560
Background: Active Wnt signaling via WNT5A through ROR1 and its partner, ROR2, or WNT5A/frizzled 2 (FZD2) is linked to processes driving tumorigenesis, disease progression and therapy resistance. ...The role of this pathway in the pathogenesis of urothelial carcinoma (UC) is not fully elucidated. In adult tissue, ROR1 is largely absent, which makes it ideal for targeted therapies, with several ROR1 targeting agents in early clinical development. We utilized a large dataset of molecularly characterized UC tumors to investigate the significance of Wnt5a/ ROR1, ROR2 or FZD2 transcriptional expression. Methods: NextGen Sequencing of DNA (592 genes or WES)/RNA (WTS) was performed for 4743 UC tumors submitted to Caris Life Sciences (Phoenix, AZ). PD-L1 expression (SP142; Positive (+): ³2+, ³%5) was tested by IHC. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy (T cell-inflamed; Bao, 2020). WNT5a, ROR1, ROR2, and FZD2-high and -low expression were defined as ³ top and < bottom quartile of transcripts per million (TPM), respectively. Mann-Whitney U and X
2
/Fisher-Exact tests were applied where appropriate, with P-values adjusted for multiple comparisons ( q < .05). Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan Meier estimates were calculated for molecularly defined cohorts. Results: We observed similar expression of these WNT5A signaling pathway genes between upper (N=795) and lower tract UC (N=3,204): WNT5A (22.7 v. 22.2 median TMP (mTPM), q = .18), FZD2 (3.4 v 3.5, q = .93), ROR1 (2.0 v. 1.7, q = .05), and ROR2 (2.1 v 2.5, q < .01). WNT family gene expression varied significantly between primary (N=2,756) and metastatic sites (N=1,361): WTN5A (25.2 v 16.8 mTPM), FZD2 (3.2 v 4.05), ROR1 (1.7 v 2.1), and ROR2 (2.4 v 2.6) for primary vs. metastatic sites respectively ( q < .05 for all). Comparison of high- and low-expression subgroups revealed variation in the prevalence of TP53, FGFR3 and RB1 mutations, as well as PDL1+ staining and T cell-inflamed scores (Table). High gene expression for ROR2 (HR 0.66, 95% CI 0.56-0.78, p < .001) and FZD2 (HR 0.75, 95% CI 0.63-0.89, p < .001) was associated with worse OS compared to low gene expression. No significant difference in OS was observed for WNT5A (HR 0.97, 95% CI 0.82-1.15, p < .76) and ROR1 (HR 0.86, 95% CI 0.72-1.01, p < .068). Conclusions: Distinct genomic and immune landscapes for the four investigated WNT pathway components were observed and should be leveraged to identify combination therapies that complement the current pipeline of WNT pathway-targeting drugs. Table: see text
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e18006
Background: Both chemoradiotherapy (CRT) and total laryngectomy (TL) with adjuvant therapy are curative-intent treatment options for patients with T4a larynx cancer. Disease ...recurrence is a known negative prognosicator, but differences in recurrence patterns and the subsequent survival associations are not well characterized. To address this knowledge gap, we present long-term recurrence and survival outcomes from a novel longitudinal data source. Methods: Retrospective study of non-metastatic T4a larynx cancer patients diagnosed between 2000-2017 who underwent curative-intent treatment (TL with adjuvant therapy or primary CRT) from the VA Informatics and Computing Infrastructure database. Adjuvant therapy consisted of either postoperative radiotherapy (RT) or CRT. Fine-Gray and Cox models were used to evaluate primary outcomes – time to locoregional recurrence and distant recurrence. Secondary outcomes included overall survival (OS), cancer-specific survival (CSS), non-cancer specific survival (NCSS), and disease-free survival (DFS). These multivariable models accounted for age, race, alcohol history, smoking status, education and income, Charlson-Deyo score, N-classification, and tumor subsite. Results: The study included 1,114 patients with a median follow-up time of 63.3 months among those alive at last follow up. In the TL group, adjuvant RT was used in 69% and adjuvant CRT was used in 31%. Median time to first recurrence was 24.4 months with overall incidence of 28.5% locoregional and 9.5% distant recurrence. Primary CRT patients had higher rates of locoregional (37.2 vs. 22.9%) and distant recurrence (13.3 vs. 7.0%) (p < 0.0001). Median OS was 27.3 months for CRT (95% CI: 23.6-32.4 months) and 47.5 months (95% CI: 39.6-52.1 months) for TL. Median DFS was 14.1 months for CRT (95% CI:12.5-17.2 months) and 37.9 months (95% CI 31.2-47.5 months) for TL. On multivariable analysis compared to CRT, TL was associated with longer time to locoregional (HR 0.50, 95% CI:0.40-0.61) and distant recurrence (HR 0.50, 95% CI:0.34-0.73). Having N+ disease increased risk of distant recurrence (HR 2.20, 95% CI:1.42-3.41). TL was associated with improved OS (HR 0.78, 95% CI:0.67 – 0.91), CSS (HR 0.73, 95% CI:0.59 – 0.89), and DFS (HR 0.58, 95% CI 0.49-0.69) compared to CRT; NCSS was equivalent between groups (HR 1.09, 95% CI:0.88-1.35). Of the CRT patients with locoregional failures, 67/163 (41.1%) were salvaged with surgery. Conclusions: In this cohort of T4a larynx cancer patients, surgical management demonstrated favorable recurrence and survival results. TL with adjuvant therapy was associated with significantly lower incidence of both locoregional and distant recurrence and increased OS, CSS and DFS compared to CRT. Lower probability of disease recurrence, in addition to a survival advantage, should be considered as an important advantage to up-front surgery.
5011 Background: Patients with mCRPC inevitably develop resistance to available therapies, eg, novel hormonal agents (NHAs), and experience disease progression. Certain mutations that can develop in ...the ligand-binding domain (LBD; amino acids 671–920) of the AR gene during mCRPC treatment have been associated with poor outcomes. ARV-766 is a novel, potent, orally administered PROTAC AR degrader that targets wild-type AR and clinically relevant AR LBD mutants, including the most prevalent AR L702H, H875Y, and T878A mutations. We report initial results from a phase 1/2 study (NCT05067140) of ARV-766 in men with mCRPC and disease progression on prior NHA therapy. Methods: Eligible patients had progressive mCRPC and ongoing androgen deprivation therapy. The phase 1 dose escalation portion evaluated the safety and tolerability of escalating doses of ARV-766 (20–500 mg once daily QD) in patients who had progressed on ≥2 prior systemic therapies (including ≥1 NHA). The phase 2 cohort expansion portion is evaluating the clinical activity and safety of 2 doses of ARV-766 (100 or 300 mg QD) in patients who had received 1–3 prior NHAs and ≤2 prior chemotherapy regimens. Here we report safety in all patients treated with ARV-766 across the phase 1/2 study and clinical activity (proportion of patients with best prostate-specific antigen PSA declines of ≥50% PSA 50 after ≥1 month of PSA follow-up) in the subgroup of patients with AR LBD mutations. Results: As of December 15, 2023, 103 patients received ARV-766 (34 in phase 1 and 69 in phase 2). Patients had received a median of 4 prior therapies (range: 1–9), including 56% with ≥1 prior taxane and 46% with ≥2 prior NHAs. Patients with AR LBD mutations (n=30) had received a median of 4 prior therapies (range: 1–9), including 60% with ≥1 prior taxane and 57% with ≥2 prior NHAs. In phase 1, there were no dose-limiting toxicities, and a maximum tolerated dose was not reached. Across 103 phase 1/2 patients, treatment-emergent adverse events led to dose reduction and treatment discontinuation, respectively, in 7 (7%) and 10 (10%). Any grade treatment-related adverse events (TRAEs) reported in ≥10% of patients were fatigue (36%; 3% grade 3), nausea (19%; 1% grade 3), diarrhea (15%; 1% grade 3), alopecia (14%), increased blood creatinine (13%; 0 grade 3), and decreased appetite (11%; 0 grade 3); there were no grade 4 TRAEs. In 28 PSA-evaluable patients with AR LBD mutations, PSA 50 was 50.0%. Preliminary pharmacokinetics indicated dose-dependent increases in ARV-766 exposure up to 320 mg QD, with exposure accumulation ranging from ≈5- to 8-fold at steady state. Conclusions: In this phase 1/2 study of pretreated patients with mCRPC, ARV-766 was well tolerated and showed promising clinical activity in those with tumors harboring AR LBD mutations. ARV-766 warrants further development in advanced prostate cancer. Clinical trial information: NCT05067140 .
4580 Background: ICIs are used for UC in different settings. Most cases have pure urothelial carcinoma (PUC) but about a third have UC mixed with SH. We examined pts with UC treated with ICI and ...hypothesized that outcomes would not differ between PUC and mixed with SH. Methods: We retrospectively included pts with PUC and any SH component treated with ICI as adjuvant, 1 st line 1L upfront, maintenance avelumab mAV, ≥2 nd line 2+L therapy; pts were divided by SH type. Pts with multiple SH were included as separate group. We excluded pts with pure non-UC histology and pts treated with neoadjuvant ICI. We calculated overall response rate (ORR), median overall, progression-free and disease-free survival mOS, mPFS, mDFS using KM method from ICI start. Analysis was stratified by therapy line; multivariable models were adjusted by Khaki factors for 1L/upfront, mAV and Bellmunt factors for 2+L; reference group was PUC. We used descriptive statistics for small subsets. Results: We included 1525 pts from 26 sites; n=752 1L, n=609 2+L; 76% men, 80% White, 69% smoking history, 80% lower urinary tract primary, 28% SH. Median f/u time from 1L ICI start 24 months (mo): mPFS was 3 (95%CI 2.8-3.2) mo for PUC (n=340), 3 (95%CI 2-4) mo for squamous (n=60) (HR=1, 95%CI 0.7-1.4), 2 (95%CI 1.4-3.2) mo for micropapillary (n=36) (HR=1.3 95% 0.9-2) and 4 (3.5-4.5) mo for ≥2 SH (n=20) (HR=0.9 95%CI 0.6-1.5). Median f/u time from 2+L ICI start 26 mo: mPFS was 3 (95%CI 2.4-3.2) mo for PUC (n=264), 4 (95%CI 2-5) mo for squamous (n=33) (HR=0.8, 95%CI 0.6-1.2), 3 (95%CI 1.6-3.7) mo for micropapillary (n=17) (HR=0.9 95% 0.6-1.7) and 3 (2.5-3.1) mo for ≥2 SH (n=10) (HR=1.2 95%CI 0.6-2.2); Table shows ORR/OS data. Data on adjuvant and mAV settings will also be presented. Conclusions: We found no significant survival difference between PUC and SH. ORR was numerically higher with sarcomatoid SH and ≥2 SH in the 1L upfront setting. Limitations: retrospective design, small sample size in a few subsets, lack of randomization and central scan/path (% SH) review, selection bias, unmeasured confounders. Table: see text
654
Background: MSI and TMB correlate with ICI efficacy. We assessed the association between TMB and MSI with outcomes in pts with aUC treated with anti-PD1/L1 in a ‘real-world’ cohort. We ...hypothesize that pts with high TMB and MSI-high (H) have better outcomes with ICI. Methods: In this retrospective study we included pts from 13 sites treated with ICI for aUC. We calculated overall response rate (ORR), median overall and progression-free survival (mOS, mPFS) using KM method from ICI start. TMB and MSI were assessed by NGS. TMB was analyzed as dichotomous (≥10 vs <10 mut/Mb) and continuous variable. The analysis was stratified by therapy line (1L/upfront, 2+L). Multivariable models were adjusted by Khaki factors for 1L/upfront and Bellmunt factors for 2+L. We separately analyzed pts on maintenance avelumab (mAV). MSI is reported with descriptive statistics only. Results: 342 pts were treated with ICI 1L/upfront or 2+L (69% pure UC, median age at ICI start 69, 77% men, 90% White, 16% upper tract primary, 12% liver metastases mets, 78% ECOG PS 0-1). Median f/u from ICI start was 34 months (mo). ORR was 36% (95%CI 26-46%) in pts with TMB≥10 vs 30% (95%CI 23-36%) with TMB<10 (OR=1.4 95%CI 0.8-2.5 p=0.3). ORR was 75% (6/8) in pts with MSI-H and 30% (60/200) with MSI stable (MSI-S). mPFS was similar between TMB≥10 and <10 groups (6 vs 4 mo; HR=0.88 95%CI 0.61-1.26 p=0.48) and between MSI-H and MSI-S (5 mo). mOS was numerically longer (not significant) in pts with TMB≥10 vs TMB<10: 25 vs 21 mo; (HR=0.7 95%CI 0.50-1.09 p=0.12) and with MSI-H and MSI-S (NR and 20 mo). A significant association was found between TMB (continuous variable) and OS (HR=0.97 95%CI 0.95-0.99 p=0.01). TMB analyses by therapy line are shown in Table. In the 1L/upfront setting (N=144), ORR 71% (5/7) vs 33% (45/135), mPFS 5 and 4 mo, mOS NR and 22 mo for MSI-H and MSI-S, respectively. Pts on mAV (n=77) were 77% men, 92% White, 16% upper primary, 13% liver mets, 84% ECOG PS 0-1 with median f/u 15 mo from avelumab start; mOS was NR for MSI-H and 24 mo for MSI-S; mPFS was 4 mo for both groups. Of 3 pts on mAV with MSI-H: 1 CR, 2 SD; of 58 pts with MSI-S: 4CR, 4PR, 24 SD, 21 PD, 5 unknown. Conclusions: MSI-H had numerically higher ORR and higher TMB was associated with longer OS with ICI, but further validation is needed. Limitations: retrospective design, small sample size for MSI-H cases, lack of randomization and central scan review, selection/confounding. Table: see text
10548
Background: Primary care physicians (PCPs) are significant contributors of early cancer detection yet few studies have investigated whether consistent primary care translates to improved ...downstream outcomes. We evaluated the impact of prior PCP utilization on metastatic disease at diagnosis and cancer-specific mortality (CSM) for a general cancer cohort and 12 tumor subtypes. Methods: We identified cancer patients ≥40 years, diagnosed from 2004-2017 within the Veterans Health Administration. For our 5-year pre-diagnostic period, we binned PCP visits into none (0 visits), some (1-4), and annual (5). Multivariable logistic regression assessed the effect of PCP utilization on metastatic disease at diagnosis and Fine-Gray regression with non-cancer death as a competing event evaluated their effect on cancer-specific mortality (CSM). These were repeated for each subtype. Results: Among 245,425 patients, mean age was 66 years with 5.7-year median follow-up. Compared with 0 visits, some PCP utilization was associated with 26% reduced odds of metastatic disease at diagnosis (odds ratio (OR), 95% confidence interval (CI): 0.74 0.71-0.76 P<0.01) and 12% lower risk of CSM (hazard ratio (HR), 95% CI: 0.88 0.86-0.89 P<0.01). Annual PCP utilization was associated with 39% reduced odds of metastatic disease (OR, 95% CI: 0.61 0.59-0.63 P<0.01) and 21% lower risk of CSM (HR, 95% CI: 0.79 0.77-0.81 P<0.01). Among subtypes, prostate cancer had the largest effect size for PCP utilization on metastatic disease at diagnosis (OR
annual
, 95% CI: 0.32 0.30-0.35 P<0.01) and CSM (HR
annual
, 95% CI: 0.51 0.48-0.55 P<0.01). Pancreas cancer had the lowest effect size on metastatic disease at diagnosis (OR
annual
, 95% CI: 0.87 0.73-1.04 P: 0.12) and CSM (HR
annual
, 95% CI: 0.89 0.82-0.97 P<0.01). The table displays additional subtypes. Conclusions: Increased PCP utilization prior to cancer diagnosis is associated with a significant decrease in metastatic disease at diagnosis and CSM, with annual utilization associated with the greatest decrease. These results are consistent when stratifying by tumor subtype. Consistent primary care must be emphasized for patients at risk of cancer. Table: see text
562
Background: Recent data suggest that patients with liver metastases (mets) are resistant to immune checkpoint inhibition (CPI) independent of historical biomarkers of CPI efficacy, raising the ...question of whether liver mets may be associated with an immunosuppressive tumor microenvironment (TME). We investigated the immune TME of hepatic and non-hepatic mets compared to primary tumors in advanced urothelial carcinoma (UC) tissue samples. Methods: NextGen sequencing (NGS) of DNA (592-gene/whole exome) and RNA (whole transcriptome) from UC tissue samples (N=4746) was performed at Caris Life Sciences (Phoenix, AZ). Immune cell infiltration was estimated by RNA expression deconvolution (MCP-counter). PD-L1 expression (SP142: immune cell stain ≥ 5%; 22c3: CPS ≥ 10) was assessed by immunohistochemistry (IHC). Deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) was tested by IHC/NGS. Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated. Mann–Whitney U and X
2
/Fischer-Exact tests were applied where appropriate, with p-values adjusted for multiple comparisons (Benjamini-Hochberg). *P<0.05. Results: UC samples included 3158 (66.5%) from primary site, 1344 (28.3%) from non-hepatic mets, and 244 (5.1%) from hepatic mets. Compared to primary tumors, hepatic mets had decreased CD8
+
T and B cells (0.55* and 0.29-fold*) but increased monocytic lineage cells (1.23-fold*), while non-hepatic mets had increased CD8
+
T, NK, and monocytic lineage cells (1.28*, 1.27*, 1.31-fold*) with no difference in B cells (1.05-fold). Hepatic mets had decreased expression of integrin LFA-1/ ITGAL (0.77-fold*), as well as hyaluronic acid (HA) receptor CD44 and synthase HAS2 (0.61 and 0.61-fold*), compared to primary tumors, whereas expression of these genes and LFA-1 ligand ICAM1 was increased in non-hepatic mets (1.08 to 1.30-fold*). Hepatic mets had increased expression of immunosuppressive cytokines CCL2 and CXCL2 (1.72* and 2.32-fold*) and decreased expression of pro-inflammatory cytokines CCL5 and CXCL10 (0.63* and 0.79-fold*) compared to primary tumors. PD-L1+ IHC was less frequent in hepatic mets compared to primary tumors and non-hepatic mets. TMB-High (≥10 mut/MB) and dMMR/MSI-H rates were similar across tumor sites. Hepatic mets (N=40) were associated with worse OS from the start of pembrolizumab compared to non-hepatic mets (N=177) (19.6 vs 4.4 months, HR 3.01, 95% CI 1.91-4.75, p<0.0001). Conclusions: This is the largest analysis of hepatic and non-hepatic met TMEs compared to primary tumor in advanced UC. Lower PD-L1 expression and differences in immune TME composition in liver mets may contribute to CPI resistance. Further analysis is warranted to determine underlying molecular mechanisms resulting in a TME that reduces response to CPI for patients with UC and liver mets.
8583
Background: Immunotherapy has shown efficacy in the treatment of recurrent, extensive-stage small cell lung cancer (ES-SCLC). In the Checkmate 032 trial, ipilimumab and nivolumab combination ...therapy resulted in a 21% objective response rate in relapsed SCLC. At present, there are no biomarkers used in clinical practice to predict treatment responsiveness in SCLC. Ipilimumab and nivolumab act by blocking key co-inhibitory immune pathways of CTLA-4 and PD-1/PD-L1, respectively, leading to reinvigoration of anti-tumor cytotoxic T cell responses and a decrease in immune suppressive tumor infiltrating leukocytes. The ratio of intratumor Teff (CD8+) cells to Treg (CD4+/Foxp3+) cells (Teff/Treg) could be a more reliable biomarker than effector cell infiltration alone. Methods: In this open-label, single arm trial, we enrolled patients with ES-SCLC who previously received platinum-based chemotherapy; prior anti-PD-1 /PD-L1 therapy was allowed. Patients were treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg, for a total of 4 doses each and received nivolumab 480 mg beginning with cycle 5, every 4 weeks until progression, unacceptable toxicity or study discontinuation. On-study biopsies were performed prior to initiation of therapy and during week 4 for the biomarker primary objective—to correlate disease response with intratumor Teff/Treg changes. Secondary objectives include determining ORR, DOR, PFS, and OS. Results: Twenty-two patients (median age 63.5 range 54-80 years, ECOG 0/1/2 41%/50%/9%, sex M/F 45%/55%) were enrolled and received treatment. Fourteen (64%) had paired biopsies while on treatment. Fifteen patients were evaluable per RECIST with an ORR of 13% (2/15, 2 partial responses 13%) and DCR was 40% (6/15, 4 stable disease 27%). Grade 3 treatment-related adverse events (TRAEs) occurred in 9/22 40%. Grade 4 TRAEs occurred in 2/22 9% (elevated lipase and elevated bilirubin) and Grade 5 TRAEs occurred in 1/22 patients (hepatic failure). Out of the 9 patients previously treated with anti- PD-1/PD-L1 therapy, 1 had a partial response and 2 had stable disease. Multiplexed quantitative immunofluorescence analysis revealed changes of both CD8+ effector T cells and Tregs in the tumor micro-environment associated with clinical benefit to immunotherapy. Conclusions: Combination immunotherapy with ipilimumab and nivolumab shows clinical efficacy in relapsed extensive-stage SCLC, including those previously treated with anti-PD-1/PDL-1 therapy. Obtaining paired biopsies was shown to be successful in this prospective trial to study the tumor microenvironment in SCLC tumors treated with checkpoint inhibitors. Early biomarker evaluation during week 4 shows local immunomodulatory effect of treatment and supports exploration as predictive biomarker in this population. Clinical trial information: 03670056.
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, X
2
, 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<0.05). Over 41% of pTERTmut were TMB-H. TERTp mutations were not associated with FGFR alterations. The frequency of co-occurring mutations was similar by specimen site. In evaluating the immune landscape (Table), pTERTmut was associated with higher expression of PD-L1 (IHC, mRNA), PD-L2 (mRNA) and TIM3 (mRNA) in tumors from primary sites (all p and q<0.05), but not in metastatic sites. Investigation of tumor-associated immune cells demonstrated that pTERTmut correlated with higher percentage of M1-macrophages and CD8+ T cells in primary tumors, and was inversely-correlated with NK cells in metastatic sites (all q<0.05). Conclusions: This is the largest analysis looking at the molecular and immune landscape of pTERTmut UC tumors. We observed differential patterns of DNA alterations and tumor immune microenvironment based on pTERTmut status. Further work is needed to understand differences in these molecular cohorts and the association of these data with clinical outcomes. Table: see text
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505
Background: Current standard therapy for most pts with aUC is first-line (1L) platinum-based chemotherapy followed by ICI maintenance (or 2L if progression). Shorter time on 1L or ...between therapy lines may be a surrogate of more aggressive disease and poor outcome, but its prognostic role in ICI response is unclear. We hypothesized that shorter time until start of 2L ICI would be associated with worse outcomes in aUC. Methods: We performed a retrospective multi-institution cohort study in pts with aUC treated with 1L platinum-based chemotherapy, who later received 2L ICI. Pts receiving maintenance ICI were excluded. We calculated the time from start of 1L platinum chemotherapy to start of 2L ICI, dichotomizing the exposure into ≤6 months and >6 months. We compared overall response rate (ORR) to 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI between the two populations. ORR was compared among groups using multivariable logistic regression and PFS, OS using cox regression. Analysis was adjusted for calculated Bellmunt score. Results: From a total of 1283 pts, 462 received 1L platinum chemotherapy; among those, 350 received 2L ICI. After exclusions, 270, 269 and 260 pts were included in the ORR, PFS and OS analyses, respectively. Median age was 70 years, 78% men, 75% White, 74% with pure urothelial histology, 21% upper tract, 60% received cisplatin in 1L. Pts with time to 2L ICI ≤6 months had significantly higher Bellmunt scores (32% vs 22% score=2, 9% vs 3% score=3). ORR and PFS were comparable between pts with ≤ and >6 months to 2L ICI. However, OS was significantly longer for pts with >6 months to 2L ICI (median mOS 13 vs 7 months, p=0.002), (Table). Conclusions: Among pts with aUC treated with 2L ICI, time to 2L ICI ≤6 months from 1L platinum based chemotherapy was associated with similar ORR and PFS but shorter OS. Limitations include retrospective nature, patient selection, confounding factors. More studies are needed on the impact of platinum resistance in pts with aUC treated with ICIs.Table: see text
