Adjuvant nivolumab (NIVO) vs placebo (PBO) for high-risk muscle-invasive urothelial carcinoma (MIUC): Additional efficacy outcomes including overall survival (OS) in patients (pts) with muscle-invasive bladder cancer (MIBC) from CheckMate 274.

4585 Background: In the CheckMate 274 trial, disease-free survival (DFS) was significantly improved with nivolumab (NIVO) vs placebo (PBO) both in intent-to-treat (ITT) patients (pts) (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P < 0.001) and in pts with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% (HR, 0.55; 98.72% CI, 0.35–0.85; P < 0.001). We report results for the subgroup of pts with bladder cancer, the most predominant type of urothelial carcinoma. Methods: CheckMate 274 is a phase 3, randomized, double-blind trial of adjuvant NIVO vs PBO in high-risk muscle-invasive urothelial carcinoma (bladder, ureter, renal pelvis) after radical resection. Pts were randomized 1:1 to NIVO 240 mg intravenously every 2 weeks or PBO for ≤ 1 year of adjuvant treatment and stratified by nodal status, prior neoadjuvant cisplatin, and tumor PD-L1 expression. Pts had radical resection ± neoadjuvant chemotherapy and were at high risk of recurrence on final pathologic staging. Primary endpoints were DFS in ITT pts and in pts with PD-L1 ≥ 1%. Non–urothelial tract recurrence-free survival (NUTRFS) was a secondary endpoint, and distant metastasis-free survival (DMFS) was an exploratory endpoint. This exploratory analysis focused on the subgroup of pts with muscle-invasive bladder cancer (MIBC) after radical resection. Results: Of 709 randomized pts in the trial, 560 had MIBC (NIVO, n = 279; PBO, n = 281). With a minimum follow-up of 11.0 months, a DFS benefit was observed with NIVO vs PBO in these pts, regardless of tumor PD-L1 expression (Table). DFS probability at 12 months in all MIBC pts was 66% with NIVO and 45% with PBO. DFS was improved with NIVO vs PBO across subgroups according to age, sex, ECOG performance status, nodal status, and PD-L1 expression status. Improvement in NUTRFS and DMFS with NIVO vs PBO was also observed (Table). Grade 3–4 treatment-related adverse events occurred in 17% and 6% of pts in the NIVO and PBO arms, respectively. Conclusions: Improvement in DFS was observed with NIVO over PBO in pts with MIBC after radical resection regardless of tumor PD-L1 expression. The DFS benefit was observed in all prespecified subgroups. These results further support adjuvant NIVO as a standard-of-care treatment for pts with high-risk MIBC after radical resection ± neoadjuvant cisplatin-based chemotherapy. Clinical trial information: NCT02632409. [Table: see text]

LBA02-08 RESULTS FROM THE EXTENDED FOLLOW-UP IN PATIENTS WITH MUSCLE-INVASIVE BLADDER CANCER IN THE CHeckMATE 274 TRIAL

391 Background: The standard of care (SOC) for patients (pts) with MIUC is radical surgery ± cisplatin-based neoadjuvant chemotherapy (chemo), but many pts are cisplatin-ineligible. There is no conclusive evidence supporting adjuvant chemo in pts who did not receive neoadjuvant chemo and in those with residual disease after neoadjuvant cisplatin. This phase 3 trial of adjuvant nivolumab (NIVO) vs placebo (PBO) in pts with MIUC after radical surgery ± neoadjuvant cisplatin (CheckMate 274) aims to address an unmet need in these pts. We report the initial results. Methods: This is a phase 3, randomized, double-blind, multicenter trial of NIVO vs PBO in pts with high-risk MIUC (bladder, ureter, or renal pelvis) after radical surgery. Pts were randomized 1:1 to NIVO 240 mg Q2W or PBO for ≤ 1 year of adjuvant treatment. Pts had radical surgery within 120 days ± neoadjuvant cisplatin or were ineligible/declined cisplatin-based chemo, evidence of UC at high risk of recurrence per pathologic staging, were disease-free by imaging, and ECOG PS ≤ 1. Primary endpoints: disease-free survival (DFS) in all randomized pts (ITT population) and in pts with tumor PD-L1 expression ≥ 1%. DFS was stratified by nodal status, prior neoadjuvant cisplatin, and PD-L1 status. Non–urothelial tract recurrence-free survival (NUTRFS) in ITT pts and in pts with PD-L ≥ 1% is a secondary endpoint. Safety is an exploratory endpoint. Results: In total, 353 pts were randomized to NIVO (PD-L1 ≥ 1%, n = 140) and 356 pts to PBO (PD-L1 ≥ 1%, n = 142). The primary endpoint of DFS was met in ITT pts (median follow-up, 20.9 mo for NIVO; 19.5 mo for PBO) and in pts with PD-L1 ≥ 1%. DFS and NUTRFS were improved with NIVO vs PBO in both populations (Table). DFS improvement with NIVO was generally consistent across subgroups. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 17.9% and 7.2% of pts in the NIVO and PBO arms, respectively. Conclusions: NIVO demonstrated a statistically significant and clinically meaningful improvement in DFS vs PBO for MIUC after radical surgery, both in ITT pts and pts with PD-L1 ≥ 1%. AEs were manageable and consistent with previous reports. These results support adjuvant NIVO as a new SOC for pts with MIUC with high risk for recurrence despite neoadjuvant chemo or those ineligible for and/or declining cisplatin-based chemo. Clinical trial information: NCT02632409 . Research Sponsor: Bristol Myers Squibb[Table: see text]

491 Background: CheckMate 274 demonstrated a significant improvement in disease-free survival (DFS) with nivolumab (NIVO) versus placebo (PBO) both in the intent-to-treat population (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P < 0.001) and in patients (pts) with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% assessed by the tumor proportion score (TPS) (HR, 0.55; 98.72% CI, 0.35–0.85; P < 0.001). An exploratory subgroup analysis showed a trend toward a DFS benefit with NIVO in pts with TPS < 1% (0.82; 95% CI, 0.63–1.06). To further characterize the relationship between PD-L1 expression and NIVO efficacy, we report an analysis of DFS based on PD-L1 expression in both tumor and immune cells using the combined positive score (CPS). Methods: CheckMate 274 is a phase 3, randomized, double-blind, multicenter trial of NIVO versus PBO in pts with high-risk muscle-invasive urothelial carcinoma after radical surgery. Pts were randomized 1:1 to NIVO 240 mg or PBO every 2 weeks intravenously for 1 year of adjuvant treatment. The primary endpoints of the study are DFS in the intent-to-treat population and in pts with TPS ≥ 1%. The Dako PD-L1 IHC 28-8 pharmDx assay was used to evaluate TPS. CPS was determined retrospectively from previously stained immunohistochemistry slides using the CPS algorithm. CPS was calculated as the number of both PD-L1 positive tumor and immune cells divided by the number of viable tumor cells in the evaluable tumor area, multiplied by 100; TPS was similarly calculated with the number of PD-L1 positive tumor cells as the numerator. This analysis only included pts with both quantifiable CPS and TPS. Results: Of the 629 pts with quantifiable TPS and CPS, 249 (40%) had TPS ≥ 1% (NIVO, n = 124; PBO, n = 125), 380 (60%) had TPS < 1% (NIVO, n = 191; PBO, n = 189), 557 (89%) had CPS ≥ 1 (NIVO, n = 281; PBO, n = 276), and 72 (11%) had CPS < 1 (NIVO, n = 34; PBO, n = 38). Within TPS < 1% pts, 81% (n = 309) had CPS ≥ 1. The number of pts and the DFS outcomes in pts with TPS ≥ 1% and CPS ≥ 1 are shown in the Table. In pts with TPS < 1% who also had CPS ≥ 1, median DFS (95% CI) was 19.2 (15.6–33.4) months with NIVO versus 10.1 (8.2–19.4) months with PBO. The HR for NIVO versus PBO in these pts was 0.73 (95% CI, 0.54–0.99). Conclusions: This exploratory analysis of PD-L1 expression by CPS showed a higher proportion of pts with CPS ≥ 1 than TPS ≥ 1%, and that most pts with TPS < 1% had CPS ≥ 1. In the CPS ≥ 1 subgroup, median DFS with NIVO was more than double that with placebo. These results support the conclusion that pts with TPS < 1% also benefit from adjuvant NIVO. Clinical trial information: NCT02632409. [Table: see text]

PD10-01 DISEASE-FREE SURVIVAL WITH LONGER FOLLOW-UP FROM THE CHECKMATE 274 TRIAL OF ADJUVANT NIVOLUMAB IN PATIENTS AFTER SURGERY FOR HIGH-RISK MUSCLE-INVASIVE UROTHELIAL CARCINOMA

LBA443 Background: The 2 primary endpoints of the CheckMate 274 trial were met as nivolumab (NIVO) improved disease-free survival (DFS) versus placebo (PBO) in the intent-to-treat (ITT) population and in patients with tumor programmed death ligand 1 (PD-L1) expression ≥ 1%. We report extended follow-up data. Methods: CheckMate 274 is a phase 3, double-blind trial of adjuvant NIVO versus PBO for high-risk muscle-invasive urothelial carcinoma (MIUC) (bladder, ureter, or renal pelvis) after radical resection. Patients were randomly assigned 1:1 to NIVO 240 mg every 2 wk or PBO for ≤ 1 year of treatment. Patients had pathologic evidence of UC at high risk of recurrence and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1. Primary endpoints were DFS in ITT patients and in patients with PD-L1 ≥ 1%. DFS was also analyzed in prespecified subgroups. Overall survival and non–urothelial tract recurrence-free survival (NUTRFS) in ITT patients and in patients with PD-L1 ≥ 1% were secondary endpoints. Distant metastasis-free survival (DMFS) and safety were exploratory endpoints. Results: There were 353 patients randomly assigned to NIVO (PD-L1 ≥ 1%, n = 140) and 356 to PBO (PD-L1 ≥ 1%, n = 142). With median follow-up of 36.1 months (minimum follow-up, 31.6 months), median DFS was 22.0 months with NIVO versus 10.9 months with PBO in ITT patients and 52.6 months with NIVO versus 8.4 months with PBO in patients with PD-L1 ≥ 1% (Table). DFS benefit was seen in most subgroups analyzed including age, sex, ECOG PS, nodal status, prior cisplatin-based chemotherapy, and PD-L1 status. NUTRFS and DMFS benefits with NIVO versus PBO were also observed in both populations (Table). Grade 3–4 treatment-related adverse events occurred in 18.2% and 7.2% of patients in the NIVO and PBO arms, consistent with the primary analysis. Overall survival will be assessed at a future database lock. Conclusions: With extended follow-up, NIVO continued to show DFS, NUTRFS, and DMFS benefits versus PBO. The hazard ratio (HR) for DFS and NUTRFS in PD-L1 ≥ 1% patients and for DMFS in both ITT and PD-L1 ≥ 1% patients also continued to improve versus the primary analysis. No new safety signals were identified. These results further support adjuvant NIVO as a standard of care for high-risk MIUC after radical resection. Clinical trial information: NCT02632409 . [Table: see text]

Introduction: CheckMate 914 (CM-914) Part A is a double-blind, phase III randomized trial of the Nivolumab (NIVO) plus Ipilimumab (IPI) vs placebo (PBO) in localized ccRCC. Our prior report from this study suggested a disease-free survival (DFS) benefit for NIVO+IPI among patients with Fuhrman grade 4, TNM stages PT2a and PT4, or sarcomatoid features, although the sample size was limited. It is known that high circulating KIM-1 is associated with worse DFS after nephrectomy. In this exploratory post hoc analysis, we investigated whether high KIM-1 may help identify a subset of patients who benefit from adjuvant NIVO+IPI. Methods: Patients (n=816) with RCC after nephrectomy were randomized in CM-914 Part A to receive NIVO+IPI or PBO as previously described. Assessment of KIM-1 levels was performed using enzyme linked immunoassay (ELISA) on pre-treatment (n=584) and matched on-treatment blood samples (n=584). We used pre-treatment tumor samples to assess PD-L1% tumor cell expression (%TC) in an PD-L1 IHC 28-8 pharm Dx assay. The association between biomarkers and DFS outcomes was investigated by Kaplan-Meier (KM) and Cox proportional hazards analysis. Results: Median baseline serum KIM-1 level was 102 (9.9 - 1055.7) pg/mL. Serum KIM-1 levels were higher in males vs females, ≥65 yrs vs <65 yrs, Asian vs white patients, and patients with partial vs radical nephrectomy. In the PBO arm, subjects with highest quartile of pre-treatment KIM-1 had significantly worse DFS than those from the three lower quartiles. In contrast, this DFS risk among the subjects within the highest KIM-1 quartile was mitigated with NIVO+IPI treatment. Among patients within the highest quartile of pre-treatment KIM-1, there was trend for better DFS for NIVO+IPI versus PBO, HR=0.6 (0.34-1.04). Increase in KIM-1 during study therapy was positively associated with higher DFS rate in both arms. Multivariable analysis showed that PD-L1 %TC was predictive at predefined PD-L1 cutoffs (>=1%, >=5%, and >=10%), associating with improved DFS compared to placebo. Subjects with high PD-L1 expression had a DFS benefit from NIVO+IPI independent of KIM-1. Conclusion: Circulating KIM-1 and tumor PD-L1 expression may enrich for benefit from IO therapy in adjuvant ccRCC and hence holds promise for informing risk stratification and patient inclusion in neoadjuvant or adjuvant clinical trials. Citation Format: Sai Vikram Vemula, Wenxin Xu, Yu Wang, Xiaowen Liu, Jorge Ruiz de Somocurcio, David McDermott, Jun Li, Rupal Bhatt, Chung-Wei Lee, Burcin Simsek, Saurabh Gupta, Robert Motzer. High serum kidney injury marker-1 and high baseline tumor PD-L1 protein expression levels are independently associated with treatment effect in adjuvant nivolumab plus ipilimumab vs placebo in localized clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5151.

Introduction: Non-metastatic muscle invasive urothelial bladder cancer (MIBC) has a poor prognosis and standard of care (SOC) consists of neoadjuvant cisplatin-based chemotherapy (NAC) combined with cystectomy. Patients receiving SOC have at best <10% improvement in five-year overall survival. Residual invasive cancer following NAC has no SOC and has high mortality risk. This major clinical problem underscores gaps in our understanding resistance mechanisms and a need for reliable pre-clinical models. The chicken embryo chorioallantoic membrane (CAM) represents a rapid, scalable, and cost-effective alternative in vivo patient-derived xenograft (PDX) platform. It leverages an easily accessible engraftment scaffold and vascular-rich, immunosuppressed environments for the engraftment of PDX tumors and subsequent functional studies. Our previous proteogenomic data on MIBCs with known chemo-resistant outcomes obtained prior to NAC (pre-NAC) suggests a benefit from treatment with kinase inhibitors (KI). Use of the CAM model in this study aims to address the MIBC pre-clinical model deficit and allow for the rapid screening of therapeutics against NAC-resistant PDXs using selected KI. Methods: We employed the CAM model to expand primary MIBC tumors and tested concordance between cisplatin-based chemotherapy response of patients to matching PDX tumors. We also tested selected KI response on chemotherapy-resistant bladder cancers. PDX growth was assessed by tumor surface area quantification following a week of growth with chemotherapy and KI treatment. Hematoxylin and eosin staining coupled with in situ hybridization, immunohistochemistry for Ki67, and cleaved PARP helped identify tumor cells on the CAM as well as their proliferative and apoptotic indexes. Results: Our initial results show pre-NAC primary MIBC tumors grown on the CAM phenocopy cisplatin-based chemotherapy resistance observed in parent tumor specimens. Histological analysis confirmed engraftment and growth of bladder tumors on the CAM. Patient tumor specimens acquired after chemotherapy treatment (post-NAC) and exhibiting NAC resistance were engrafted successfully on the CAM. Such CAM PDX tumors displayed decreased tumor growth size and proliferation in response to treatment with a dual EGFR and HER2 inhibitor, but had no significant response to either CDK4/6 or FGFR inhibition. Conclusion: Our data suggests concordance between Cisplatin-based chemotherapy resistance phenotypes in primary patient tumors and CAM PDX models. Further, proteogenomic informed KI use on MIBC CAM PDX models suggests a benefit from integration of rapid in vivo testing of novel therapeutics to inform more complex, pre-clinical mouse PDX experiments for more effective clinical trial design aimed at achieving optimal precision medicine for patients with limited treatment options. Citation Format: Hugo Villanueva, Patricia Castro, Andrew G. Sikora, Seth P. Lerner. Targeting resistance mechanisms in muscle invasive bladder cancer using the chicken egg chorioallantoic membrane patient-derived xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2998.

Estimating the Impact of Adjuvant Treatment With Nivolumab on Long-Term Survivorship Rates Compared With Surveillance in Muscle Invasive Urothelial Carcinoma: Mixture Cure Modeling Analyses of Disease-Free Survival From the Phase 3 CheckMate 274 Trial.

LBA8010 Background: The phase 3 CheckMate 77T study demonstrated statistically significant and clinically meaningful improvement in EFS with perioperative NIVO vs PBO in pts with resectable NSCLC. pCR rates were also improved. Here, we report updated EFS, OS from the first prespecified interim analysis, and exploratory biomarker analyses. Methods: Pts with resectable stage IIA–IIIB (N2; AJCC v8) NSCLC were randomized 1:1 to neoadjuvant (neoadj) NIVO + chemotherapy (chemo) Q3W (up to 4 cycles [cyc]) followed by adjuvant (adj) NIVO Q4W (up to 13 cyc) or neoadj PBO + chemo Q3W (up to 4 cyc) followed by adj PBO Q4W (up to 13 cyc). The primary endpoint was EFS per BICR. Secondary endpoints included pCR, OS, and safety. Exploratory analyses included efficacy by pCR status, presurgery ctDNA clearance (CL), and tumor genomic alterations. Results: At a median follow-up of 41.0 mo (database lock, 16 Dec 2024), NIVO continued to provide EFS benefit vs PBO (HR [95% CI], 0.61 [0.46–0.80]; 30-mo EFS rates, 61% vs 43%) in all randomized pts and regardless of disease stage, tumor histology, or PD-L1 expression (Table). EFS from surgery (HR [95% CI]) continued to favor NIVO vs PBO in pts with pCR (0.90 [0.19–4.15]) or without (w/o; 0.72 [0.50–1.05]). In biomarker-evaluable pts (NIVO, 98; PBO, 92), pts with ctDNA CL had greater EFS benefit (assessed from randomization) vs pts w/o (HR [95% CI]: NIVO, 0.41 [0.20–0.86]; PBO, 0.62 [0.31–1.22]); pts with ctDNA CL with or w/o pCR had improved EFS vs pts w/o ctDNA CL and pCR (data to be presented). EFS (HR [95% CI]) favored NIVO vs PBO in pts with tumor genomic alterations ( KRAS , and/or STK11 , and/or KEAP1 mutations; 0.63 [0.32–1.23]) or w/o (0.65 [0.39–1.10]). Higher ctDNA CL and pCR rates were seen with NIVO vs PBO regardless of mutation status; additional efficacy and ctDNA outcomes will be presented. At the first prespecified interim OS analysis, NIVO showed a trend of OS improvement vs PBO in all randomized pts (HR [97.63% CI], 0.85 [0.58–1.25]; median OS, not reached in both tx arms; 30-mo OS rates, 78% vs 72%). Safety outcomes were consistent with previous reports. Conclusions: In this update, perioperative NIVO continued to show long-term EFS benefit and a favorable OS trend vs PBO in pts with resectable NSCLC; no new safety signals were observed. In exploratory analyses, presurgery ctDNA CL was associated with EFS benefit. EFS favored NIVO vs PBO regardless of KRAS , STK11 , and KEAP1 mutation status. Clinical trial information: NCT04025879 . All pts Stage II Stage III Squamous Non-squamous PD-L1 < 1% PD-L1 ≥ 1% NIVO (N = 229) vs PBO(N = 232) NIVO (n = 80) vs PBO(n = 81) NIVO (n = 149) vs PBO(n = 149) NIVO (n = 116) vs PBO(n = 118) NIVO (n = 113) vs PBO(n = 114) NIVO (n = 93) vs PBO(n = 93) NIVO (n = 128) vs PBO(n = 128) Median EFS, mo 46.6 vs 16.9 NR vs NR 42.1 vs 13.4 NR vs 16.4 40.1 vs 16.9 40.1 vs 19.8 46.6 vs 15.1 HR (95% CI) 0.61(0.46–0.80) 0.77(0.46–1.30) 0.54(0.39–0.74) 0.53(0.35–0.80) 0.69 (0.48–1.00) 0.79(0.52–1.21) 0.53(0.36–0.76)

Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC

4000 Background: At 24.4-month (mo) median follow-up, adjuvant nivolumab demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) vs placebo with a well-tolerated safety profile in patients (pts) with resected EC/GEJC with residual pathologic disease following neoadjuvant CRT and surgery in the primary analysis from the global, phase 3 CheckMate 577 study (NCT02743494). We report the final analysis of the hierarchically tested secondary endpoint of OS along with longer follow-up of DFS. Methods: Adults with resected (R0) stage II/III EC/GEJC who received neoadjuvant CRT and had residual pathologic disease were randomized 2:1 to nivolumab 240 mg or placebo Q2W for 16 weeks, followed by nivolumab 480 mg or placebo Q4W. Maximum treatment duration was 1 year. The primary endpoint was DFS. OS was a secondary endpoint, and exploratory endpoints included safety, distant metastasis-free survival (DMFS), and progression-free survival on subsequent systemic therapy (PFS2). Results: 794 pts were randomized (nivolumab, n = 532; placebo, n = 262). With a median follow-up of 78.3 (range, 60.1–96.6) mo, adjuvant nivolumab continued to show DFS benefit vs placebo (HR 0.76 [95% CI 0.63–0.91]; Table). Median OS was numerically longer with nivolumab vs placebo (51.7 vs 35.3 mo), although the difference was not statistically significant (HR 0.85 [95.87% CI 0.70–1.04]; P = 0.1064; Table). OS rates at 3 and 5 years with nivolumab vs placebo were 57% vs 50% and 46% vs 41%, respectively. OS subgroup analyses will be presented. Clinically meaningful improvement in DMFS with nivolumab vs placebo was maintained (Table). PFS2 favored nivolumab vs placebo (HR 0.81 [95% CI 0.67–0.98]). In the nivolumab group, 46% of pts received subsequent therapy vs 60% in the placebo group; 5% vs 15% received subsequent immunotherapy. No new safety signals were identified. Conclusions: Adjuvant nivolumab demonstrated sustained long-term DFS benefit and numerical improvement in OS vs placebo in pts with resected EC/GEJC and residual pathologic disease following neoadjuvant CRT. The safety profile of adjuvant nivolumab remained well-tolerated with longer follow-up. These results further support the use of adjuvant nivolumab in this pt population. Clinical trial information: NCT02743494 . Efficacy Nivolumab(n = 532) Placebo(n = 262) Median DFS (95% CI), mo 21.8 (16.6–29.7) 10.8 (8.3–14.3) HR (95% CI) 0.76 (0.63–0.91) Median OS (95% CI), mo 51.7 (41.0–61.6) 35.3 (30.7–48.8) HR (95.87% CI; P value) 0.85 (0.70–1.04; P = 0.1064) Median DMFS (95% CI), mo 27.3 (21.4–36.0) 14.6 (10.9–20.3) HR (95% CI) 0.75 (0.62–0.90) Safety, n (%) n = 532 n = 260 Any-grade/grade 3–4 TRAEs 379 (71)/75 (14) 124 (48)/17 (7) Any-grade/grade 3–4 TRAEs leading to discontinuation 48 (9)/26 (5) 8 (3)/7 (3) TRAE, treatment-related adverse event.

LBA8007 Background: In CheckMate 77T, perioperative NIVO showed statistically significant EFS improvement vs neoadjuvant (neoadj) chemo followed by adjuvant (adj) placebo (PBO) in pts with stage (stg) II or III resectable NSCLC. We report clinical outcomes by baseline (BL) stg III N2 status, a subgroup with poor historical 5 y survival (26%–36%; Goldstraw J Thorac Oncol 2016). Methods: Adults with resectable stg IIA–IIIB (N2; AJCC v8) NSCLC were randomized to neoadj NIVO 360 mg Q3W + chemo (4 cycles [cyc]) followed by adj NIVO 480 mg Q4W (13 cyc) or neoadj PBO Q3W + chemo (4 cyc) followed by adj PBO Q4W (13 cyc). Primary endpoint: EFS per BICR. Exploratory analysis: efficacy and safety in pts with BL clinical stg III N2 or non N2 disease (dz). Results: BL characteristics were generally similar between pts with stg III N2 (NIVO, 91; PBO, 90) and non N2 dz (55; 57), and between treatment (tx) arms, except a higher percent of pts with N2 dz had NSQ histology and ECOG PS 0 (both arms). Pts with N2 dz had improved EFS with NIVO vs PBO (HR 0.46; 1 y EFS 70% vs 45%) and higher pCR (22.0% vs 5.6%; median f/u 25.4 mo; Table). Pts with non N2 also had EFS benefit with NIVO vs PBO (HR 0.60; 1 y EFS 74% vs 62%) and higher pCR (25.5% vs 5.3%; Table). Surgical feasibility was similar between pts with N2 and non N2 dz and numerically higher with NIVO vs PBO. Of pts with N2 dz, 77% (NIVO) vs 73% (PBO) had definitive surgery (pneumonectomy 1% vs 14%; R0 resection 86% vs 86%); of pts with non N2 dz, 82% vs 79% had definitive surgery (pneumonectomy 13% vs 9%; R0 resection 84% vs 87%). Tumor downstaging postsurgery was seen in most pts with stg III dz and was deeper with NIVO vs PBO: 61% vs 50% (N2; 33% vs 14% to ypT0), 87% vs 76% (non N2; 27% vs 11% to ypT0). Of all pts with stg III dz, nodal downstaging postsurgery was 52% (NIVO) vs 45% (PBO); 46% vs 36% to ypN0. Grade 3–4 TRAEs occurred in 34% (NIVO) and 26% (PBO) of pts with N2; 29% and 21% of pts with non N2 dz. Conclusions: In this exploratory analysis, perioperative NIVO showed clinical benefit vs PBO in pts with stg III NSCLC, regardless of N2 status. Over half of pts with stg III dz had nodal downstaging with NIVO; majority downstaged to ypN0. This first comprehensive analysis by nodal status among pts with stg III dz from a global phase 3 study of perioperative immunotherapy further supports perioperative NIVO as a tx option for pts with resectable NSCLC. Clinical trial information: NCT04025879 . [Table: see text]

549 Background: MA.17 evaluated letrozole (LET) or placebo (PLAC) after 5 years of tamoxifen (Tam) and showed [median follow-up 30 months (mos)] significant improvement in disease-free survival (DFS) for LET [hazard ratio (HR) 0.57, p = 0.00008]. The trial was unblinded and PLAC patients (pts) were offered LET. An ITT analysis of all outcomes, before and after unblinding, based on the original randomization was performed. Methods: A stratified log-rank test was used to compare DFS, distant (D)DFS, overall survival (OS) and incidence of contra-lateral breast cancer (CBC). The Cox regression model used baseline stratification variables and two prespecified factors, menopausal status at the start of Tam and time on Tam. Subgroup analyses for DFS and OS were performed for the two prespecified subsets. All p-values were two-sided Results: 5187 pts were randomized at baseline and, at unblinding, 1655 of 2268 PLAC pts accepted LET. At median follow-up of 54 mos (range,16–86) 363 recurrences or CBC’s (144 LET and 219 PLAC) occurred; 118 LET and 176 PLAC pts had recurrent disease and 26 LET and 43 PLAC pts had CBC. 4 year DFS was 94.3% (LET) and 91.4% (PLAC) (HR 0.64; 95% CI, 0.52 - 0.79; p = 0.00002). Corresponding 4 year DDFS was 96.2% and 94.9% (HR 0.76; 0.58–0.99; p = 0.041). 4 year OS was 95.0% (LET) and 95.1% (PLAC) (HR 1.00; 0.78–1.28; p = 0.99). LET was equally effective in node +ve and -ve pts (i.e., similar HRs) in DFS. OS was not significantly different for LET and PLAC in any subgroup. The annual rate of CBC was 0.29% LET (0.18–0.40) and 0.47% PLAC (0.34–0.61); HR 0.61 (0.38–0.98) p = 0.037. 255 pts had died as of the data cut-off (128 LET and 127 PLAC). Conclusions: In this ITT analysis, pts originally randomized to LET within 3 months of stopping Tam did better than PLAC pts in DFS, DDFS and CBC, despite 73% of PLAC pts crossing to LET after unblinding. This highlights the strong beneficial effect of extended adjuvant therapy with LET. [Table: see text]

528 Background: Durable DFS and cure are the ultimate goals for the treatment of muscle invasive urothelial carcinoma (MIUC) with radical cystectomy. This analysis employed mixture cure models (MCMs) to estimate the underlying cure fraction among high-risk MIUC patients following radical resection in the Phase 3 CheckMate-274 study. Methods: MCMs were applied to patient-level DFS data from the trial (minimum follow-up: 31.6 months). Intention-to-treat (ITT) population and the subpopulation with tumor PD-L1 expression ≥1% were analyzed separately for nivolumab (NIVO) and placebo (PBO) arms. In MCMs, the patient populations were assumed to consist of two exclusive subgroups as cured and uncured. Cured subgroup was assumed to be free of disease recurrence and disease-related mortality risks. The uncured subgroup was at the risk of both disease recurrence and all-cause mortality. DFS for the cured subgroup was estimated using background mortality rates published by WHO matched to the trial’s demographic characteristics. DFS for the uncured subgroup was modelled using parametric distributions, which were characterized along with the cure fraction by maximum likelihood methods. Model selection was primarily based on clinical plausibility of estimated DFS for the uncured subgroup. Visual comparison of the fits from the MCMs to the reported DFS data from the trial and goodness-of-fit statistics also assisted model selection. Results: In the trial, 353 patients were treated with NIVO (mean age: 65.3; male: 75.1%; PD-L1≥1%: 39.7%) and 356 patients were in PBO control (mean age: 65.9; male: 77.2%; PD-L1≥1%: 39.9%). Selected models estimated almost all uncured patients to experience recurrence within 5 years. The estimated cure fraction in the ITT population ranged from 43.1%-45.1% in the NIVO arm (95% CI: 36.7%-51.6%), and 36.4%-37.0% in the PBO arm, (95% CI: 30.9%-43.0%) for clinically plausible models. Projected range of 10-year mean DFS for the ITT patients was 4.38-4.47 years in the NIVO arm and 3.61-3.64 years in the PBO arm. Estimated cure fractions in the PD-L1≥1% subpopulation ranged from 59.1%-61.0% in the NIVO arm (95% CI: 48.9%-72.0%), and 35.9%-36.9% in the PBO arm, (95% CI: 27.5%-45.9%). Projected range of 10-year mean DFS for the PD-L1≥1% subpopulation was 5.54-5.65 years in the NIVO arm and 3.54-3.57 years in the PBO arm. Conclusions: In the adjuvant treatment of MIUC, relative to radical resection only, systemic therapy with NIVO is associated with a 6-9 percentage points higher cure fraction in the ITT population. Tumor PD-L1≥1% expression was associated with higher cure fractions in the NIVO arm but had only negligible impact on the underlying cure fraction in the PBO arm. Clinical trial information: NCT02632409 .