OS is 83% (CI 72%-90%) and 89% (CI 68%-96%) in the ITT and AS groups, respectively. Associations between mutation presence and MFS or UC recurrence were not observed. Conclusions: The 72% 2-year MFS rate in this MIBC cohort treated with a risk-adapted approach did not satisfy the pre-specified non-inferiority condition. 38% of AS patients developed metastatic disease, with most patients first recurring locally in the bladder. With a median follow-up of 41 months, although 50% of AS patients have been able to avoid cystectomy without metastatic disease, further refinement of this approach is necessary. Clinical trial information: NCT02710734 .

377 Background: Metformin impacts immune response in several ways. It protects CD8 TILs from apoptotic death, downregulates CD39 and CD73, reduces MDSC activity and suppresses the transcription of PD1 thus enhancing CD8+ T cell antitumor activity (Ma et al, 2000, Nature). There is limited data on the immunologic impact of metformin treatment in hormone sensitive prostate cancer. Methods: We conducted an open label, randomized, phase II trial of bicalutamide with or without metformin of patients with high risk, biochemically recurrent prostate cancer (NCT02614859). Patients were randomized 1:2 to observation for an initial 8 weeks or metformin 1000 mg twice daily. Bicalutamide 50 mg/day was added after 8 weeks to both arms. The study discontinued accrual after interim analysis indicated no difference in PSA at 32 weeks between the two arms; however, metformin monotherapy for 8 weeks induced modest PSA declines observed in 40% of patients. Here we report immune responses in a subgroup of patients (N=12), including systemic cytokine levels and 158 circulating immune cell subsets after 8 weeks of metformin monotherapy. Results: Twelve patients treated at the NCI were analyzed. After 8 weeks, the metformin arm showed increased pDCs and lower Tregs compared to baseline. Significant differences in the percent change of immune parameters after 8 weeks of metformin monotherapy compared to 8 weeks of observation are summarized. Conclusions: Metformin has been shown to reduce markers of immune exhaustion in hormone sensitive prostate cancer which is supported by a greater reduction of PD-1+ and Tim3+ NK cells. Additional immune changes included increases in activated subpopulations of natural killer (NK) cells, which have been reported as a potential predictive biomarker of prolonged treatment response to hormone therapy in prostate cancer (Pasero et al, Oncotarget, 2015). Clinical trial information: NCT02614859 . [Table: see text]

4524 Background: TERT is a catalytic subunit of telomerase, the unique enzyme that confers immortality to cells and is expressed in >90% of cancer cells. Mutations in the TERT promoter region (pTERTmut) are the most prevalent noncoding mutations in cancer. Recent data suggest pTERTmut are associated with improved outcomes in patients with UC treated with immune checkpoint inhibitors. We evaluated the molecular and immune landscape of UC with and without pTERTmut. Methods: UC tissue samples were analyzed for DNA alterations (NextSeq, 592 Genes; NovaSeq, WES) and mRNA expression (NovaSeq, WTS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). PD-L1 expression was assessed by immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). MSI/MMR was tested by fragment analysis, IHC and NGS. TMB-H was based on a cut-off of > 10 mut/MB. We compared alterations between samples with and without detected pathogenic pTERTmut. Significance was determined by Mann–Whitney U, X2, and Fischer-Exact and p adjusted for multiple comparisons (q) was < 0.05 using Benjamini-Hochberg. Results: Overall, 1686 UC samples were analyzed, 1166 from primary lesions and 499 from a lymph node or metastatic site. pTERTmut was present in 68% of primary and 61% of metastatic tumors, and correlated with modest increase of TERT expression (1.18 fold, p=0.015). pTERTmut was associated with less frequent alterations in TP53, KMT2D, CCND1, MYC, KEAP1 and less MSI/dMMR. By contrast, pTERTmut was associated with more frequent alterations in ARID1A, TSC1, PIK3CA and TMB-H (all q

Purpose Standard frontline treatment of patients with metastatic renal cell carcinoma currently includes sunitinib. A barrier to long-term treatment with sunitinib includes the development of significant adverse effects, including diarrhea, hand-foot syndrome (HFS), and fatigue. This trial assessed the effect of an alternate 2 weeks on, 1 week off (2/1) schedule of sunitinib on toxicity and efficacy in previously untreated patients with metastatic renal cell carcinoma. Methods Patients started with oral administration of 50 mg sunitinib on a 2/1 schedule and underwent schedule and dose alterations if toxicity developed. The primary end point was < 15% grade ≥ 3 fatigue, diarrhea, or HFS. With 60 patients, the upper bound of the CI would fall below the published 4/2 schedule grade ≥ 3 toxicity rate of 25% to 30%. Results Fifty-nine patients were treated between August 2014 and March 2016. Seventy-seven percent were intermediate or poor risk per Memorial Sloan Kettering Cancer Center criteria. With a median follow-up of 17 months, 25% of patients experienced grade 3 fatigue, HFS, or diarrhea; 37% required a dose reduction, and 10% discontinued because of toxicity. The overall response rate was 57%, median progression-free survival was 13.7 months, and median overall survival was not reached. At 12 weeks, Functional Assessment of Cancer Therapy–General scores dropped between 0% and 10% from baseline, with less reduction in patients who continued treatment longer. Conclusion The primary end point of decreased grade 3 toxicity was not met; however, treatment with a 2/1 sunitinib schedule is associated with a lack of grade 4 toxicity, a low patient discontinuation rate, and high efficacy.

291 Background: Combination systemic therapy with tyrosine kinase inhibitors (TKIs) and an immune checkpoint inhibitor (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We performed a phase I/II study to investigate the safety and efficacy combining the TKI axitinib (axi) with the IO agent nivolumab (nivo). Methods: This phase I/II study investigated the combination of axi and nivo in an initial dose finding phase I portion with a 3+3 design to determine the recommended phase 2 dose (RP2D) of axi. The phase II portion included 2 parallel arms: treatment naïve mRCC patients and mRCC patients previously treated with TKIs alone or IO/IO combination (NCT03172754). We are presenting results from the treatment naïve arm only. Included patients had to have histology with any clear cell component, ECOG performance status of 0-1, no known or symptomatic brain metastases, and no history of autoimmune disease. The RP2D of axi was 5 mg BID from the phase I portion and patients could be treated for up to 2 years. The primary endpoint of the phase II portion was objective response rate (ORR) per investigator assessment. Results: Forty-four patients were accrued to the treatment naïve arm. One withdrew consent and was replaced but is included in the safety analysis, while 42 patients are evaluable for efficacy. The median age was 65 yrs (range: 42-84 yrs) and the group was predominantly male (83.7%) and white (95.3%). Using the IMDC risk group grading, 18 patients (41.9%) were favorable risk, 22 patients (51.2%) were intermediate risk and 3 patients (7 %) were poor risk. Median follow-up was 11.5 months. Best response data is shown in the table and is notable for an ORR of 69.0%, with only 1 patient (2.4%) experiencing primary progressive disease, for a disease control rate of 97.6%. Median progression free survival was 16.4 months (95% CI: 10.6 - 21.9 mo), and median overall survival (OS) was not reached. OS at 12 months was 86.7%. Adverse event (AE) data was similar to published data for IO/TKI combinations, with no grade 4-5 AEs. Twenty-nine patients experienced a grade 3 AE (70.7%), the most common of which was hypertension, and 14.0% discontinued the study due to treatment-related toxicity. Conclusions: The combination of axi/nivo for treatment naïve patients with mRCC demonstrated efficacy comparable to available IO/TKI combinations with a similar safety profile. Clinical trial information: NCT03172754. [Table: see text]

311 Background: The immuno-oncology (IO) therapy combination nivolumab + ipilimumab, and the IO-tyrosine kinase inhibitor (TKI) combination pembrolizumab + axitinib, received US FDA approvals in 2018 and 2019, respectively, as first-line (1L) therapy for advanced renal cell carcinoma (aRCC). We examined physician perceptions of concerns about and barriers to 1L treatment by class of regimen (IO-IO, IO-TKI, and single-agent TKI [SA-TKI]) in the United States. Methods: US-based oncologists treating ≥ 5 aRCC patients in the prior 12 months were identified from the Cardinal Health network, a community of > 800 oncologists. Physicians were surveyed about concerns in prescribing and barriers to treating by class (scale of 1–5; 1 = no concern/not a barrier, 5 = most concerning/major barrier); mean scores are reported. Adverse events (AEs) of concern were selected from a prespecified list and respondents rank-ordered from most to least concerning by class. Physicians were also asked to gauge affordability and to rank-order 13 characteristics to identify key factors in prescribing preference. The impact of COVID-19 on aRCC care in practice was also assessed. Results: A total of 49 providers (84% community, 16% academic) treating a median of 20 (IQR 14–30) aRCC patients from across the United States participated. For IO-IO, the top 3 concerns in prescribing were AEs (4.3), patient out-of-pocket costs (OOP; 3.7), and unexpected late AEs (3.6), whereas patient OOP (4.3), AEs (4.1), and patient adherence (3.9) were of most concern for IO-TKI. For SA-TKIs, the top 3 concerns were patient adherence (3.9), patient OOP (3.9), and AEs (3.6). High patient OOP and impact on quality of life were the top 2 barriers in using IO-TKI therapy. The most concerning AEs were colitis, pneumonitis, and hypertension for IO-IO or IO-TKI, and diarrhea, fatigue, hand-foot syndrome, and hypertension for SA-TKI. Overall survival (OS), progression-free survival (PFS), and complete response (CR) were ranked 1st, 2nd, and 3rd factors in prescribing preferences while patient compliance, patient preference, and practice reimbursement ranked 11th, 12th, and 13th. Patient OOP and drug acquisition costs (DAC) were the most important factors when considering the affordability of treatment, with the perception that IO-IO was the most expensive among the classes of therapy. The overall impact of COVID-19 on caring for aRCC patients was very limited, with a moderate increased use of telemedicine and a slight impact on the timing and number of routine care visits. Conclusions: OS, PFS, and CR ranked highest among the most important factors influencing selection of 1L treatment for aRCC. Factors of concern and barriers varied by class of treatment, with patient adherence and OOP affecting use of TKI or IO-TKI therapies, and AEs affecting the use of IO-based therapy. This study revealed perceptions of high patient OOP and DAC of IO-IO therapy, in contrast to our expectations.

95 Background: mCRPC remains an incurable disease with unmet need for improved therapies. PARP inhibition has demonstrated antitumor activity, and preclinical studies suggest synergy between PARP and AKT inhibition. This phase Ib trial (NCT03840200) sought to determine the maximum tolerated dose of PARP inhibitor rucaparib (ruca) with AKT inhibitor ipatasertib (ipat) and explore early safety and efficacy in patients (pts) with mCRPC. Methods: The study had 2 parts: a part 1 dose-escalation phase (cohort [C]1: ipat 300 mg QD + ruca 400 mg BID; C2a: ipat 300 mg QD + ruca 600 mg BID; C2b ipat 400 mg QD + ruca 400 mg BID; C3: ipat 400 mg QD + ruca 600 mg BID) in unselected pts with mCRPC or advanced breast or ovarian cancer, and a Part 2 dose-expansion phase in pts with mCRPC whose previous androgen deprivation therapy failed. The primary safety endpoints were AEs and dose-limiting toxicities, with the goal of identifying a recommended phase II dose (RP2D). The primary efficacy endpoint was prostate-specific antigen (PSA) response (PSA reduction of ≥ 50%) in pts with mCRPC. Secondary efficacy endpoints included ORR per RECIST 1.1, radiographic PFS (rPFS) per Prostate Cancer Working Group 3 and OS in pts with mCRPC. We assessed homologous recombination deficiency (HRD), PIK3CA/ AKT1/ PTEN status and other alterations by next-generation sequencing. Results: Part 1 enrolled 21 pts: 17 with mCRPC, 3 with ovarian cancer and 1 with breast cancer (C1 [n=8], C2a [n=6] and C2b [n=7], C3 [not opened]). Ipat 400 mg QD + ruca 400 mg BID was the selected RP2D. 30 pts enrolled in Part 2, so 37 pts with mCRPC (C2b + Part 2) received the RP2D (median follow-up 93 days). All grade AEs occurred in 37 pts (100%), serious AEs in 8 pts (22%) and AEs leading to treatment modification in 26 pts (70%). The most frequent AEs (all grade and grade 3, respectively) were diarrhea (35 [95%] and 2 [5%]); asthenia (24 [65%] and 4 [11%]); and nausea (24 [65%] and 2 [5%]). There was 1 grade 4 AE (anemia) and no grade 5 AEs. See the table for efficacy data. In biomarker subgroups, the PSA response rate was 50% (3/6) in pts with HRD tumors vs 25% (4/16) in pts with HR-proficient tumors, and 14% (1/7) vs 40% (6/15) in pts with PIK3CA/ AKT1/ PTEN–altered or intact tumors, respectively. Conclusions: The combination of ipat and ruca was well tolerated but did not show clinically relevant antitumor activity in pts with mCRPC, including in predefined biomarker subpopulations. Clinical trial information: NCT03840200. [Table: see text]

265 Background: Adherence to oral chemotherapy (OC) is a critical factor in achieving optimal oncologic outcomes. Correct dosing, education, and symptom management are essential to maximizing adherence. As part of the 2020 Quality Oncology Practice Initiative Certification Program Fox Chase Cancer Center (FCCC), a NCCN Comprehensive Cancer Center, learned that only 33% of patients on OC had a documented OC plan, 7% were assessed for adherence, and 0% had documentation reflecting efforts to address non-adherence. Methods: Our goal was to create and implement an electronic medical record (EMR) tool (Oral Chemo Smart Form) to address the variance and deficiencies in monitoring adherence to OC. The Smart Form (SF) was designed to include fields to document the OC plan (drug, indication, dose, schedule, duration of cycle, initial start/end date) as well as provide a standard for documentation of education, management of toxicity and non-adherence. We integrated the SF into nursing, pharmacy, and physician workflows to capitalize on shared EMR tools. A series of Plan-Do-Study-Act cycles were conducted over 8 weeks within pilot clinics. Weekly review of the SF and feedback forms generated real-time progress reports which were serially appraised and shared with stakeholders. Results: Two oncologists (piloted in Genitourinary and Breast Cancer clinics), two pharmacists, and several nurses used the SF March 15, 2021 to May 7, 2021. Over these 8 weeks, 223 patients on OC were seen in clinic. If the OC was dispensed from FCCC, pharmacists were to complete the SF at the time of initial OC prescription, 7 days after dispensing, and with each refill. Pharmacists also identified patients receiving OC through a specialty pharmacy and routed a message to clinic nurses via an EMR message pool. The message became the trigger for nurses to call patients within two weeks to troubleshoot dispensing issues and/or complete the SF. Oncologists were to complete the SF with each clinic visit for a patient on OC. Feedback from the clinical and pharmacy teams motivated changes in the content fields of the SF and workflow. Ultimately, 45% of patients on OC had the SF completed. An OC plan was documented in 41% of patients, compared to 33% at baseline; 87% had an administration schedule compared to 81%. There was an increase in the number of patients contacted following start of OC, 35% from 4%. Medication adherence was assessed in 35% of patients, up from 7%. Documented discussions addressing medication adherence increased to 78%, from 0%. Conclusions: Introduction of the Oral Chemo SF in pilot clinics improved documented OC plans and administration schedules. Its use introduced a standard process for monitoring safety, assessing and addressing non-adherence, while troubleshooting specialty pharmacy dispensing issues. The SF will be implemented throughout FCCC and further evaluated with efforts focused on adopting and streamlining this as standard work.

305 Background: Nivolumab plus ipilimumab (NIVO+IPI), a first-in-class combination immunotherapy, was approved by the US Food and Drug Administration in April 2018 for the treatment of intermediate- or poor-risk advanced renal cell carcinoma (RCC), and the treatment paradigm has changed dramatically over the past few years. This real-world study examined treatment patterns and sequences, treatment response, safety, and survival outcomes with this novel first-line (1L) combination therapy among patients diagnosed with metastatic RCC (mRCC) in a community oncology practice setting. Methods: A retrospective analysis of the US Oncology Network’s iKnowMed medical data examined adult patients with an International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognosis of intermediate- or poor-risk clear cell mRCC who received 1L NIVO+IPI between April 1, 2018, and March 31, 2020. Baseline demographic and clinical characteristics, treatment patterns, and treatment sequence were examined descriptively. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), time to treatment discontinuation (TTD), and time to treatment response (TTR) were analyzed using the Kaplan–Meier method. Treatment-related adverse events (TRAEs) and healthcare resource utilization were also analyzed. Results: A total of 193 adults with stage IV mRCC treated with 1L NIVO+IPI were identified. Median age (range) was 63 (30.0–89.0) years, 73.1% were male, 69.4% were white, 56.7% were IMDC intermediate risk, and 60.6% had a documented Eastern Cooperative Oncology Group performance status of 0 or 1. Median follow-up time (range) was 9.7 (0.1–24.7) months. Median PFS (95% CI) was 17.1 (12.6–21.2) months, and the 1-year landmark PFS rate was 58.3% (50.4–65.4). At 12 months, the OS rate (95% CI) was 75.4% (67.8–81.4). The ORR (95% CI) was 43.2% (34.6–52.1) among patients with a response assessment; the median TTR (range) was 2.8 (0.3–4.1) months and median DoR was not reached. Median TTD (95% CI) was 5.8 (4.5–7.5) months. Among the 63 (31.3%) patients who received second-line therapy, 50.8% received cabozantinib and 12.7% received pazopanib. TRAEs were reported in 47.2% of patients—the most frequently reported were fatigue (13.5%), rash (10.4%), diarrhea (6.7%), nausea (6.2%), colitis (3.6%), and pruritus (3.6%). The treatment-related hospitalization rate was 5.5% and the emergency department visit rate was 3.1%. Conclusions: This real-world study supports the clinical efficacy of 1L NIVO+IPI for patients with mRCC. Our findings also suggest that the NIVO+IPI combination was generally well tolerated in the real-world setting, with low rates of adverse events and healthcare resource utilization.

1528 Background: The COVID-19 pandemic has disrupted US healthcare delivery and led to delays in life-prolonging therapy for some conditions. Its impact on diagnosis and timely care delivery for patients (pts) with cancer is unknown. We assessed the pandemic’s impact on time from advanced diagnosis to systemic treatment initiation (TTI) for pts with newly diagnosed advanced solid cancers. Methods: We performed a controlled interrupted time series analysis using the nationwide Flatiron Health electronic health record-derived de-identified database, which originated from ̃280 US cancer clinics. The study sample included pts ≥ 18 years diagnosed with advanced solid cancers from Jan 1-Jul 31 in 2019 or in 2020, excluding a 30-day period (Mar 8-Apr 7) encompassing the start of most state stay-at-home orders. We used Cox proportional hazards models to estimate standardized predicted probabilities of TTI within 30 days of advanced diagnosis before (Jan-Mar) and during (Apr-Jul) the pandemic in 2020, compared to historical controls in 2019, adjusted for age, sex, race, insurance, performance status, and cancer type. Interactions by cancer type and race examined heterogeneity of effects. Results: The study included 12,977 pts (median age 69 yrs [IQR 61-77]; 47.4% female; 59.4% non-Hispanic white). At the time of analysis, fewer advanced cancer diagnoses were recorded in 2020 (Jan-Mar 2,409; Apr-Jul 3,027) than in 2019 (Jan-Mar 2,910; Apr-Jul 4,631). Compared to Apr-Jul 2019, pts diagnosed with advanced cancer during the COVID-19 period were more likely to have de novo (vs recurrent) disease (67.3% vs 56.8%). In adjusted models, the COVID-19 period was associated with an increased probability of treatment within 30 days (adjusted difference-in-differences +5.2 percentage points [ppts]). TTI improvements were not observed for pts with advanced breast cancer or Black pts, but effect differences across subgroups were not statistically significant (Table). Conclusions: Among pts diagnosed with advanced cancer, the COVID-19 pandemic was associated with shorter time to systemic therapy initiation. These treatment patterns may reflect the fewer advanced cancer diagnoses and higher proportion of de novo cancers observed during this period. Longer follow-up and data maturity are needed to understand the impact of the pandemic on clinical outcomes.[Table: see text]

4551 Background: Front-line treatment for patients (pts) with metastatic clear cell renal cell carcinoma (mRCC) has undergone rapid advances in the last five years. This evolution has led to uncertainty about the optimal first line combination regimen. Herein, we compare real-world outcomes in pts treated with either axitinib/pembrolizumab (A/P) or ipilimumab/nivolumab (I/N) reported by International Metastatic RCC Database Consortium (IMDC) score. Methods: The nationwide Flatiron Health electronic health records-derived database was used to select pts diagnosed with mRCC and treated with front-line A/P or I/N from 2018-2020. The primary endpoints were overall-survival (OS) and real-world progression free survival (rwPFS). The survival analyses were adjusted using propensity score-based Inverse Probability of Treatment weighting, providing balance on age, gender, insurance, race, IMDC, practice type, and nephrectomy. Survival was assessed from beginning of therapy, and survival by treatment groups was compared using weighted and unweighted Kaplan-Meier curves with log-rank tests and weighted Cox proportional hazards regressions. Disease characteristics between the treatment groups were compared using chi-square and T-tests. Results: 821 pts received frontline A/P (n=259) or I/N (n= 562). Demographics and clinical parameters were similar between the two cohorts. Median age was 66 years, 73% were male, and 54.9% had a nephrectomy. 459 pts had all IMDC criteria factors available, 242 pts had missing factors but enough to define as intermediate/poor risk, 120 pts had unknown IMDC risk. Adjusted median OS was not statistically different: mOS for A/P was not reached (NR) while I/N was 22 mo (95% CI, 19.8-NR; p=0.40). Twelve-month survival was 68.5% for A/P treated pts and 65.8% for I/N treated pts (P=0.41). Twelve-month rwPFS was 41.4% for A/P treated pts and 39.7% for I/N treated pts (P=0.14). No statistical difference in survival was seen within IMDC risk strata (see table). Conclusions: In this retrospective, real-world study of pts treated with front-line A/P or I/N, 12-month survival was not statistically different irrespective of IMDC risk. Longer follow-up will be necessary to discern any significant differences.[Table: see text]

4535 Background: Treatment of advanced urothelial carcinoma (mUC) has improved following approvals of PD-1/PD-L1 inhibitors. Platinum chemotherapy remains the standard-of-care in the first-line (1L). Cisplatin (Cis) regimens are accepted to be superior to carboplatin (Carbo) regimens for patients (pts) who are Cis-eligible. We sought to evaluate if differences in efficacy of 1L Cis vs. Carbo have meaningful impact on overall survival (OS) in the era of second-line (2L) immunotherapy (IO). Methods: We conducted a retrospective, observational cohort study to compare OS for pts treated with 1L Cis or Carbo combined with gemcitabine (Gem) followed by 2L IO using patient-level data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Pts included were diagnosed with mUC between 9/1/2015 and 9/15/2020. 2L IO was defined as single-agent atezolizumab, avelumab, durvalumab, nivolumab, or pembrolizumab. OS was calculated from start of 1L and 2L therapy and compared using Kaplan-Meier curves. Time to 2L IO was calculated from start of 1L to start of IO. Adjusted OS was calculated using multivariable Cox regression models, adjusting for age, gender, race, ECOG performance status, primary site, prior cystectomy, smoking status, and year of diagnosis. Results: A total of 1882 pts were included, 924 (49.1%) received Gem/Cis and 958 (50.9%) received Gem/Carbo in 1L. A similar percentage of pts did not receive any 2L therapy following Gem/Cis (46.4%) or Gem/Carbo (46.0%). Our analysis focused on the 780 pts (41.4%) who received 2L IO—381 after Gem/Cis and 399 after Gem/Carbo. Median follow-up time for the group was 35 months (mo). Pts in the Gem/Cis cohort were younger, had better performance status and lower incidence of upper tract disease (Table). OS from start of 1L therapy was numerically longer in pts who received Gem/Cis compared to Gem/Carbo on unadjusted (median 18.0 v 16.2 mo, p = 0.06) and adjusted analyses (HR = 0.83, 95% CI 0.69-1.00, p = 0.055) but neither result was statistically significant. Time to 2L IO was longer for pts receiving Gem/Cis (6.5 mo) vs Gem/Carbo (5.5 mo, p = 0.008). Survival time on 2L IO did not differ significantly by 1L regimen (Gem/Cis 8.0 mo vs Gem/Carbo 8.2 mo p = 0.36). Conclusions: Real world data suggests that in pts with mUC who are able to receive second-line IO, the choice of first-line platinum chemotherapy may not provide a distinguishable OS benefit. Despite methodologic limitations of this data, a greater focus in discussions with patients on toxicity associated with cisplatin vs carboplatin may be warranted.[Table: see text]

4501 Background: Dysregulated metabolism is a hallmark of RCC, driven by overexpression of glutaminase (GLS), a key enzyme of glutamine metabolism. Telaglenastat (Tela) is an investigational, first-in-class, selective, oral GLS inhibitor that blocks glutamine utilization and critical downstream pathways. Preclinically, Tela synergized w/ cabozantinib (Cabo), a VEGFR2/MET/AXL inhibitor, against RCC tumors. In a Ph 1 study cohort, Tela+Cabo showed encouraging safety/efficacy as 2L+ therapy for mRCC. This trial compared Tela+Cabo vs Pbo+Cabo in previously treated pts w/ clear-cell mRCC (NCT03428217). Methods: Eligible pts had 1-2 prior lines of systemic therapy for mRCC, including ≥1 anti-angiogenic therapy or nivolumab + ipilimumab (nivo/ipi), KPS ≥70%, measurable disease (RECIST 1.1), no prior Cabo or other MET inhibitor. Pts were randomized 1:1 to receive Cabo (60 mg PO QD) with either Tela (800 mg PO BID) or Pbo, until disease progression/unacceptable toxicity, and were stratified by prior PD-(L)1 inhibitor therapy (Y/N) and IMDC prognostic risk group. Primary endpoint was progression-free survival (PFS; RECIST 1.1) by blinded independent radiology review. The study was designed to detect a PFS hazard ratio (HR) of 0.69 w/ alpha 0.05 and 85% power. Data cutoff date: August 31, 2020. Results: 444 pts were randomized (221 Tela+Cabo; 223 Pbo+Cabo). Baseline characteristics were balanced between arms. Median follow-up was 11.7 mo; 276 pts received prior ICI, including 128 w/ prior nivo/ipi. Median PFS (mPFS) was 9.2 mo for Tela+Cabo vs 9.3 mo for Pbo+Cabo (HR = 0.94; 95% CI: 0.74, 1.21; stratified log-rank P= 0.65) with overall response rates (ORR; confirmed) of 31% with Tela+Cabo vs 28% Pbo+Cabo, respectively. Overall survival was not mature at data cutoff. In a prespecified subgroup analysis in pts w/ prior ICI, mPFS was numerically longer w/ Tela+Cabo than Pbo+Cabo (11.1 vs 9.2 mo, respectively; unstratified HR = 0.77; 95% CI: 0.56, 1.06). In the Pbo+Cabo arm, mPFS was 9.2 mo for pts w/ prior ICI exposure and 9.5 mo for pts without, and ORR was 32% and 20%, respectively; if ICI included nivo/ipi, ORR was 37%. Rates of adverse events (AEs) were similar between arms.Grade 3-4 AEs occurred in 71% of Tela+Cabo pts and 79% of Pbo+Cabo pts and included hypertension (17% vs 18%) and diarrhea (15% vs 13%). Cabo was discontinued due to AEs in 10% of Tela+Cabo pts and 15% of Pbo+Cabo pts. Conclusions: The addition of Tela did not improve the efficacy of Cabo in mRCC in this study. Tela+Cabo was well tolerated with AEs consistent with known risks of both agents. The study provides valuable insight on efficacy outcomes of a contemporary population of pts w/ mRCC who receive Cabo in the 2/3L setting. Clinical trial information: NCT03428217.

4578 Background: Nivolumab in combination with cabozantinib (N+C) has demonstrated significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS), compared with sunitinib as a first-line (1L) treatment for aRCC in the phase 3 CheckMate (CM) 9ER trial. As there are no head-to-head trials comparing N+C with pembrolizumab in combination with axitinib (P+A), this study compared the efficacy of N+C with P+A as 1L treatment in aRCC. Methods: An MAIC was conducted using individual patient data on N+C (N = 323) from the CM 9ER trial (median follow-up: 23.5 months) and published data on P+A (N = 432) from the KEYNOTE (KN)-426 trialof P+A (median follow-up: 30.6 months). Individual patients within the CM 9ER trial population were reweighted to match the key patient characteristics published in KN-426 trial, including age, gender, previous nephrectomy, International Metastatic RCC Database Consortium risk score, and sites of metastasis. After weighting, hazards ratios (HR) of PFS, duration of response (DoR), and OS comparing N+C vs. P+A were estimated using weighted Cox proportional hazards models, and ORR was compared using a weighted Wald test. All comparisons were conducted using the corresponding sunitinib arms as an anchor. Results: After weighting, patient characteristics in the CM 9ER trial were comparable to those in the KN-426 trial. In the weighted population, N+C had a median PFS of 19.3 months (95% CI: 15.2, 22.4) compared to a median PFS of 15.7 months (95% CI: 13.7, 20.6) for P+A. Using sunitinib as an anchor arm, N+C was associated with a 30% reduction in risk of progression or death compared to P+A, (HR: 0.70, 95% CI: 0.53, 0.93; P = 0.015; table). In addition, N+C was associated with numerically, although not statistically, higher improvement in ORR vs sunitinib (difference: 8.4%, 95% CI: -1.7%, 18.4%; P = 0.105) and improved DoR (HR: 0.79; 95% CI: 0.47, 1.31; P = 0.359). Similar OS outcomes were observed for N+C and P+A (HR: 0.99; 95% CI: 0.67, 1.44; P = 0.940). Conclusions: After adjusting for cross-trial differences, N+C had a more favorable efficacy profile compared to P+A, including statistically significant PFS benefits, numerically improved ORR and DoR, and similar OS.[Table: see text]

5063 Background: ATM mutations, one of a family of DNA repair defects prevalent in prostate cancer, have been included in a list of actionable mutations for PARP inhibitor (PARPi) therapeutic trials. Despite preclinical evidence, PARPi have shown minimal clinical activity in ATM mutant prostate cancer (ATMmPCa). The present analysis explores co-occurring genomic alterations that may drive outcomes of metastatic PCa (mPCa) patients with tumors harboring ATM mutations and provide clues for understanding therapy resistance and potential targets. Methods: This study included molecular profiling analysis of 1375 cases of mPCa. Tumors were analyzed using next-generation sequencing (NGS), whole transcriptome sequencing (WTS), and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). dMMR/MSI-H status was determined by IHC, NGS, and fragment analysis and tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations. We performed differential gene expression analysis of HR-associated transcripts such as ATR, PARP1-3, RAD50, RAD51A/B/C/D and RAD54. Significance was determined using the ꭓ2 test and Benjamini-Hochberg method. Results: Fifty-nine (4.2%) cases harbored pathogenic ATM mutations, 84 (6.2%) harbored BRCA2 mutations. 1018 tumors (74%) were deemed homologous recombination proficient (HRP) and 155 tumors (11.3%) were HR Deficient (HRD); harboring one or more mutation in HR-related genes excluding ATM and BRCA2. The mutation rate of TP53 was significantly lower in ATMmPCa (12.0%) compared to BRCA2mPCa (35%), HRD (35%) and HRP (46.6%) tumors. ATMmPCa showed higher rates of SMAD2 (3.7%/1%) and FLCN (5.2%/0.3%) alterations compared to HRP cases. PARP1 and RAD51D gene expression was reduced in ATMmPCa compared to HRP (p < 0.05) and BRCA2mPCa ( p < 0.05) tumors, respectively. No differences in gene expression levels were detected for ATR, PARP2, PARP3, RAD50, and RAD54. Chromosomal segments demonstrating differential CNA in ATMmPCa vs HRP, HRD, or BRCA2mPCa included FGF19, FGF4, PTPN11, ALDH2, DAXX, BCL7A, CCND1, BMPR1A and MEF2B (Q-value < 0.05 determined by ꭓ2). The most common CNA in ATMmPCa was CCND1, present in approximately 13% (7/55) of cases. Compared to BRCA2mPCa and HRD cases, ATMmPCa cases are less likely to display markers of immunotherapy response such as dMMR/MSI-H or TMB ≥10 mutations/MB. Conclusions: ATMmPCa demonstrated several differences in co-occurring alterations compared to BRCA2mPCa, HRD and HRP mPCa. ATMmPCa tumors were less likely to harbor alterations in TP53 compared to BRCA2, HRD or HRP tumors. CNA in ATMmPCa occurred in 9 genes across distinct mPCa molecular subtypes and were enriched for those associated with the 11q13 amplicon harboring Cyclin D1. The FGF and PTPN11 related pathways are potentially targetable pathways in ATMmPC and may merit further study.

5013 Background: HPN424 is a prostate-specific membrane antigen (PSMA)-targeting T cell engager designed to redirect T cells to kill PSMA-expressing prostate cancer cells; engineered with three binding domains: anti-PSMA for tumor cell engagement, anti-albumin for half-life extension and anti-CD3 for T cell engagement. HPN424 is optimized for small size and increased stability compared to other bispecific platforms. Methods: This Ph1/2a study is evaluating HPN424 in mCRPC patients (pts) who have received > 2 prior systemic therapies. Primary endpoints are safety, tolerability and determination of MTD/RP2D. Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity and preliminary anti-tumor activity. HPN424 is administered IV once weekly. Tumor assessments include PSA, CT and bone scans every 9-weeks. Results: As of 2/8/21, 80 pts were dosed in 15 cohorts with target doses ranging from 1.3 to 160ng/kg fixed dose, and up to 300ng/kg with step dosing to the target dose after initial priming dose. Pts had received a median of 6 prior systemic regimens, 75% received prior chemotherapy for mCRPC. Median age was 70 (43 – 91). Most common grade > 3 TEAEs were AST increase (18%), anemia (11%) and ALT increase (11%). DLTs include CRS G3 (n = 3), elevated lipase G3 (n = 1) and seizure G3 (n = 1). These events did not limit escalation, MTD has not been reached and escalation continues. All grade CRS occurred in 63% of pts, 4% grade 3 per ASTCT and no Grade 4/5 CRS. CRS G3 events occurred after first administration of target dose (n = 2 fixed dose, n = 1 step dose). Transaminase elevation occurred predominantly during Cycle 1, was transient and had no clinical sequelae. Disease progression was the primary reason for drug discontinuation; 2 pts (3%) discontinued due to TRAE. Reduction in circulating tumor cells (CTC) was seen in 32 of 56 pts (57%) with measurable CTC at baseline. Fifteen of 62 pts (24%) with > 24 weeks follow-up remained on treatment ≥ 24 weeks. Thirteen of 63 pts (21%) with post-baseline levels had PSA declines from baseline, including 3 PSA50, 2 PSA30 responses. In chemo-naïve pts, 5 of 15 (33%) showed PSA declines post-baseline. In the highest fixed dose cohort (160ng/kg) tested to-date, 3 of 7 evaluable pts had PSA declines from baseline and 1 had a confirmed partial response per RECIST. Conclusions: HPN424, a novel half-life extended PSMA-targeting T cell engager, was well tolerated when administered once weekly. AEs were transient, manageable and consistent with class of agent. Grade 3 CRS was observed in 4% of patients, occurring with first administration of target dose. Evidence of antitumor activity included PSA and CTC reductions and treatment duration > 24 weeks in 15/62 pts. Encouraging signals were seen at the highest fixed dose cohort including a confirmed RECIST partial response. NCT03577028 Clinical trial information: NCT03577028.

4538 Background: Knowledge of large-scale real-world treatment patterns and clinical outcomes in patients (pts) with metastatic urothelial carcinoma (mUC) is limited. We conducted this study to address the lack of knowledge and identify unmet needs in pts with mUC in real-world clinical practice. Methods: The US nationwide Flatiron Health electronic health records–derived, de-identified database, comprised of 280 oncology practices across the US, was utilized to conduct a retrospective cohort analysis of pts diagnosed with mUC between Jan 1, 2011, and Aug 31, 2020. Baseline pt characteristics were assessed descriptively, and treatment patterns were classified by cisplatin (CIS) eligibility. Kaplan–Meier methods were used to evaluate overall survival (OS) and progression-free survival (PFS). In a subgroup analysis of cisplatin-ineligible (CIS-inelig) pts, a multivariable model adjusting for baseline covariates was used to assess survival outcomes. Results: Of 8183 pts with mUC, median age was 73.0 years at diagnosis. Primary tumor sites were bladder (78.5%), upper tract (20.6%), and urethra (0.9%). Median (range) follow-up from mUC diagnosis was 9.7 (0.2-116.6) months. Of 5855 (71.6%) pts who received first-line (1L) systemic therapy, 1764 (30.1%) were CIS eligible (CIS-elig), 2293 (39.2%) were CIS-inelig, and 616 (10.5%) did not receive CIS despite qualifying ECOG PS (0–1) and renal function; CIS eligibility was unknown in 1182 (20.2%). Among all 1L pts, 4380 (74.8%) received chemotherapy and 1410 (24.1%) received immunotherapy (IO); of the IO users, 1345 (95.4%) received monotherapy. Among CIS-elig pts, CIS plus gemcitabine (GC) and methotrexate, vinblastine, doxorubicin, CIS (MVAC) accounted for 1562 (88.5%) of 1L therapy. Among CIS-inelig pts, carboplatin plus gemcitabine (GCa; 36.1%), pembrolizumab (pembro) monotherapy (18.5%), and atezolizumab (atezo) monotherapy (15.1%) were the most common 1L therapies. Across CIS eligibility groups, the most common second-line therapies included pembro, atezo, and GCa; the most common third-line therapies included atezo, pemetrexed, paclitaxel, and GCa. Median OS (95% CI) was longer in pts who received ≥ 1 line of systemic therapy (14.5 [14.0–15.2] months) than in those who did not receive therapy (6.8 [6.2–7.3] months). Median (95% CI) OS and PFS were also longer in CIS-elig pts (OS, 19.7 [18.2–21.4] months; PFS, 11.5 [10.8–12.1] months) than in CIS-inelig pts (OS, 11.4 [10.8–12.0] months; PFS, 7.0 [6.7–7.4] months), irrespective of receiving treatment. In a subgroup analysis of CIS-inelig pts, 1L IO monotherapy was associated with worse OS than 1L chemotherapy (HR, 1.26; 95% CI, 1.13–1.40, P < 0.0001). Conclusions: This study of > 8000 mUC pts, of whom almost 30% never received systemic therapy, demonstrates real-world treatment patterns in mUC and highlights the substantial unmet need in this population, in particular for CIS-inelig pts.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 64-year-old man presented to the clinic to discuss treatment options for progressive metastatic urothelial carcinoma (UC). At age 57 years, he underwent cystoprostatectomy for bacillus Calmette-Guérin–refractory, high-grade noninvasive UC. He was well until age 61 years, when he developed a left upper-tract UC. He underwent left nephroureterectomy, revealing locally advanced high-grade UC invading the renal parenchyma (pT3). Postoperatively, his renal function precluded adjuvant cisplatin-based chemotherapy. He enrolled onto a clinical trial of autologous cellular immunotherapy targeting human epidermal growth factor receptor 2, for which he was eligible on the basis of human epidermal growth factor receptor 2 positivity (≥ 1+ by immunohistochemistry) in his nephrectomy tumor specimen. He was randomly assigned to observation. Two years later, he developed a left pelvic mass. Biopsy confirmed metastatic high-grade UC. He was briefly treated with gemcitabine and carboplatin, but this was discontinued as a result of rapid symptomatic and radiographic progression at 8 weeks. He underwent palliative radiation to the left pelvic mass to relieve symptoms of pain and leg edema and subsequently elected to enroll onto a clinical trial of a programmed death 1 inhibitor. Concurrently, his previously obtained pelvic mass biopsy sample was sent for panel-based genomic profiling. He now returns for his first restaging evaluation. Imaging shows marked progression on study with new metastases to the liver as well as progressive edema and pain in the left leg, limiting ambulation. Review of his now-available genomic testing results reveals alterations in HRAS (G12D) and ATR (S296, Q257). He elected to enroll onto a single-arm, open-label trial of a farnesyl transferase inhibitor for patients with HRAS mutations.

288 Background: The introduction of second-line (2L) nivolumab (NIVO) in 2015 (CheckMate 025) and first-line (1L) NIVO plus ipilimumab (NIVO+IPI) in 2018 (CheckMate 214) revolutionized the management of mRCC in the US. This study sought to leverage real-world (RW) data by applying CheckMate 214 inclusion criteria to develop a RW comparator for the trial to assess treatment patterns and sequences in RW patients (pts) with mRCC after receiving 1L NIVO+IPI or sunitinib (SUN). Methods: This retrospective study identified pts with clear cell mRCC from the Flatiron Health EHR-derived de-identified database who received 1L NIVO+IPI or SUN monotherapy on or after December 2015. Pts must have met the strict selection criteria from CheckMate 214 for this analysis. Evaluation of 1L, 2L, and third-line (3L) therapies was stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk (favorable [FAV] and intermediate/poor [I/P]). Results: Of 401 mRCC pts included in the study, 197 (49.1%) received NIVO+IPI and 204 (50.9%) received SUN as 1L therapy (Table). The median follow-up time was 10.1 months in NIVO+IPI pts and 20.2 months in SUN pts ( P < 0.0001). Among 66 (33.5%) NIVO+IPI pts who received 2L line therapy, the 2 most common therapies were cabozantinib (CABO; 50.0%), and pazopanib (PAZO; 12.1%). Among 119 (58.3%) SUN pts who received 2L therapy, the most common therapies were NIVO (48.7%), and PAZO (8.4%). The 2 most common 3L therapies were axitinib (AXI; 18.2%) or everolimus plus lenvatinib (EVE+LEN; 18.2%) for NIVO+IPI pts, and CABO (26.7%) or NIVO (15.0%) for SUN pts. The treatment sequence is similar between patients with FAV and I/P risk. Conclusions: In the RW setting, the treatment sequences after NIVO+IPI and SUN were largely similar across the IMDC risk groups. CABO was the most common therapy in 2L after NIVO+IPI in RW pts, and NIVO was the most common 2L therapy after SUN monotherapy, which was consistent with the sequence in the trial. [Table: see text]

53 Background: Multiple phase III trials have proven that Abi and Doc both improve overall survival (OS) in men with mHSPC. No randomized trials have compared the two approaches. Methods: We conducted a retrospective, observational study to compare OS in de novo M1 men, treated with Abi vs. Doc using patient-level data from the Flatiron health EHR-derived de-identified database. We also compared this real-world OS to trial level data using extracted data points along the OS curves from CHAARTED and LATITUDE trials. OS was compared via Kaplan-Meier curves. Analyses were adjusted via propensity score weighting for age, Gleason score, PSA at diagnosis, race, ethnicity, ECOG PS, insurance type and treatment setting. Results: The cohort included 418 Abi pts and 807 Doc pts (Table). Median follow-up was 13.5 mo for Abi and 31.6 mo for Doc. Unadjusted median OS for Abi and Doc were 31.6 mo (95% CI 28.1-NA) and 41.8 mo (95% CI 37.4-46.3) respectively (P=0.09). Twelve mo and 24 mo OS for Abi was 86.3% and 69%; for Doc it was 89.8% and 72.1 %. Median adjusted OS for Abi and Doc were 31.6 mo (95% CI 28.0-undefined) and 38.8 mo (95% CI 33.1-46.3) respectively (P=0.4). Twelve mo and 24 mo adjusted OS for Abi was 86.6% and 69.4%; for Doc it was 87.9% and 69.2%. Based on extracted trial data, in LATITUDE, Abi treated pts had 12 mo and 24 mo OS of 93.5% and 77.0%; in CHAARTED, Doc treated pts had 12 mo and 24 mo OS of 94.3% and 83.6%. Conclusions: Utilizing real-world data, we demonstrate that 12 and 24-months OS are clinically and statistically similar between Abi and Doc in men with mHSPC. Median OS is also similar, although due to limited follow-up, the estimate of median OS for Abi has large variability. In addition, we show that clinical trial pts had superior outcomes to those in a real-world clinic population. Recent meta-analyses of trial data have not found significant differences in OS for Abi vs. Doc; this analysis of real-world data confirms these findings and indicates that they may be generalizable to a broader patient population. Although this observational study is subject to residual confounding and missing data, it provides further evidence to support the use of both Abi and Doc in men with mHSPC. Differentiating costs, side-effects and QOL can thus become more prominent when making decisions about therapy. [Table: see text]

215 Background: With early screening and advances in treatment, prostate cancer (PC) patients are living longer and facing increasingly complex therapeutic decisions alongside significant financial burden related to care (e.g., copays, coinsurance, other out-of-pocket (OOP) costs). Conversations with providers about financial concerns can help patients navigate these decisions, thereby promoting delivery of quality care and improving quality of life. We characterized financial toxicity (FT) and patient-provider communication about cancer-related cost among PC patients and survivors. Methods: 107 PC patients and survivors enrolled in Cancer Support Community’s Cancer Experience Registry completed items assessing FT (11-item FACIT-COST measure; range = 0-44, lower scores indicate greater FT). Items include ability to meet monthly expenses, financial stress, and cancer/treatment influence on financial situation. Frequencies and correlations between FT, health care team (HCT) communication, and socio-demographics were examined. Results: Participants were 89% non-Hispanic White, 5% Black, 2% Hispanic; mean age was 68 years (SD = 7.5). Median time since diagnosis was 3 years; 19% reported experiencing symptoms of PC at the time of diagnosis. 21% were ever metastatic, 22% experienced a recurrence, and 48% reported currently receiving treatment. 29% were employed full- or part-time; 52% spent at least $100/month on all OOP PC costs, 30% spent $250 or more, 16% spent $500 or more. Mean FT score was 28 (SD = 11.9). 67% reported members of their HCT did not discuss cost of treatment, 55% did not discuss impact of PC and treatment on work, 77% did not discuss financial distress. While most participants were satisfied with their doctor’s explanation of benefits (89%) and risks/side effects (79%) for each treatment option, only 49% were satisfied with how much their HCT discussed financial costs of each option. Greater patient confidence in communicating with doctor about PC was significantly associated with less FT ( r= .19, p< .05), but experiencing more FT was not correlated with a greater likelihood of HCT discussing cost of treatment ( r= -.05, p= .63) or discussing impact of cancer and treatment on work ( r= .04, p= .67). Conclusions: Results indicate that patients with greater financial toxicity report less confidence in communicating with their doctor about PC, however providers are not frequently or systematically initiating discussions around cost and impact on work even among those experiencing the highest levels of financial burden. Findings underscore the critical value of transparency about health care costs and impact, as well as support for providers in communicating effectively with patients about costs and available resources, to improve patient quality of life and health outcomes.

397 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy (Cx) or chemoradiation (CRT) is the standard of care for urothelial carcinoma (UC) pts with muscle invasive bladder cancer (MIBC). Both Cx and CRT have potential short and long-term toxicity and QOL implications. Mutations in DNA damage repair/response genes are associated with pathologic downstaging after NAC. Methods: We conducted a phase II, multi-institutional clinical trial (NCT02710734) to evaluate a risk-adapted approach to treatment of MIBC. Pts with cT2-T3N0M0 UC of the bladder, ECOG PS 0-1 and CrCl≥50 mL/min, underwent NAC with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC). Pre-NAC TURBT specimens were sequenced (Caris Life Sciences) for mutations (pathogenic or VUS) in ATM, ERCC2, FANCC or RB1. Pts with at least one mutation and no clinical evidence of disease by restaging TUR and imaging post-NAC began pre-defined active surveillance (AS). Remaining pts underwent bladder-directed therapy: intravesical therapy ( < cT2 post-NAC), CRT or Cx. The primary endpoint was metastasis-free survival (MFS) at 2 years which is not mature. We herein report key interim results of clinically-meaningful intermediate endpoints. Results: Seventy-one (ITT) pts were enrolled over 33 months at four academic centers. Median age was 70 years (47-83), 74% were male, 92% Caucasian, 81% ECOG PS 0 and 79% cT2. 90% completed 3 cycles of NAC and with 17% grade 3-4 TRAEs and one death during AMVAC. At the time of data cut-off (September 11, 2020), for the ITT pts, 32 pts have had a Cx, 5 underwent CRT and 7 underwent intravesical therapy, at some point during the trial. Thirty-three pts (46%) had a mutation of interest and 28 pts (39%) started AS (2 of the 28 pts on AS did not have a mutation but elected to start AS after achieving cT0 post AMVAC). 76% of those with a mutation were cT0 at post-NAC TURBT. With a median follow-up of 14.9 mo (range: 3.1-35.3 mo), 14 AS pts recurred (50%). Of the 14 recurrences, 2 recurred with locally advanced or metastatic disease and have died, 5 had MIBC with one eventual metastatic recurrence, and 7 had NMIBC. Six (14%) non-AS pts have died. Out of the 40 pts who did not go to upfront Cx [AS (N = 28), CRT (N = 5), intravesical tx (N = 7)], 3 (7.5%) (all in the AS group) went on to Cx later. The bladder preservation rate is 55% for ITT pts and 89% for the AS group. In the AS cohort, mutations were seen in RB1 (50%), ATM (42%), ERCC2 (31%), FANCC (4%) with lowest rate for recurrence in ERCC2 (25% recurrence) vs RB1 (62% recurrence). Conclusions: Interim results of a phase II trial of risk enabled therapy utilizing a selection of clinical and genomic factors in pts with cT2-T3 MIBC demonstrates a 50% rate of any UC recurrence and a 11% rate of locally advanced/metastatic disease in the AS group. 89% of AS pts have retained their bladder. Follow-up continues for the primary endpoint of 2-year MFS. Clinical trial information: NCT02710734.

343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.

e13679 Background: The role of germline genetic testing (GGT) is rapidly changing for men with PCa. We describe the characteristics of men with PCa diagnosed with pathogenic (P) and likely pathogenic (LP) mutations on GGT. Methods: We conducted a retrospective single-institution study for all men with PCa who received single gene or multi-gene GGT from 1997-2019, unselected for disease stage, Gleason score, or age at diagnosis, and while most had a family history of cancer, some did not. All participants were from the Risk Assessment Program (RAP) database at FCCC and consented for research purposes at the time of GGT. Results: 160 men with PCa had GGT. 72/160 (45%) patients had no mutations. 41/160 (26%) patients had a variant of undetermined significance (VUS) (13 with 2 VUS, 1 with 3 VUS). 47/160 (29%) men were found to have a P or LP germline mutation. 26/47 (55%) with recurrent disease, and 1/47 (2%) unknown. 46 were Caucasian, and 1 was African American ( PALB2). 28/47 (60%) had Gleason Scores (GS) ≤7. 6/47 (13%) had a Prostate Specific Antigen (PSA) at diagnosis < 4.0 ng/mL. 23/47 (49%) were diagnosed < 60 years of age, and 8/47 (17%) at ≤ 50. 19/23 (83%) PCa cases with P/LP diagnosed below age 60 had DNA repair genes: BRCA2 (8), BRCA1 (4), CHEK2 (4), ATM (2), and PALB2 (1). 74/160 (46%) were tested after PCa NCCN genetics guidelines changed (October 2017), of which 19/74 (25%) had P/LP, and of those positive for P/LP, 6/19 (32%) had non-metastatic disease. Two patients had small cell neuroendocrine PCa ( CHEK2 and BRCA2), the remaining had adenocarcinoma PCa. Please see Table for full results. Conclusions: To our knowledge, this is the largest single-institution study reporting PCa characteristics and incidence of P/LP germline mutations. Rates of DNA-repair gene mutations were higher than previously reported, possibly reflecting our specialized cancer center’s population. While BRCA1/2 mutations were the most represented (55%), we describe PCa patients with mutations in ATM, CHEK2, NBN, PALB2, CFTR, and MUTYH, recognizing a few are not known to be linked to PCa. More than half of P/LP mutation carriers had GS ≤7. Additionally, 13% of the men with P/LP germline mutations had low PSA ( < 4.0 ng/mL) at diagnosis. Our findings highlight the importance of the new guidelines and GGT importance in some men with PCa, particularly if they could benefit from a different therapeutic approach, or be influenced into cascade GGT. [Table: see text]

5000 Background: Radical surgery ± cisplatin-based neoadjuvant chemo (NAC) is the mainstay treatment (tx) for MIUC, with no conclusive level 1 evidence for adjuvant chemo (AC). Here we present the primary analysis from IMvigor010, a global, open-label, multicenter, randomized trial of adjuvant atezo (anti–PD-L1; approved in metastatic UC [mUC] settings) in pts with MIUC at high risk of recurrence following primary resection. Methods: Pts with MIUC (bladder, upper tract [UT]), ECOG PS 0-2 and resected tissue for PD-L1 testing on immune cells (IC; VENTANA SP142 assay) were enrolled ≤ 14 wks after radical cystectomy/nephroureterectomy with lymph node (LN) dissection. Pathologic stage: 1) ypT2-4a or ypN+ if pts had NAC or 2) pT3-4a or pN+ if pts did not have NAC. No postsurgical radiation or AC was allowed; if no NAC was given, pts must have been ineligible for or declined cisplatin-based AC. Pts were randomized 1:1 to atezo 1200 mg IV q3w or obs for 16 cycles or 1 y (stratification factors: no. of LNs resected, pathologic nodal status, pathologic tumor stage, PD-L1 status, prior NAC). Disease-free survival (DFS) was the primary endpoint (EP). Final DFS, first interim overall survival (OS; secondary EP) and safety are reported. Results: The ITT population included 809 pts (median follow-up, 21.9 mo). In the atezo and obs arms, respectively, 48% and 47% had NAC; 7% and 6% had UTUC as primary disease; 48% each had LN+ disease. DFS and OS are in Table. Baseline prognostic/clinical factors did not influence DFS tx benefit; stratified HR was 0.81 (95% CI: 0.63, 1.05) in IC0/1 pts (PD-L1 < 5%; n = 417) and 1.01 (0.75, 1.35) in IC2/3 pts (PD-L1 ≥ 5%; n = 392). 16% of atezo-treated pts had a tx-related G3-4 AE. Skin and gastrointestinal toxicities most commonly led to tx discontinuation. Conclusions: IMvigor010, the first phase 3 adjuvant study of a checkpoint inhibitor in MIUC, did not meet its primary EP of DFS. More tx discontinuation due to AEs was seen vs mUC studies. Safety was generally consistent with previous studies. Clinical trial information: NCT02450331 . [Table: see text]

Purpose This study sought to define and identify drivers of trends in cost and use of targeted therapeutics among privately insured nonelderly patients with cancer receiving chemotherapy between 2001 and 2011. Methods We classified oncology drugs as targeted oral anticancer medications, targeted intravenous anticancer medications, and all others. Using the LifeLink Health Plan Claims Database, we studied and disaggregated trends in use and in insurance and out-of-pocket payments per patient per month and during the first year of chemotherapy. Results We found a large increase in the use of targeted intravenous anticancer medications and a gradual increase in targeted oral anticancer medications; targeted therapies accounted for 63% of all chemotherapy expenditures in 2011. Insurance payments per patient per month and in the first year of chemotherapy for targeted oral anticancer medications more than doubled in 10 years, surpassing payments for targeted intravenous anticancer medications, which remained fairly constant throughout. Substitution toward targeted therapies and growth in drug prices both at launch and postlaunch contributed to payer spending growth. Out-of-pocket spending for targeted oral anticancer medications was ≤ half of the amount for targeted intravenous anticancer medications. Conclusion Targeted therapies now dominate anticancer drug spending. More aggressive management of pharmacy benefits for targeted oral anticancer medications and payment reform for injectable drugs hold promise. Restraining the rapid rise in spending will require more than current oral drug parity laws, such as value-based insurance that makes the benefits and costs transparent and involves the patient directly in the choice of treatment.

506 Background: NAC improves survival in pts with MIBC eligible to receive cisplatin-based chemotherapy. Prospective data supports the use of aMVAC, however concerns about toxicity limits usage compared to gemcitabine and cisplatin, especially in the elderly. We investigated the safety and efficacy of aMVAC as a function of age. Methods: We conducted a retrospective analysis of pts with MIBC at Fox Chase Cancer Center who received NAC with aMVAC from 2008-2017. Pts were excluded for non-urothelial histology, non-muscle-invasive or primary upper tract disease, or if final pathology was not available. Clinicopathologic variables were extracted from charts and pts were grouped into 3 cohorts by age ( < 65, 65-74, ≥75). Associations between age group (gp) and categorical/continuous factors were evaluated using Fisher’s exact/Wilcoxon rank sum tests. Results: A total of 90 pts ( < 65: 40; 65-74: 28; ≥75: 22) were evaluable for safety and 84 for efficacy. The majority of pts were male (72%), PS 0 ( < 65: 85%; 65-74: 85%; ≥75: 68%) and Caucasian (90%). Baseline clinical staging was cT2 in 50%, cT3 in 27% and > cT3 in 14%, with 9% lacking clinical staging. Mean number of aMVAC cycles delivered was numerically similar between age gps, though statistically different (3.1 v 2.8 v 2.6; p = 0.01). There were no statistically significant differences in dose reductions, treatment interruptions, or time to surgery (10.7 v 10.7 v 10.1 wks, p = 0.91) by age. Grade ≥3 AEs were most frequent in the youngest age gp (14.4% v 2.2% v 8.9%, p = 0.018). Split-dose cisplatin was increasingly used in advanced age (2.5% v 17.9% v 31.8%, p = 0.003). Although glomerular filtration rate (GFR) at baseline inversely correlated with age (105 v 93 v 63 ml/min, p < 0.0001), there was no difference in % GFR decline at 90 days or 1 year. The downstaging rate to < pT2N0 disease was similar in all age gps (41.0% v 29.6% v 38.9%; p = 0.41). At median follow-up of 20 months, recurrence rates were 30.0% v 25.9% v 28.6% (p = 0.95). Conclusions: NAC with aMVAC yields similar safety and efficacy outcomes regardless of age, thus age should not be a factor in determining treatment eligibility.

716 Background: Pembrolizumab/axitinib significantly prolonged progression-free survival (PFS) and overall survival (OS) vs. sunitinib in a phase 3 trial KEYNOTE-426 among previously untreated patients with advanced renal cell carcinoma (RCC). This study assessed the cost-effectiveness of pembrolizumab/axitinib vs. other first-line treatments of advanced RCC from a US payer perspective. Methods: A partitioned survival model with 3 states (progression-free, progressed, death) evaluated costs and quality-adjusted life years (QALYs) for pembrolizumab/axitinib and other first-line regimens: sunitinib and pazopanib in the overall population; sunitinib, cabozantinib, and nivolumab/ipilimumab in the subgroup with poor/intermediate IMDC risk. Time on treatment, PFS, and OS were extrapolated using parametric models fitted to KEYNOTE-426 data (24 Aug 2018 cutoff) for pembrolizumab/axitinib and sunitinib, and hazard ratios from network meta-analyses for other comparators. Costs of first-line and subsequent treatment, adverse events, medical resources, and terminal care were estimated based on trial results, drug labels, and published sources. Utilities were derived through mixed-effects regressions of KEYNOTE-426 EQ-5D data. Results: Over a lifetime, the incremental cost-effectiveness ratios (ICERs) for pembrolizumab/axitinib were below willingness-to-pay thresholds of $150,000/QALY or $180,000/QALY (approx. 3 × gross domestic product per capita) vs. all comparators in the overall and intermediate/poor risk populations (table). Results were robust in deterministic and probabilistic sensitivity analyses. Conclusions: Pembrolizumab/axitinib is associated with higher QALYs and considered cost-effective vs. other first-line treatments of advanced RCC in the US.[Table: see text]

85 Background: Metformin (MET) may play a role as an anti-proliferative and anti-carcinogenic agent. Epidemiological studies have demonstrated that MET is associated with decreased prostate cancer (PCa) incidence, including decreased PCa specific mortality in diabetic men with PCa. Preclinical studies have shown synergistic effect of MET with bicalutamide, thus prompting this clinical trial evaluating the combination (NCT02614859). Methods: This was an open label, randomized, phase II trial of pts with biochemically recurrent PCa, PSA doubling time 3-9 months, normal testosterone, and BMI > 25. Pts were randomized (2:1) either to MET 1000 mg twice daily orally or observation for initial 8 weeks. Bicalutamide 50 mg orally daily was added to both arms after 8 weeks. Total duration of treatment was 32 weeks. The primary objective was to determine number of pts with undetectable PSA ( < 0.2 ng/mL) at the end of study with key secondary objectives of evaluating PSA declines of ≥ 85%, PSA responses to MET alone and safety. An early stopping rule for futility was set at 39 pts, but due to slow accrual, an unplanned interim analysis was undertaken. Results: 28 patients were randomized between December 2015 and September 2019. Treatment was well tolerated with no dose reductions or treatment discontinuation. No Grade 3 treatment-related adverse events were observed. Conclusions: PSA responses were seen in 50% pts with MET monotherapy after 8 weeks. Although well tolerated, there was no difference in PSA at 32 weeks between the two arms. The trial will be stopped early due to poor accrual and inability to achieve its primary endpoint. Ongoing larger studies of MET in PCa (STAMPEDE) will define it’s utility in prostate cancer. Clinical trial information: NCT02614859. [Table: see text]

523 Background: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by cystectomy is the standard of care for muscle-invasive urothelial bladder cancer (MIBC). 15-35% of MIBC patients present with ureteral obstruction. Poor renal function increases cisplatin toxicity. It is unknown whether patients with ureteral obstruction which has been relieved (whether by nephrostomy tube or nephroureteral stent) have the same risk of toxicity as patients without ureteral obstruction. Methods: We retrospectively reviewed an institutional database of all patients undergoing NAC for MIBC with either dose dense MVAC (ddMVAC) or gemcitabine and cisplatin (GC) from January 2004 through May 2017. Patients without ureteral obstruction prior to initiation of NAC (Group A) were compared to those who had ureteral obstruction which was relieved prior to undergoing NAC (Group B). Continuous variables were compared using the Wilcoxon rank-sum test and categorical variables were compared using Fisher’s exact test. The primary outcome was premature discontinuation of NAC, which was defined as failure to complete all planned cycles. Logistic regression was used to test for differences between the groups in this outcome adjusting for age, ECOG performance status, and baseline glomerular filtration rate (GFR). Results: 160 patients in Group A and 59 patients in Group B were identified. Baseline age, Charlson Comorbidity Index, race, smoking status, and ECOG performance status were similar. Patients in Group B had lower GFR (99.2% vs 78.8% p

4567 Background: Drug combinations targeting vascular endothelial growth factor (VEGF) and the programmed death one (PD-1) pathway have demonstrated encouraging efficacy in patients (pts) with mRCC. We are conducting a phase I/II trial combining the VEGF-targeting tyrosine kinase inhibitor (TKI) axi and the PD-1 inhibitor nivo in mRCC pts. Methods: The phase I portion of this investigator-initiated, multi-center trial enrolled pts with TKI-refractory mRCC (any line) and no prior anti-PD-1. It used a 3+3 design, with axi dosing starting at 3 mg orally BID, escalating to a target dose of5 mg BID. Nivo dosing was fixed at 240 mg IV Q2 weeks or 480 mg Q4 weeks. Eligible pts received axi alone for a one week induction, followed by combination dosing. There was a 4 week period to assess for dose limiting toxicities (DLTs). The primary endpoint for phase I was safety and establishment of a recommended phase II dose (RP2D) for axi. Safety and early efficacy data for the phase I cohort are presented. Results: Twelve pts received treatment during the phase I portion, with all evaluable for toxicity. Ten were 2nd line and 2 were 3rd line or beyond. One DLT was noted in the first cohort of three pts (grade 3 autoimmune disorder), thus that cohort was expanded. No further DLTs were reported at axi 3 mg BID, or at further expansion to 5 mg BID. Grade 3 adverse events (AEs) at least possibly related to one of the drugs included expected side effects HTN, hyperglycemia, and transaminitis. One patient received steroids for an immune related AE (grade 3 transaminitis) that resolved to grade 1 with steroids. No grade 4-5 AEs occurred. Axi at 5 mg BID was chosen as the RP2D. With 10 pts evaluable for efficacy, 4 pts had partial responses, 4 pts had stable disease, and 2 had progressive disease. Updated efficacy data will be presented. Conclusions: The phase I portion of this phase I/II trial has demonstrated expected safety and established 5 mg BID as the RP2D axi dose. This ongoing VEGF TKI/PD1 trial incorporating two drugs already approved for mRCC pts has shown encouraging signs of efficacy and has now expanded to include treatment naïve pts in addition to TKI-refractory pts as part of phase II. Clinical trial information: NCT03172754.

4504 Background: Platinum-based chemotherapy for 1st-line treatment of pts with metastatic urothelial cancer (mUC) is typically administered for a fixed duration followed by observation until recurrence. PD-1 blockade with pembro improves survival of pts with mUC progressing despite platinum-based chemotherapy. We explored the potential benefit of earlier use of PD-1 blockade using a "switch maintenance" approach. Methods: Pts with mUC achieving at least stable disease after up to 8 cycles of 1st-line platinum-based chemotherapy were enrolled. Pts were randomized 1:1 to pembro 200 mg IV q3 weeks versus placebo for up to 24 months; pts progressing on placebo could cross over to pembro. Randomization was stratified based on pre-chemotherapy visceral metastases (Y/N) and response to 1st-line chemotherapy (CR/PR vs. SD). The primary objective was to determine the progression-free survival (PFS) as per irRECIST among pts treated with pembro versus placebo. Results: Between 12/2015 and 11/2018, 107 pts were randomized to placebo (n=52) versus pembro (n=55). The baseline pt characteristics are shown in the Table. Pts randomized to placebo and pembro received a median of 6 and 8 cycles, respectively. Excluding patients with baseline CRs, the objective response rate was 12% (5/42) on placebo and 22% (10/46) on pembro. Grade 3-4 treatment emergent adverse events occurred in 48% of pts on placebo and 56% on pembro. At a median follow-up of 14.7 months, 41 pts have died and 26/52 pts randomized to placebo have crossed over to pembro. PFS was significantly longer in patients randomized to pembro vs. placebo (Maximum Efficiency Robust Test p=0.036; log-rank p = 0.038). The 18-month restricted mean progression-free survival time was 5.6 months with placebo and 8.2 months with pembro (p=0.023). Conclusions: Switch maintenance pembro may “deepen” responses achieved with 1st-line chemotherapy. Switch maintenance pembro prolongs PFS in pts with mUC completing 1st-line platinum-based chemotherapy. Clinical trial information: NCT02500121. [Table: see text]

TPS67 Background: Treatments for 1L advanced/metastatic UC include platinum-based chemotherapy, an immune checkpoint inhibitor (ICI) or clinical trial enrollment. Not all patients benefit from, or are eligible for, specific therapies due to comorbidities and performance status. There is an urgent need for biomarker-directed strategies to enable patient selection and improve outcomes. Currently the only clinically used molecular biomarker is PD-L1 protein expression in tumor tissue. Although inconsistent and variable among assays, higher PD-L1 expression generally correlates with increased ICI response rate. Improved understanding of the prevalence and potential prognostic and/or predictive role of PD-L1 can further enhance its clinical utility and guide novel clinical trial designs. Methods: This observational study will enroll 250 patients with advanced UC prior to starting or during 1L therapy, as initiated at the discretion of participating clinicians, from 60 US community sites. The primary endpoint is prevalence of PD-L1 expression by VENTANA SP263 Assay (exact [Clopper-Pearson] 95% CI) on pre-treatment tumor tissue. Secondary endpoints include the association of pre-treatment PD-L1 expression with pre-treatment tumor tissue mutational burden (tTMB), descriptions of treatment response and outcomes (ORR based on RECIST 1.1, PFS, OS) and assessment of their correlations with PD-L1 expression. Exploratory endpoints include the association of pre-treatment tumor tissue PD-L1 with pre-treatment blood-based tumor mutational burden (bTMB), changes in circulating tumor DNA (ctDNA) levels at various timepoints, the correlation between tTMB and bTMB values, and the association of those biomarkers for outcomes of PFS and OS. Enrollment will take place over 24 months with follow-up to 30 months from study enrollment. With 250 patients, the 95% CI for 30%, 45%, and 60% observed prevalence of PD-L1 high are (24.4%, 36.1%), (38.9%, 51.2%), and (53.6%, 66.1%), respectively; the various secondary and exploratory analyses will be descriptive.

399 Background: Adenocarcinoma (ADA) and squamous cell carcinoma (SCC) are rare, aggressive subtypes of bladder cancer, for which no clear standard of care exists. We report on survival of pts with ADA and SCC and identify potential therapeutic targets using molecular profiling via next generation sequencing (NGS). Methods: Survival trends, demographics, pt characteristics were obtained from the Surveillance, Epidemiology, and End Results (SEER) Database. In a separate cohort, NGS results from 72 specimens (50% metastatic) were also analyzed, using either a hotspot 47 gene panel or a 592 gene assay (Caris Life Sciences, Phoenix, AZ). Results: In SEER, 235,537 cases of bladder cancer were extracted from 1988-2008, of which 3096 were SCC and 671 were ADA. 90% of pts were white, although more African-American patients (15%) were seen in those with ADA. Among all stages, median overall survival (mOS) and 5-yr survival rates were 17.9 mos and 58% for ADA and 15 mos and 37% for SCC. Via NGS testing, 43 patients (28 ADA, 15 SCC) were tested with a 47 gene panel and 29 (21 ADA, 8 SCC) with a 592 gene panel. In the 47 gene panel, among ADA pts, the highest mutation rates were TP53 (57.1%), KRAS (21.4%), SMAD4 (14.8%), PIK3CA (10.7%) and BRCA2 (7.7%). Among SCC pts, the highest mutation rates were TP53 (66.7%), PIK3CA (33.3%), HRAS (14.3%), FBXW7 (6.7%) and AKT1 (6.7%). In the 592 gene assay, the genes with the highest mutation rates in pts with ADA were TP53 (81%), SMAD4 (33.3%), KRAS (23.8%), KMT2C (11.8%), ARID1A (11.1%), BRAF (9.5%), CTNNB1 (9.5%), KMT2D (9.5%), TSC1 (9.5%), KDM6A (5.9%), CDKN2A (5%). Among SCC pts, the highest mutation rates were TP53 (75%), CDKN2A (42.9%), FGFR3 (25%), PIK3CA (25%), CIC (14.3%), KDM6A (14.3%), BRAF (12.5%), BRCA1 (12.5%), FH (12.5%), HRAS (12.5%) and KMT2D (12.5%). Only 1 pt had high TMB. Conclusions: Genomic profiling identifies differences in underlying tumor biology of bladder ADA and SCC, which on a population level are rare with poor survival. Overall, the alterations in the PIK3CA/ AKT/ mTOR and TP53 pathways are similar to what has been reported in UC. Future analyses of these malignancies should investigate the emerging actionable targets, such as TSC1, FGFR3, BRCA1/2 and BRAF.

TPS682 Background: Glutamine metabolism is upregulated in renal cell carcinoma (RCC) and important for RCC tumor cell proliferation and survival. CB-839 is a first-in-clinic, potent, oral inhibitor of the mitochondrial enzyme glutaminase (GLS), which controls a critical step in tumor cell metabolism of glutamine. CB-839 demonstrated synergistic anti-tumor activity when combined with cabozantinib, a VEGFR2/MET/AXL inhibitor, in preclinical RCC models. In a phase 1 study cohort, CB-839 plus cabozantinib as 2L+ therapy showed encouraging safety and efficacy results, with 50% overall response rate (ORR; RECIST v1.1) and 100% disease control rate in 10 patients with clear cell advanced/metastatic RCC (mRCC). A randomized, double-blind study comparing CB-839 plus cabozantinib vs. cabozantinib plus placebo has been initiated in patients with clear cell mRCC. Methods: In this ongoing international, randomized, double-blind, multi-center study, enrollment is planned for ~300 patients with clear cell mRCC. To be eligible, patients should have received 1-2 prior lines of systemic therapy for mRCC including ≥1 anti-angiogenic therapy or the combination of nivolumab + ipilimumab, have KPS ≥70%, measurable disease (RECIST v1.1), and no prior cabozantinib (or other MET inhibitor). Patients are randomized 1:1 to receive either CB-839 (800 mg twice daily per oral [PO] route) plus cabozantinib (60 mg daily PO) or cabozantinib plus placebo in 28-day cycles until disease progression or unacceptable toxicity. Patients are stratified by prior PD-1/PD-L1 inhibitor therapy and by IMDC prognostic risk group (favorable vs. intermediate vs. poor). The primary endpoint is progression-free survival (PFS) per RECIST v1.1, determined by blinded independent radiology review. Secondary endpoints are investigator-assessed PFS and overall survival. Safety, response per RECIST, and quality of life are also assessed. Findings of this randomized, international clinical trial will inform the efficacy and safety profile of CB-839, a first-in-clinic metabolic inhibitor, in combination with cabozantinib in patients with mRCC. Clinical trial information: NCT03428217.

378 Background: The WHO recognizes multiple variant histologies of urothelial carcinoma (vUC), many of which have been associated with poor outcomes compared with urothelial carcinoma (UC). We aimed to explore molecular differences between aggressive vUC and UC. Methods: 23 micropapillary (MP), 16 plasmacytoid (P), 23 sarcomatoid (S), 7 nested (N), 6 clear cell (CC), and 2 giant cell (GC) vUC specimens were tested between 2012 to 2018 via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (next generation sequencing [NGS]), gene amplification (CISH or NGS), and protein expression (immunohistochemistry [IHC]). Findings were compared to 435 control UC specimens using the Chi-square test. Results: 84% of samples were from primary tumor. Alterations identified are summarized in Table 1, and are notable for high rates of TP53 mutations across histologic subtypes, varying rates of RB1, ERBB2 and FGFR mutations, and overall low rates of DNA damage repair (DDR) mutations (29 genes reported) except in S. There were more ARID1A mutations detected in MP than UC (100% [3 specimens] v. 41.3%, p=0.044), and more CDH1 mutations in P than UC (50% [4 specimens] v. 2%, p5%) in a high proportion of S (55.6%, p=0.002) but in a lower proportion of other vUC (e.g. absent in P). Tumor mutational burden (TMB) was high in a lower proportion of vUC: 18.4% UC vs. 14.3% MP, 0% P, 16.7% S. Conclusions: Aggressive variant histology UCs have a differential profile of molecular aberrations compared to UC, with notable differences in potential targets such as HER2 and DDR genes as well as immunotherapy biomarkers. Further studies are needed to confirm these findings, and may support therapy development for these rare, aggressive UC subtypes. Aberrations (%) in Variant Histology UC. [Table: see text]

560 Background: Level I evidence exists demonstrating the efficacy of the mTOR inhibitor everolimus (EVE) in decreasing tumor volume of syndromic angiomyolipomas (AMLs) among patients with Tuberous Sclerosis. No prospective data are available regarding the effect of mTOR inhibition on growth kinetics in patients with sporadic AMLs. Methods: We conducted a multi-institutional, prospective, phase 2 trial with an optimal two-stage Simon design in patients presenting with > 3cm sporadic AMLs who were candidates for surgical or percutaneous intervention. Response was defined as ≥25% volumetric reduction of the AML. Planned enrollment was 43 patients to test the null hypothesis at a 5% level of significance with 80% power. Baseline, 4- and 6-month volumetric analysis was performed by dynamic contrast-enhanced MRI (DCE-MRI). Patients received EVE 10mg for four 28-day cycles, at which point EVE was discontinued in those with < 25% volumetric reduction. Those with ≥ 25% volumetric reduction received two additional cycles of EVE. Dose reductions and interruptions were allowed to 5 mg QOD. Conservative stopping rules were established for toxicity, given the benign nature of AMLs. Results: The early stopping rules for both efficacy and toxicity were invoked. We enrolled 20 patients (median age = 68) from 5 centers with 21 sporadic AMLs. 11/20 (55%) patients completed 4 cycles of EVE, while 7/20 (35%) completed 6 cycles. Median days on treatment was 88 (2 cycles). 4/20 (20%) patients were withdrawn due to toxicity, while 8/20 (40%) withdrew due to personal preference. Dose reductions were required in 6/20 (30%) patients, and 5/20 (25%) patients had grade 3 toxicities which resolved upon discontinuation or dose reduction of EVE. At 4-month MRI, 10/16 (62.5%) patients had a ≥25% reduction in volume (mean = 54.1% decrease). At 6-month MRI, 8/12 (66.6%) patients had a ≥25% reduction in volume (mean = 51.5% decrease). Conclusions: EVE was effective in reducing tumor volume in patients with sporadic AMLs but was associated with a high rate of treatment termination due to patient preference or prespecified AEs. Neoadjuvant EVE may be useful in potentiating surgical resection of large or anatomically complex AMLs. Clinical trial information: NCT02539459.

274 Background: Despite improvements in the medical management of advanced prostate cancer (aPC), it continues to be the 2nd leading cause of cancer death in American men. The contemporary management of men with aPC is increasingly complex and can vary based on access to up-to-date treatments, which is often found at busier treatment centers. We thus evaluated the relationship between facility volume and survival outcomes in aPC. Methods: The National Cancer Database (NCDB) was queried from 2004-2014 for aPC, defined as T4, N+, or M+ disease. Six pre-defined patient cohorts were evaluated. Cohort A = patients with aPC (N = 64,815); cohort B = M0 patients (N = 27,155); cohort C = M0 patients undergoing active treatment (N = 21,755); cohort = all M1 patients (N = 37,660); cohort E = M0 patients undergoing active treatment (N = 30,643); and cohort F = M1 patients who underwent active treatment and who had known metastatic sites (N = 12,452). Treatment facilities were divided into quartiles based on median treatment volume: 5.6 patients/year. Regression models were adjusted along a set of covariates available in the NCDB. The primary outcome was overall survival (OS). Results: OS improved with each increase in volume quartile. The top quartile (>5.6 pts/yr) demonstrated significantly greater OS compared to the bottom quartile (5.6 pts/yr) confers a significant OS advantage when compared to management at a facility in the lowest quartile (

4579Background: Cabo shows robust clinical activity in advanced clear cell RCC. nccRCC, a heterogeneous mix of diseases, have been underrepresented in clinical trials and effective systemic therapy...

6514Background: Therapies previously reserved for castration resistant prostate cancer (CRPC) have demonstrated improved progression-free (PFS) and overall survival (OS) in mHNPC. Four randomized t...

4545Background: Neoadjuvant cisplatin (70mg/m2) based chemotherapy (NAC) prior to cystectomy is standard of care for MIBC. Many patients (pts) cannot receive cisplatin due to impaired renal functio...

DOI: 10.1200/JCO.2012.48.2059 The inbox of my work e-mail was neatly organized into folders—an attempt to keep some semblance of control over my life as a hematology-oncology fellow in a busy academic medical center. Recently, with my training near its end and with the knowledge that I would be leaving the university, I decided to clean out the thousands of emails I had accumulated. At first, I found this easy, clicking the “Delete” button again and again with a growing sense of satisfaction and accomplishment...until I reached the “Patient e-mails” folder. I found myself staring at hundreds of e-mails with familiar names. No different than tombstones at a cemetery, these e-mails were neatly lined up, organized by date and a few subject words. I clicked the “From” button, rearranging the e-mails by sender, and suddenly, the stories returned. KV (cholangiocarcinoma): questions about pain, diarrhea, shingles, mouth sores, Ativan; then silence. BD (pancreatic cancer): e-mails about nausea, weight loss, rearranging Monday’s chemotherapy appointment, lab results, fatigue; silence. EH (lung cancer): an inquiry about an appointment time, an episode of confusion, a fall, pain, hospitalization; silence. MP (renal cell carcinoma): low blood counts, a note of thanks, a Happy New Year greeting, a request for a second opinion, pain; silence. What happened in the space of those silences? I realized that, for the most part, I never kept in touch with my patients once chemotherapy stopped working, instead handing off care responsibility to my hospice and palliative care colleagues. As I read through those e-mails and recalled my relationships with those patients, I wondered if this well-meaning transition, although in many ways appropriate, should be reexamined for its effects on patients, doctors, and the doctor-patient relationship. My eyes returned to two particular patients— L.B. and M.M.—and I couldn’t help but smile but thinking about them. L.B. was a bright, well-respected physician with a horrible cancer. He came to our hospital for a second opinion and stayed under our care as we enrolled him onto a clinical trial. It was the first time I had taken care of another physician for an extended period of time, and I got to know L.B. well. I met his family and talked to him about his practice and the challenges of transitioning away from it prematurely. I fielded many of his calls and e-mails, and he was kind enough to allow me to be his primary oncologist. In return, I allowed him as much control as possible in his care. L.B. did well at first, with the tumor shrinking and pain abating, which allowed him to travel. He continued to chair national meetings and to bring gifts of fruit baskets for all of us in the clinic. But inevitably, as he and I had known from the start would happen, his cancer began to grow once again, and soon a permanent abdominal drain was required. A new course of chemotherapy was useless and then came weight loss, fatigue, thrush, blood clots, and pain. We met and spoke about hospice. He agreed that it was time, and we made a referral. He jokingly said that he would not bother me so much anymore, because the hospice doctor would take over. That was the last time we spoke until I received an e-mail from his wife informing me of his death at home, followed several weeks later by a card from his family thanking me for his care. At the same time, I was taking care of M.M., a recently retired school teacher, avid golfer, fisherman, and tennis player. His cancer, originally diagnosed as localized and treated with liver surgery, had returned and was no longer curable. M.M. was stoic, calm, and accepting of his diagnosis. His wife was obviously in love with M.M. and shocked and confused about their new predicament. She told me during our first meeting that they were looking for a doctor who would be with them “throughout his illness,” until the end. I promised that I would do just that. And indeed I watched him go through months of chemotherapy as well as yoga, acupuncture, daily tennis, and numerous fishing trips (we joked that he fished more in one year than most people do in a lifetime). Eventually, his cancer, too, progressed. As I was trying to manage M.M.’s pain and arrange for initiation of palliative radiation, I left for vacation. On my return, I found that M.M. had been referred to palliative care by one of our nurses and JOURNAL OF CLINICAL ONCOLOGY A R T O F O N C O L O G Y VOLUME 31 NUMBER 12 APRIL 2

641 Background: Weighing operative, oncologic and comorbid risks guide treatment recommendations for localized kidney cancers. We hypothesize that individualized surgical decision making may also be influenced by surgical center and volume. Methods: The National Cancer Database (NCDB) was queried for patients 18-80 years old with pT1a-T2bN0M0 RCC, treated by partial (PN) or radical nephrectomy (RN), or ablation (ABL) from 2004-2014. After adjusting for clinicopathologic characteristics, we evaluated the association of hospital volume (vol) and center classification with receipt of PN. High vol was defined as the top 10% in treatment volume. Results: 142,090 patients met inclusion criteria, where 58% (n = 82,498) and 41% (n = 58,873) were treated by RN and PN, respectively, and 1% (n = 719) by ABL. The utilization of PN increased over time (2004: 24% vs 2014: 53%; p < 0.001). Stratified by tumor stage, 60% (n = 47,484) of pT1a and 24% (n = 9,906) of pT1b tumors were treated by PN. On multivariate analysis, patients treated at a high-vol center (OR 1.89, 95% CI 1.57-2.28) had a greater likelihood of receiving a PN when compared to treatment elsewhere. Additionally, compared to a community cancer program, treatment at a comprehensive community cancer center (OR 1.39, 95%CI 1.23-1.57), academic/research (OR 1.67, 95%CI 1.47-1.90), or integrated network cancer program (OR 1.48, 95%CI 1.24-1.77) had a higher likelihood of receiving a PN. The median distance travelled was 9.8 and 18.1 miles, for treatment at non high vol and high vol centers, respectively. An inverse correlation was noted between increasing tumor stage and receipt of PN, compared to pT1a tumors (pT1b [OR 0.22, 95%CI 0.20-0.23], pT2a [OR 0.06, 95%CI 0.05-0.06], pT2b [OR 0.03, 95%CI 0.02-0.03]). Conclusions: In the NCDB, despite increased utilization of PN at higher vol centers, the majority of localized renal tumors are still treated with RN. Smaller tumor size, treatment at a higher vol centers, comprehensive community cancer centers, academic/research programs, or integrated network cancer programs increase the likelihood of receipt of PN. Evaluation of population based trends aid in understanding localized RCC surgical management and may help quality improvement efforts.

264 Background: Small cell bladder cancer (SCBC) and small cell prostate cancer (SCPC) are rare and aggressive cancers. Standard therapy remains a platinum agent combined with etoposide, with few options after recurrence. Advances in molecular genomics and drug development have altered our approach to cancer. These same novel approaches may alter how we approach SCBC and SCPC. The purpose of this study is to identify potential targets and compare molecular profiles of SCBC and SCPC to SCLC. Methods: In total, 21 SCBC and 19 SCPC were identified from a de-identified database (Caris Life Sciences). Specimens were evaluated for genetic aberrations (Sanger or next generation sequencing [NGS], ISH) and/or protein expression (immunohistochemistry [IHC]). Comparisons were made against a de-identified cohort of SCLC (n = 428). Results: Pathogenic/presumed pathogenic mutations in SCBC were found in TP53 (91.7%, 11/12), RB1 (18.2%, 2/11), PTEN (8.3%, 1/12), EGFR (7.7%, 1/13), and PIK3CA (7.1%, 1/14). SCPC genetic aberrations were detected in TP53 (72.7%, 8/11) and RB1 (25.0%, 2/8). No carcinomas in this cohort had a high mutational burden or MSI-high status (0%, 0/7). Amplified genes found in SCBC included DDR2 (50%, 1/2) and EGFR (25.0%, 1/4). In SCPC, gene amplification was found in AKT2 (20%, 1/5), CCNE1 (20%, 1/5), FGFR1 (20%, 1/5), and MYC (20%, 1/5). The highest protein expression rates in SCBC involved MRP1 (100%, 5/5), TOP2A (94.1%, 16/17), and RRM1 (81.3%, 13/16). The highest protein expression rates in SCPC were MRP1 (100%, 6/6), TUBB3 (100%, 9/9), and TOP2A (94.4%, 17/18). Comparisons between SCBC and SCPC with SCLC revealed more similarities than differences. Significant differences were found in RRM1 by IHC between SCBC and SCLC. Also, significant differences were found between SCPC and SCLC in AR and PTEN by IHC. Conclusions: Comparisons of GU small cell carcinomas reveal similarities to SCLC. Both TP53 and RB1 mutations were found in both SCBC and SCPC. Amplification in genes CCNE1 and FGFR1, frequently identified in SCLC, were also found in SCPC. The high protein expression in biomarkers like MRP1 may explain the poor response to cytotoxic chemotherapy. Prospective studies are urgently needed.

594 Background: Higher treatment facility (TF) volume has been linked with improved surgical and hematologic malignancy outcomes. We evaluated the association between TF volume and overall survival (OS) in pts with metastatic renal cell carcinoma (mRCC). Methods: The National Cancer Data Base was queried for all pts with mRCC and survival data available (2004 to 2013, cohort A). We defined high volume TFs as those in the top 20th percentile of mean number of mRCC pts treated per year ( > 5 pts). The effect of volume on OS was determined using unadjusted Kaplan-Meier curves and Cox regression models (MVA) adjusting for pt (age, sex, race, ethnicity, insurance type, income, Charlson-Deyo Score), facility (location, practice setting) and clinical characteristics (histology, presence or absence of liver and lung metastasis). Increasingly more stringent inclusion criteria were used to confirm the overall cohort association (cohort B = mRCC pts with active treatment; cohort C = mRCC pts with systemic therapy; cohort D = mRCC pts with systemic therapy at the reporting institution; cohort E = mRCC pts with systemic therapy at the reporting institution with liver and lung metastatic status known). Results: There were 44,109 mRCC pts treated at 1,224 TFs. The median age was 65, 66% were men and 75% had clear cell mRCC. Median TF volume was 2.4 pts/year (range 0.1-46.8). High volume TFs treated 54% of all mRCC pts. The unadjusted median overall survival of mRCC patients (cohort A) treated at high vs low volume TFs was 9.2 vs 6.4 months (P < 0.0001). This difference was maintained in all cohorts: cohort B = 13.7 vs 10.9, cohort C = 12.4 vs 10.0, cohort D = 12.5 vs 9.3, and cohort E = 13.4 vs 10.6 months (P < 0.0001 for all cohorts). MVA confirmed that facility volume was associated with all-cause mortality after adjustment: HR = 0.85, [95% CI 0.82-0.88], P < 0.001. These results were consistent regardless of inclusion criteria, e.g. for cohort E: HR = 0.839, [95% CI 0.785-0.897], P < 0.0001. Considering the definition of high volume, all thresholds > 5 pts/year showed a survival benefit, with the largest effects at ≥10 pts/year. Conclusions: Patients with mRCC treated at higher volume facilities had a longer survival compared with those treated at lower volume facilities.

TPS537 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy (Cx) or chemoradiation (CRT) is the standard of care for urothelial carcinoma (UC) pts with muscle invasive bladder cancer (MIBC). Both Cx and CRT carry potential short and long-term toxicity and quality of life implications. Recent work has shown that mutations in DNA damage repair/response genes are predictive of pathologic downstaging after NAC at the time of Cx, with those pts achieving pT0 disease demonstrating excellent long-term survival (Van Allen et al. Cancer Discov. 2014; Plimack et al. Eur Urol. 2015; Liu et al. JAMA Oncol. 2016; Teo et al. CCR. 2017). Sparing pts Cx or CRT after NAC without compromising oncologic outcomes would improve quality of life and decrease morbidity. Methods: A phase II, parallel arm, multi-institutional clinical trial (NCT02710734) is being conducted to evaluate a risk-adapted approach to treatment of MIBC. Pts with cT2-T3N0M0 UC of the bladder, ECOG PS 0-1 and CrCl≥50 mL/min, undergo NAC with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin. Simultaneously, the pre-NAC TURBT specimen is submitted for deep sequencing to identify variants in a panel of cancer-relevant genes (Caris Life Sciences, Phoenix, AZ). Those with an alteration in ATM, RB1, FANCC or ERCC2 and no clinical evidence of disease by restaging TUR and imaging post-NAC will begin a pre-defined active surveillance regimen that includes urinary cytological, cystoscopic, and radiographic evaluations. The remaining pts will undergo bladder-directed therapy at the discretion of the pt and clinician applying either intravesical therapy ( < cT2 post-NAC), CRT or Cx (≤cT2 post-NAC) or Cx (≥cT3 post-NAC). The primary objective is metastasis-free survival (MFS) at 2 years for all enrolled and evaluable pts. The trial has a non-inferiority design with a 14% margin between risk-adapted treatment (MFS = 78%) and standard-of-care (MFS = 64%) with a sample size of 70 pts, 82% power and a type I error of 0.045. Key secondary and translational objectives: assess the rate of UC recurrence in active surveillance pts; validate biomarkers of response to NAC; evaluate urinary biomarkers consistent with persistent UC. Clinical trial information: NCT02710734.

170 Background: Historically, responses to chemotherapy beyond the first line for lung cancer range from 5-10%. The effect of antecedent immunotherapy on the response and reaction to chemotherapy is not well-established, but the immunomodulatory effects of many chemotherapy agents may lead to synergistic effects including both improved responses and unique toxicities. Methods: We reviewed the charts of patients at our institution who received at least one dose of an anti-PD-1 agent (aPD-1) as monotherapy prior to June 1, 2017. Patients with a diagnosis of non-small cell lung cancer or small cell lung cancer who received subsequent chemotherapy were included for analysis. Charts were assessed for response to aPD-1, occurrence of immune-related adverse event (irAE) on aPD1, type of post-aPD-1 (PaPD-1) chemotherapy, PaPD-1 best response to chemotherapy, and occurrence of irAE during PaPD-1 chemotherapy. irAEs were assessed based on treating physician diagnoses. We tested the association between response and treatment characteristics using Fisher’s exact and Wilcoxon rank-sum tests. Results: A total of 40 patients met criteria for inclusion. Histology was NSCLC in 38 (95%) and SCLC in 2 (5%). Median age was 68 and mean number of lines of therapy prior to aPD-1 was 2.00 (95% CI, 1.72-2.28). PaPD-1 chemotherapies included paclitaxel (15%), docetaxel (28%), gemcitabine (23%), docetaxel-ramucirumab (7.5%), pemetrexed (2.5%) and platinum doublet (15%). The disease control rate to PaPD-1 chemotherapy was 35% and the ORR was 15% (0 complete responses, 6 partial responses). The response to PaPD-1 was not higher in taxane-containing regimens than in non-taxane-containing regimens (16% v. 13%, p = 0.99). Four (10%) patients were diagnosed with an irAE during their receipt of PaPD-1 chemotherapy. These PaPD-1 irAEs included dermatitis, colitis, and pneumonitis that responded to steroid therapy and occurred on various chemotherapy agents (gemcitabine, paclitaxel, docetaxel). Conclusions: In lung cancer, the response to chemotherapy beyond first line may be modestly higher when administered after aPD-1 therapy. Immune-related adverse events can occur during chemotherapy administered after aPD-1 therapy has been stopped.