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4559 Background: The International Metastatic RCC Database Consortium (IMDC) risk model was developed for prognosis of patients with mRCC treated with vascular endothelial growth factor (VEGF)-targeted monotherapy in the first-line setting. Efficacy in trials of anti-VEGF therapy has been generally consistent across risk groups, including for overall survival (OS). For trials of immunotherapy combinations, the small numbers of OS events for the favorable risk group in each trial limited reliable conclusions; however, there was a suggestion of possible differential effects on OS between favorable risk and other risk groups. Methods: We pooled individual patient data (n=3447) from four phase III randomized trials of combinations of immunotherapy + immunotherapy (n=1) or immunotherapy + anti-VEGF therapy (n=3) submitted to the US Food and Drug Administration in support of marketing applications. All trials calculated IMDC risk group for each patient and used a control arm of sunitinib. We combined intermediate and poor prognostic groups (“intermediate/poor”) and compared their OS to that of the favorable risk group using Kaplan-Meier and Cox Proportional Hazards methods. Results: In this pooled analysis, treatment with combination immune checkpoint therapy did not demonstrate an improvement in OS compared to sunitinib in the favorable risk group (HR 0.953; 95% CI: 0.72, 1.27). An improvement in OS was observed in the intermediate/poor risk group (HR 0.696; 95% CI: 0.62, 0.78). Conclusions: Our analysis of OS in patients treated with immunotherapy combinations compared to sunitinib suggests possible differential benefit in the favorable risk compared to the intermediate/poor risk group. These results are not conclusive and considered exploratory due to the relative immaturity of OS in the favorable risk group. Follow-up for survival continues in each study to allow for more definitive results.[Table: see text]

12038 Background: The FDA has approved three androgen receptor (AR) inhibitors for nonmetastatic castration-resistant prostate cancer (nmCRPC) based on improvements in metastasis-free survival (MFS). MFS is an earlier endpoint, defined as the time from randomization to either imaging-detectable distant disease or death. This pooled analysis examines MFS, time to initiation of cytotoxic chemotherapy (TTCyto), and safety outcomes in men over 80 treated with AR inhibitors. Methods: Data was pooled from three randomized controlled studies (n=4117) of AR inhibitors for nmCRPC. The treatment effect of AR inhibitors on MFS and TTCyto across age groups was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. Hazard Ratios for MFS and TTCyto were adjusted for baseline ECOG, total Gleason score, PSA doubling time, and prior bone-targeting therapy. Results: For patients age 80 years or older (n=675) who were treated with AR inhibitors, the hazard ratio was 0.38 (95% CI 0.29, 0.49) with an estimated median MFS of 40 months (95% CI 36, 41) versus 22 months (95% CI 18, 29) for those treated with placebo (n=348). For patients

5045 Background: Although recent evidence has suggested that patients who receive antibiotics (ABX) during the course of ICI treatment might decrease overall survival (OS) (1), our previous analysis did not support a difference in OS in urothelial cancer patients who did and did not use ABX during the course of ICI treatment without regard to timing (2). This updated analysis aims to addresses the question of timing; specifically, use of ABX in the 30-day window pre- or post- initiation of ICI treatment. Methods: We pooled data from 7 trials that led to drug approval and which included 1747 patients with advanced urothelial cancer treated with an ICI. Five trials enrolled patients who received prior platinum and 2 enrolled cisplatin-ineligible patients. Concomitant medication datasets were searched for systemic ABX use. The association between ABX use and survival was evaluated using Kaplan-Meier estimates and Cox proportional hazards regression models stratified by study. Results: Overall, 56% of patients were exposed to antibiotics (ABX+) and 43% were not exposed (ABX-). In an exploratory analysis, median OS was similar between arms: 9.7 vs. 9.3 months in ABX+ vs. ABX- patients, respectively (HR 0.96). However, OS results differed in the 27% of patients who were exposed to antibiotics in the 30-day window pre- or post- initiation of ICI treatment, for whom median OS was 4.7 months vs. 11.5 months in the ABX+ vs. ABX- patients, respectively (HR 1.8). This remained true after controlling for baseline risk prognostic factors (Bajorin and Bellmunt scores). Similar trends were observed for progression-free survival (PFS). Conclusions: Patients treated with ABX while on therapy with an ICI for urothelial cancer had similar OS outcomes to those not treated with ABX. However, in an exploratory analysis looking at ABX use in the 30-day window pre- or post-initiation of ICI treatment, OS appeared decreased in ABX+ vs ABX- patients. Our exploratory analyses appear to show an association of OS/PFS with timing of antibiotics. References: 1) Routy B, Science (2017) 2) Weinstock C, ASCO 2019, abstract. [Table: see text]

4557 Background: Previous data has suggested that patients treated with anti-PD-1/L1 antibodies who receive antibiotics during their therapy might have dramatically decreased progression-free and overall survival 1,2. This has clinical implications for management of patients with suspected bacterial infection while on treatment with these agents. We assessed the relationship between antibiotic use and tumor response rate, progression-free survival, and overall survival in a large dataset of patients with urothelial cancer treated with anti-PD-1/L1 antibodies. Methods: We examined seven trials that led to drug approval and which included 1747 patients with metastatic or locally advanced urothelial cancer treated with an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy and two enrolled patients who were cisplatin-ineligible. Six were single arm trials and one was a randomized controlled trial whose control arm is not included in these analyses. Concomitant medication datasets were searched for systemic antibiotic used by each patient while on treatment. Results: Overall, 51% of patients (n=892) were exposed to antibiotics (ABX+) and 49% (n=855) were not exposed (ABX-). In these exploratory analyses, small numeric differences in OS, PFS, and ORR were seen in ABX+ vs. ABX- patients. Median OS was 9.23 vs. 9.86 months, median PFS was 105 vs 101 days, and ORR was 20% vs. 21% in ABX+ vs. ABX- patients, respectively. Conclusions: Patients who were treated with antibiotics while on therapy with an anti-PD-1/L1 antibody for urothelial cancer had similar outcomes to those who were not treated with antibiotics. Numeric differences in outcomes were not significant and did not duplicate previous analysis demonstrating a median OS that was doubled in ABX- patients1. Our exploratory analyses do not appear to demonstrate a clear need for practitioners to avoid antibiotic use in patients treated with PD-1/L1 agents for fear of significantly impacting clinical outcomes. References: 1) Tinsley et. al., ASCO annual meeting 2018, abstract 3010 2) Routy et. al., Science 05 Jan 2018: Vol. 359, Issue 6371. [Table: see text]

4556 Background: Registrational trials of PD-1/PD-L1 inhibitor therapy help inform clinicians and patients about the expected outcomes of patients receiving these drugs. However, the clinical trial population does not reflect all patients with the underlying disease. There have been ongoing efforts to expand eligibility criteria for clinical trial enrollment that are expected to mitigate some of these factors. We reviewed four registrational trials of PD-1/PD-L1 inhibitor therapy to better understand why patients were deemed ineligible for trial enrollment and whether expanded eligibility criteria may have addressed the reasons for ineligibility. Methods: We reviewed four trials that led to approval of PD-1/PD-L1 inhibitor therapy. These trials screened 1931 and enrolled 1253 patients with metastatic or locally advanced urothelial cancer who had previously received platinum-based therapy. We examined the datasets to determine patient demographics and reasons for trial ineligibility. Results: There were no differences in the demographics characteristics of patients who were eligible or ineligible for study treatment. However, when compared to the SEER database the screened population was younger, and minorities were under-represented. Causes of patient ineligibility included: 1) Lack of Tumor Tissue/PD-L1 Low Tumor Staining (23%), 2) Underlying Disease characteristics were not met (19%), 3) Laboratory Abnormalities (18%), 4) Excluded Co-morbid Conditions (16%), 5) Poor Performance Status (15%), 6) Refused Consent (10%), 7) Other (7%), and 8) Incorrect Prior Therapy (5%). Conclusions: Clinical trial accrual should be representative of all patients with the underlying disease. Changes in trial eligibility criteria such as less stringent requirements concerning tumor tissue (when possible), co-morbid conditions, laboratory abnormalities, and performance status may improve patient accrual. These, when added together, formed the majority of the reasons for clinical trial ineligibility.

4549 Background: To assess the relationship between tumor response rate, overall survival, and the development of related adverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients with urothelial cancer treated with anti-PD-1/L1 antibodies. Methods: We examined seven trials that led to drug approval and which included 1747 patients with metastatic or locally advanced urothelial cancer treated with an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy and two enrolled patients who were cisplatin-ineligible. The datasets were searched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined by the Investigator. Immune-mediated adverse events were defined as AESIs treated with topical or systemic corticosteroids. Results: In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti-PD-1/L1 antibody while a related imAE occurred in 28% and 12% of patients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overall survival was seen in patients with related AESIs compared to those with no related AESI [hazard ratio (HR) 0.42; 95% CI: 0.37, 0.49]. Fifty-seven percent of responding patients with a related AESI reported a related AESI prior to documentation of response. Conclusions: Patients who responded to treatment with an anti-PD-1/L1 antibody were more likely to report a related AESI or related imAE. This relationship did not appear to be due to the increased duration of exposure in responding patients. Systemic corticosteroid use did not appear to affect the duration of response.

2565 Background: PD-1/L1 inhibitor therapy has become the standard of care for many advanced solid tumors. A notable limitation of PD-1/L1 inhibitor therapy is the concern for AESI that are likely to be immune related. It is unclear whether a history of autoimmune events is a predisposing risk making these adverse events more likely. We aimed to evaluate the association between autoimmune-associated PMH and AESI on PD-1/L1 inhibitors. Methods: We pooled data across seven pivotal trials for PD-1/L1 inhibitors in urothelial cancer (UC) identifying patients with AESI submitted from 2016 - 2017. AESI were determined using a pooled preferred term list for each trial. Information collected from trials included PMH, AESI events and toxicity grade. Results: In total, 1747 immunotherapy treated patients were identified, with 1068 (61%) having an AESI and 277 (26%) having an autoimmune-related PMH. The most common autoimmune-associated events in the PMH were thyroid disorders (64%), asthma (23%), atopic dermatitis/eczema (6%), irritable bowel syndrome (5%), and psoriasis (4%). AESI occurred in 68% of patients with an autoimmune-related PMH and 60% of patients without an autoimmune-related PMH. The most common AESI in patients with an autoimmune-related PMH were diarrhea (35%), rash (27%), renal disorder (27%), and pruritis (23%). The most common AESI in the general trial population were diarrhea (28%), pruritis (26%), rash (25%), increased creatinine (14%), and elevated AST and ALT (10% and 9%). The majority of events were Grade 1-2 (87% in patients with an autoimmune-related PMH and 84% in the general trial population). Conclusions: Pooled clinical trial data shows a slight numeric increase in AESIs in patients with autoimmune-associated PMH. Limitations include potential lack of consistency of PMH documentation and adverse event reporting. There did not appear to be a pattern of association between PMH and type of AESI event. Grades of AESI events in the population with autoimmune-associated PMH were similar to the general trial population. This suggests that PD-1/L1 inhibitors may be safely administered to patients with UC and a PMH of some autoimmune-associated events. Further exploration is needed.

6052 Background: Regulations require IND application review by the FDA prior to initiation of the clinical study. Deficiencies identified in the study protocol require communication between the FDA reviewers and the Sponsor for resolution. If the deficiencies are not adequately resolved, clinical hold and subsequent delay in the start of the clinical study results. To identify and analyze the commonly encountered IND application deficiencies, data from recent reviews were collected. Methods: Eight clinical reviewers analyzed the deficiencies that had been identified in 268 IND applications reviewed in the DDOP FDA from January 2003 to June 2005. All of the study protocol deficiencies leading to a clinical hold, or requiring resolution prior to study initiation were categorized as deficiencies pertaining to: patient eligibility; starting drug dose; study conduct (toxicity management, dose adjustment, stopping criteria); statistical or endpoints; non-clinical; and other issues. Results: 268 IND applications reviewed over a 30-month period by eight medical officers were analyzed. One hundred and twelve (42%) of the applications had no deficiencies; however, 156 (58%) had one (31%) or multiple (69%) deficiencies. Deficiencies pertained to study conduct/scheme (65%), dose (48%), patient eligibility (46%), others (31%), statistics or endpoints (15%), and non-clinical (4%) issues. In 141 (90%) of the deficient applications the deficiencies were adequately addressed by FDA reviewer-Sponsor communication and the trials could start as scheduled. Fifteen (10%) deficient trials were placed on clinical hold. Fourteen (93%) of these trials had multiple deficiencies that pertained to patient eligibility in 12 (80%), starting drug dose in 12 (80%), study conduct in 11 (73%), other in 7 (47%), and non-clinical and statistical issues in 2 (13%) each. Conclusions: Deficiencies were identified in 58% of the reviewed IND applications: 90% of these were resolved by FDA-Sponsor communication. Only 10% of deficient studies were placed on clinical hold; all except one had multiple deficiencies. The most common deficiencies leading to clinical hold pertained to eligibility of study population and proposed starting drug dose. No significant financial relationships to disclose.