e17095 Background: sRCC have a generally poor prognosis though recent clinical trial data suggest improved outcomes with CPI. We present a real-world experience of metastatic sRCC patients (pts) treated with a variety of CPI. Methods: Pts with sRCC treated with CPI Cleveland Clinic from 1/1/2015 to 12/31/2019 were identified. Overall survival (OS) was estimated using Kaplan-Meier and compared by log rank test. Results: Of 28 eligible pts identified with sRCC, median age 58, 82% Caucasian, all KPS score > 80%, 86% had IMDC intermediate/poor risk disease, 75% were clear cell, and 71% had prior nephrectomy. 46.4% had prior non-CPI systemic therapy. CPI therapy in this cohort included: 46% nivolumab monotherapy, 18% axitinib/pembrolizumab, 21% ipilimumab/nivolumab, 4% atezolizumab/bevacizumab, 7% atezolizumab, 4% carboplatin/pemetrexed/pembrolizumab. At a median follow up of 13.6 months (range 6.5-31.4), ORR was 36% (4% CR, 32% PR) and median OS was 13.8 months (95% CI: 9.23-NA). Median time to response was 3.2 months (range 2.4-13.1) and median duration of response was 8.1 months (range 0-25.5). Ten of the 13 patients started subsequent therapy due to progression. At the time of analysis, 39% were still alive and 25% of patients were still on initial I/O therapy (7+ -30+ months). There were no clear correlations between specific disease-related factors (including IMDC risk, time-to treatment of > or < 1 year, or prior systemic therapy) and response (all were p > 0.05). Conclusions: ORR and CR rates were lower in this real-world population of metastatic sRCC pts compared to clinical trial data, which should be a result of various CPI treatments and lines of treatment. However, these data highlight the heterogeneity of sRCC in general and need for additional investigations into impact of percentage of sarcomatoid features, genomic analyses, line of therapy, and CPI choice to optimize outcomes in sRCC pts.
e17050 Background: The role of Neutrophil to Lymphocyte Ratio (NLR) and Platelet to Lymphocyte Ratio (PLR) in prognostication of MIBC is not clearly understood. There is growing evidence that, as markers of inflammation, they may have prognostic utility in MIBC at radical cystectomy (RC). Methods: We performed a retrospective analysis of MIBC patients who underwent RC at the Cleveland Clinic from 2/2015 to 1/2018. 84 patients were identified who were either diagnosed with TaN0M0 treated with Neoadjuvant Chemotherapy (NAC) or T1-T4N0M0 disease treated with or without NAC. For NAC, 27 patients received gemcitabine and cisplatin, 2 patients received gemcitabine and carboplatin, 4 patients received unknown regimen, and 3 patients received MVAC. Of the patients, there were 1 with Ta, 34 with T1, 44 with T2, 1 with T3 and 4 with T4 disease. Complete Blood Count with Differential closest to or on the day of resection was used. NLR and PLR were calculated by dividing Absolute Neutrophil Count and Platelet Count by the Absolute Lymphocyte Count, respectively. PLR and NLR were dichotomized at the median. Outcomes were analyzed via Kruskal-Wallis test. Results: Median follow up of patients was 28.8 months. Median NLR and PLR were 15.7 and 263, respectively. Mean NLR and PLR were 18.9 and 310, respectively. NLR and PLR did not correlate with overall survival, recurrence free survival, T or N stage post resection, or pathological response. Females were found to have a higher NLR than males. Conclusions: Contrary to previous reports, our study did not find any prognostic value of NLR and PLR in MIBC patients at RC. Further evaluation of PLR and NLR in MIBC and correlation with molecular features may help understand its potential prognostic role in patients undergoing surgical resection.
411 Background: Most patients (pts) with metastatic urothelial carcinoma (mUC) will receive immune checkpoint inhibitors (ICI) at some point during treatment. As such, understanding of immune-mediated toxicity is integral to optimal patient management. We describe the clinical characteristics, treatment, and outcomes of ICI-treated mUC pts who experienced irAEs requiring treatment interruption (TI). Methods: ICI-treated mUC pts who developed > grade 2 (per CTCAEv5) irAEs leading to >2 week TI were retrospectively reviewed. Patient-, disease-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per CTCAEv5. Time to treatment interruption (TTI), treatment-free interval (TFI), time to next treatment (TTNT), and duration of response (DoR) were assessed descriptively. Results: Of 200 ICI-treated mUC pts, 18 (9%) experienced irAEs necessitating TI. 12 (43%) were male; median age at diagnosis was 72.5 (range, 45-80); 15 (83%) had KPS > 80. 8 (44%) had pure UC histology, 14 (78%) had prior cystectomy or nephroureterectomy, and 11 (61%) received platinum-based chemotherapy in the perioperative setting. 4 (22%) received 1L platinum-based Tx for mUC. ICI therapy was distributed evenly between atezolizumab (50%, n = 9) and pembrolizumab (50%, n = 9). Median TTI was 6.5 months (mos) (range, 1-19). The most common irAEs were dermatitis (22%, n = 4), colitis (17%, n = 3), and transaminitis (17%, n = 3); the majority were grade 2 (72%, n = 13). No grade 4/5 events occurred. 14 pts (78%) were treated with methylprednisolone and/or prednisone. Median initial prednisone-equivalent steroid dose was 45 mg/day (range, 30-1,250) with a median steroid duration of 42 days (range, 4-198). ICI were held and later re-challenged in 10 pts (56%), permanently discontinued in 7 pts (39%), and transitioned to a subsequent Tx in 1 pt (5%). Of 10 pts re-challenged with ICI, 7 (70%) experienced an irAE upon re-challenge (4 with recurrent irAEs, 3 with new irAEs); ICI was permanently discontinued in 3 of these pts. For pts receiving subsequent Tx, median TFI was 1 month (range, 0-12) and median TTNT was 5 mos (range, 2-31). Median DoR among all pts with initial response to ICI therapy was 15.5 mos (range, 2-52). Of 7 pts who permanently discontinued ICI and received no further Tx, 6 (86%) demonstrated an ongoing sustained therapy response with median DoR of 22.5 mos (range, 12-52). Conclusions: In this cohort, ICI-treated mUC pts who developed irAEs requiring treatment interruption had a high rate of subsequent irAEs upon ICI re-challenge. Importantly, pts who discontinue ICI due to irAE can have durable responses off treatment, consistent with data from other cancers.
664 Background: EV-302 /KEYNOTE-A39 (NCT04223856) demonstrated significant progression-free survival (PFS) and overall survival (OS) benefit with first-line (1L) EV+P vs chemo in patients (pts) with la/mUC. EV+P is the standard of care (SOC) in global treatment guidelines for pts with untreated la/mUC. We present 12 mo of additional follow-up for EV-302 (>2 y of median follow-up) and an exploratory analysis of pts with confirmed complete response (cCR). Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive EV (1.25 mg/kg; Days 1 and 8; IV) and P (200 mg; Day 1; IV) or gemcitabine with cisplatin or carboplatin every 3 wks. Dual primary endpoints were PFS by blinded independent central review (BICR) and OS. Select secondary endpoints were confirmed objective response rate (cORR), duration of response (DOR), and safety. An exploratory analysis evaluated treatment outcomes and safety in pts with cCR. Results: 886 pts were randomized to receive EV+P (n=442) or chemo (n=444). At data cutoff (Aug 8, 2024), median follow-up was 29.1 mo (95% CI, 28.5-29.9). PFS by BICR (HR, 0.48 [95% CI, 0.41-0.57]) and OS (HR, 0.51 [95% CI, 0.43-0.61]) were improved in the EV+P vs chemo arms (Table). OS benefit was seen irrespective of cisplatin eligibility or presence of liver metastases (mets). In the response-evaluable set, cORR was 67.5% for EV+P and 44.2% for chemo. Median DOR was 23.3 mo (95% CI, 17.8-not estimable [NE]) for EV+P and 7.0 mo (95% CI, 6.2-9.0) for chemo. 30.4% of pts in the EV+P arm and 14.5% in the chemo arm achieved cCR. Median duration of cCR was not reached for EV+P and 15.2 mo (95% CI, 10.3-NE) for chemo. Grade ≥3 treatment-related (TR) adverse events (AEs) in the EV+P vs chemo arms occurred in 57.3% vs 69.5% of pts in the safety analysis set (Table) and 61.7% vs 71.9% of pts in the cCR subgroup, respectively. TR deaths occurred in 1.1% vs 0.9% of pts in the safety analysis set in the EV+P vs chemo arms, respectively; none occurred in the cCR subgroup. Conclusions: EV+P continues to demonstrate superior efficacy vs chemo in a broad population, consistent with the primary analysis. Results confirm durable EV+P efficacy with no new safety signals, reinforcing EV+P as SOC for the 1L treatment of pts with la/mUC. Clinical trial information: NCT04223856 . Key efficacy and safety outcomes. EV+P Chemo EV+P vs chemo Efficacy (intent to treat set) n mo n mo HR (95% CI) Median PFS 442 12.5 (95% CI, 10.4-16.6) 444 6.3 (95% CI, 6.2-6.5) 0.48 (0.41-0.57) Median OS 442 33.8 (95% CI, 26.1-39.3) 444 15.9 (95% CI, 13.6-18.3) 0.51 (0.43-0.61) Cisplatin eligible 244 36.7 234 18.7 0.54 (0.42-0.70) Cisplatin ineligible 198 25.6 210 12.7 0.50 (0.39-0.64) Liver mets present 100 19.1 99 10.1 0.56 (0.40-0.78) Liver mets absent 342 39.3 345 18.3 0.50 (0.40-0.62) Safety (safety analysis set) n n Grade ≥3 TRAE 440 252 (57.3%) 433 301 (69.5%) –
PURPOSE Sapanisertib is a kinase inhibitor that inhibits both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. In this multicenter, single-arm phase II trial, we evaluated the efficacy of sapanisertib in patients with treatment-refractory metastatic renal cell carcinoma (mRCC; NCT03097328 ). METHODS Patients with mRCC of any histology progressing through standard therapy (including prior mTOR inhibitors) had baseline biopsy and received sapanisertib 30 mg by mouth once weekly until unacceptable toxicity or disease progression. The primary end point was objective response rate by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. RESULTS We enrolled 38 patients with mRCC (clear cell = 28; variant histology = 10) between August 2017 and November 2019. Twenty-four (63%) had received ≥ 3 prior lines of therapy; 17 (45%) had received prior rapalog therapy. The median follow-up was 10.4 (range 1-27.4) months. Objective response rate was two of 38 (5.3%; 90% CI, 1 to 15.6); the median progression-free survival (PFS) was 2.5 months (95% CI, 1.8 to 3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events, with no grade 4 or 5 toxicities. Alterations in the mTOR pathway genes were seen in 5 of 29 evaluable patients ( MTOR n = 1, PTEN n = 3, and TSC1 n = 1) with no association with response or PFS. Diminished or loss of PTEN expression by immunohistochemistry was seen in 8 of 21 patients and trended toward shorter PFS compared with intact PTEN (median 1.9 v 3.7 months; hazard ratio 2.5; 95% CI, 0.9 to 6.7; P = .055). CONCLUSION Sapanisertib had minimal activity in treatment-refractory mRCC independent of mTOR pathway alterations. Additional therapeutic strategies are needed for patients with refractory mRCC.
