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4516 Background: Immunotherapy-based combination therapies (IO-X) are standard of care for metastatic RCC (mRCC) in the frontline setting. Limited data is available on the role of cytoreductive nephrectomy prior to IO-X in patients (pts) with mRCC (Bakouny, et al. GU ASCO 2020). We assessed the correlation between nephrectomy prior to IO-X and overall survival (OS) in pts with de novo mRCC. Methods: We pooled data from trials submitted for FDA review of a checkpoint inhibitor combination as first-line treatment for pts with mRCC. We only included trials with available data for stage at initial diagnosis (dx) to identify pts with stage IV disease at initial dx and to exclude those with nephrectomy in the non-metastatic setting. Kaplan-Meier method was used to estimate median OS in pts with de novo mRCC with and without nephrectomy prior to IO-X. Results: Five trials met inclusion criteria, all of which evaluated IO in combination with a kinase inhibitor. Data for stage at initial dx was available in 1708 pts who received IO-X. The majority of pts were male (72%) and White (80%). Among the 849 pts (50%) with stage IV RCC at initial dx, 523 pts (62%) had nephrectomy prior to IO-X. All pts had clear cell histology; Sarcomatoid differentiation was present in tumor pathology of 25% and 10% of pts with and without prior nephrectomy, respectively. Proportion of pts with favorable, intermediate and poor risk disease was 10%, 70% and 20%, respectively. OS appeared better in those with stage IV disease at dx who had prior nephrectomy compared to pts without nephrectomy (Hazard ratio (HR) = 0.53, 95% CI: 0.42, 0.68), even after adjusting for age and prognostic risk group (HR = 0.59, 95% CI: 0.46, 0.75) (see table). Conclusions: In this retrospective exploratory analysis, nephrectomy prior to IO-X in pts with new dx of stage IV RCC appeared to be associated with improved OS, even when controlling for age and prognostic risk group. The decision for nephrectomy is affected by factors such as medical comorbidities which could not be completely controlled. Results should be considered hypothesis generating.[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]

5081 Background: Time to treatment discontinuation (TTD) has been proposed as a potential pragmatic real-world data (RWD) endpoint, and was closely correlated with progression-free survival (PFS) in pooled analyses of non-small cell lung cancer (NSCLC) and breast cancer trials across therapeutic classes (Blumenthal, Ann Onc 2019; Gao, SABCS Abstract P5-14-02). Methods: We analyzed data from all randomized patients (pts) in the phase 3 trials submitted to FDA 2016-18 evaluating a combination therapy (Rx) of an immuno-oncology agent and another systemic Rx (IO-X) versus sunitinib (SUN) for treatment-naïve advanced renal cell carcinoma (RCC). Protocols specified treatment until progression, but treatment beyond progression was allowed. TTD was defined as the time from the start of Rx to time of treatment discontinuation of both drugs in combination Rx or SUN. We measured TTD in treatment-defined subgroups (IO-X and SUN) and across all pts, and pt-level correlation (Pearson’s r) between TTD and PFS and between TTD and overall survival (OS). We also determined rates of disparity between TTD and PFS greater than 3 months. Results: Of 3758 pts (IO-X, n=1878; SUN, n=1880), 3190 pts (85%) had a TTD event, and 1899 pts (51%) had a PFS event. Median TTD was longer among pts receiving IO-X than SUN (12.3 versus 8.0 months). Regardless of drug class, more pts had early (TTD shorter than PFS by ≥ 3 months) TTD events than late TTD (13.4% versus 6.4%, overall). We found higher correlation between TTD and PFS in pts receiving SUN ( r = 0.89) than pts receiving IO-X ( r = 0.72). Overall, TTD was more closely associated with PFS ( r = 0.80) than with OS (0.61). Conclusions: Observed correlations of TTD to PFS were stronger compared to the correlation of TTD to OS. This may be expected because OS is farther removed in time from TTD than is PFS. In contrast to TTD in NSCLC, more than twice as many pts in RCC trials had early TTD than late TTD, regardless of Rx group, which may indicate earlier discontinuation with combination Rx due to additive toxicity. Limitations include the censoring of PFS and OS and the post-hoc nature of this analysis. [Table: see text]

9541 Background: Previous studies have suggested that tumor growth rate (g), estimated using prostate-specific antigen values, is associated with overall survival (OS) in prostate cancer (Wilkerson, 2016). We performed a retrospective pooled analysis in non-small cell lung cancer (NSCLC) to investigate the extent to which g values estimated using radiological tumor measurements in clinical trials are associated with survival. Methods: We identified 24 randomized clinical trials submitted to FDA between 2013 and 2019 investigating either immune checkpoint inhibitor (ICI) or targeted therapy (TT) in pts with metastatic NSCLC. Of 9934 patients (pts) enrolled, 5532 pts (2401, 1189, and 1942 pts treated with ICI, TT, and chemotherapy respectively) had sufficient data to derive a valid g. The g was evaluated by both type and line of therapy. Pts were then grouped according to quartiles of g, with Q1 being the lowest. We calculated OS and progression-free survival (PFS) for each group via the Kaplan-Meier method, and used the Cox model for group comparison. Results: Median g was 9.7E-4, 1.4E-3, and 2.2E-3/day, and median OS was 34.2, 21.3, and 15.3 months (mo), in pts treated with TT, ICI, and chemotherapy, respectively, regardless of lines of therapy. When treated with the same type of therapy, pts receiving 2nd line therapy had a higher median g than those receiving 1st line. The median survival and log-rank hazard ratios for pts treated with 1st line ICI monotherapy are shown in the Table. Conclusions: TT is associated with the lowest median g, followed by ICI, and then chemotherapy, perhaps due to patient selection, better inherent biology/natural history, or favorable results of TT on selected tumors. Regardless, we found that g is inversely associated with survival, across treatment types. This relationship is also observed in pts treated with the same type and line of therapy (for example, 1st line ICI), where Q1 has the longest survival, followed by Q2, Q3, and then Q4. In summary, our exploratory analysis suggests that g derived from radiological tumor measurements in NSCLC may relate to survival. Prospective studies are needed to evaluate if g might be an earlier endpoint compared to classical response criteria. [Table: see text]

38 Background: FDA approved 3 androgen receptor inhibitors for nonmetastatic castration-resistant prostate cancer (nmCRPC) based on global randomized trials with control arms of placebo + ADT. Despite similar enrolled populations, grade 1 or higher investigator-reported, Common Terminology Criteria for Adverse Events (CTCAE)-graded fatigue ranged 11-25% in the placebo arms. We sought to characterize variability in investigator-reported, CTCAE-graded fatigue across geographic regions and compare this with the variability in patient-reported fatigue. Methods: Data from patients receiving ≥ 1 placebo dose were reviewed from control arms of 3 nmCRPC double-blind, placebo-controlled trials submitted to FDA. We determined worst grade clinician-reported (ClinRO) CTCAE fatigue, and most severe fatigue reported by patient-reported outcome (PRO) for each patient at any time during treatment or within 30 days of last dose in each trial by geographic region: North America/Western Europe (NAWE) versus rest of the world (ROW). We compared variability in fatigue rates to those of a more objective AE, CTCAE-defined anemia. Results: NAWE enrollment comprised 46-75% of placebo cohorts. Median age was comparable across trials and regions. ClinRO CTCAE fatigue was higher in NAWE (15-33%) compared to ROW (8-14%) in each of the 3 placebo cohorts (see Table). Rates of PRO fatigue varied by region (50-73% in NAWE compared to 42-59% in ROW), and the regional differential was present at baseline. Anemia rates were similar in NAWE and ROW in each trial ( < 5%) per CTCAE. Conclusions: CTCAE reporting of fatigue, a subjective symptom, was inconsistent across sites. Anemia, an objective AE, was more consistently reported. ROW investigators less frequently reported fatigue compared to NAWE investigators. Reasons for this are unclear, but could include cultural and language factors. PRO fatigue was relatively consistent across trials and regions. These results should be interpreted with caution, as we acknowledge the limitations of cross-trial comparison.[Table: see text]

e20690 Background: Asian pts tend to be well-represented in mNSCLC clinical trials, and drug development in Asia is growing. We sought to investigate outcomes of Asian pts enrolled in clinical trials testing ICI in mNSCLC. Methods: We identified 11 ICI mNSCLC randomized trials submitted to FDA 2014-2018. We divided the trials into 3 groups: 1st-line monotherapy (1L-M), 1st-line combination with chemotherapy [chemo] (1L-C), and 2nd-line monotherapy (2L-M). Overall survival (OS) and progression-free survival (PFS) were evaluated with Kaplan-Meier methodology. We performed meta-analyses to assess if treatment effect is consistent across Asian and non-Asian populations. Results: There were 3399 patients enrolled in five 2L-M trials, 1579 in two 1L-M trials, and 2500 in four 1L-C trials. Most Asian pts were located geographically in Asia (90%). Asians comprised 15% of patients enrolled in 2L-M trials, 27% in 1L-M, and 11% in 1L-C. Compared to non-Asians, a higher proportion of Asians were never-smokers (32% vs. 13%) and EGFR-mutated (13% vs. 4%). Asian pts had better unadjusted and adjusted OS than non-Asian pts for each treatment in each line of therapy. The 3 covariates with greatest prognostic impact on OS in 2L-M were race, performance status, and histology. The magnitude of ICI treatment effect relative to chemo was similar for Asian and non-Asian pts. Conclusions: Asians appear to have better prognosis than non-Asians; no uniquely better or worse benefit was observed from ICI when compared to chemotherapy. [Table: see text]

e21110Background: Anti-programmed cell death (anti–PD-1) response in patients with advanced non-small cell lung cancer (NSCLC) varies greatly. Higher neutrophil/lymphocyte ratio (NLR) or lower adva...