Michiel Simon Van Der Heijden

Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) - a selective, potent, oral IDO1 inhibitor - combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320.

4506 Background: Atezolizumab is a PD-L1 inhibitor which is licenced in metastatic urothelial cancer. This study investigates the efficacy and safety of neoadjuvant atezolizumab given prior to cystectomy in operable muscle invasive transitional cell carcinoma bladder cancer. Methods: This single arm phase 2 study investigated 2 cycles of atezolizumab (1200mg Q3) prior to cystectomy in muscle invasive transitional cell cancer (T2-4N0M0). Pathological complete response (pCR) occurring in ≥20% of patients was the primary endpoint. Biomarker analysis on sequential tissue was a co-primary endpoint. Cross sectional imaging was performed at baseline and prior to cystectomy which occurred 4 - 8 weeks after starting atezolizumab. Radiological response was assessed. Adverse events (AEs) and surgical complications were assessed using CTCAE v4.03 and the Clavien-Dindo classification. The IDMC reviewed the first 69 patients (of 85) and supported this interim presentation. Results: The median age of the 69 patients was 73 years (range 54-88). At baseline pT2, T3, T4 disease occurred in 77%, 16% and 7% of patients respectively. 14 (20%) patients had only 1 cycle (8 due to AEs). 7 patients did not have cystectomy ( 1 disease progression, 2 treatment related AE). There was 1 potential treatment related death during treatment/perioperative period (cardiovascular disease). Treatment related grade 3/4 toxicity occurred in 12% of patients. Grade 3 or 4 surgical complications occurred in 31% of pt. The pCR rate was 18/62 (29%) [95%CI: 18% to 42%] (pT0 23%, Tis 6%, T1 10% T2 21% T3 24% T4 16% stage at surgery). 39% of patients were down staged to non-muscle invasive disease. 3/18 (17%) of the pCR patients had pT3/4 disease at baseline. 30 patients had sequential imaging and radiologically measurable disease at baseline. 23% [95%CI, 10% to 42%] and 13% [95%CI, 4% to 31%] of these patients radiologically responded and progressed respectively. Biomarker results including T cell infiltration and PD-L1 status before and after therapy will be presented. Conclusions: Neoadjuvant atezolizumab is safe and associated with a meaningful pathological CR rate at this interim stage. Further exploration is justified. Clinical trial information: NCT02662309.

355 Background: The ORR and survival of mUC patients (pts) who progress after platinum-based chemotherapy (pctx) are poor. Atezolizumab (atezo) reinvigorates antitumor immunity by targeting PD-L1 and has shown promising Ph 1 activity in mUC. Methods: IMvigor 210 cohort 2 (NCT02108652) enrolled 316 mUC pts who progressed during or following pctx. Pts received atezo at 1200 mg IV q3w until loss of clinical benefit. The SP142 IHC assay centrally assessed PD-L1 expression. Pts/investigators were blinded to PD-L1 status. Co-primary endpoints were confirmed ORR by RECIST v1.1 per central review (IRF) and modified (m) RECIST per investigator, which were met if null hypothesis (ORR = 10%) was rejected (α = 5%). ORR endpoints were stratified by PD-L1 tumor-infiltrating immune cell (IC) status: IC2/3, IC1/2/3, all comers. Results: Efficacy/safety-evaluable pts (N = 311) had a median age of 66 y, CrCl < 60 mL/min (35%) and ≥ 2 prior regimens for mUC (40%). Many had poor prognostic factors (Table). At 5/5/15 data cutoff (follow up ≥ 24 w), 43/47 responding pts had ongoing responses. Both IRF (Table) and mRECIST ORR correlated with IC status. Durable responses were seen including poor prognostic subgroups (Table). mDOR was not reached in any PD-L1 or prognostic subgroup. mPFS was 2.1 mo in all PD-L1 subgroups. Median treatment duration was 12 w (range 0-46). Treatment-related AEs (most commonly fatigue) occurred in 66% of pts (all Grade); 15% had G3-4 related AE and 4% had G3-4 immune-mediated AE. 27% of AEs led to dose interruption and 3% led to withdrawal. No renal toxicity was seen. Conclusions: IMvigor 210, the first Ph 2 study targeting PD-L1/PD-1 in mUC, demonstrated significantly improved ORR vs historic controls. Responses were durable and associated with higher PD-L1 IC expression; poor prognostic factors did not preclude response. Atezo was well tolerated, and a randomized Ph 3 study vs ctx is ongoing (IMvigor 211; NCT02302807). Clinical trial information: NCT02108652. [Table: see text]

409 Background: IMvigor211 is a global study of atezo vs chemo in platinum-treated mUC. The study did not meet its primary endpoint of overall survival (OS) in programmed death-ligand 1 (PD-L1)–selected patients (pts), 1 but exploratory analyses showed improved OS for atezo in the intent-to-treat (ITT) population. Here we compare clinical outcomes in ITT and prespecified PD-L1 subgroups with those in subgroups defined by immune transcriptional gene expression (tGE) signatures and TMB. Methods: Pts with ≤ 2 prior lines of therapy for mUC who progressed during or following platinum treatment were randomized 1:1 to atezo or chemo (vinflunine, paclitaxel or docetaxel, per physician). The primary endpoint was OS, hierarchically compared between treatment arms in PD-L1–selected and ITT pts. Planned exploratory biomarker analyses included tGE (RNA-seq) and TMB (FoundationOne). Results: The ITT population included 931 pts (atezo arm, 467; chemo arm, 464), and biomarker-evaluable subgroups were representative of the ITT population. PD-L1 expression positively correlated with tGE (R = 0.61) but not TMB (R = 0.13). OS and hazard ratios (HRs) are listed in the Table. Conclusions: In this randomized Phase III study, we show that high PD-L1 and high tGE are associated with improved outcomes with both chemo and atezo. In contrast, higher TMB predicted OS in favor of atezo; however, clinical benefit with atezo was also seen in the ITT population. Clinical trial information: NCT02302807. [Table: see text]

104 Background: Biomarkers of clinical benefit of immunotherapies, such as non-synonymous mutations, mutational load, PD-L1 IHC and immune signatures, have not been systematically evaluated in mUC patients (pts) treated with anti–PD-L1 agents. Methods: Exploratory analyses of immune and genetic predictors of response to atezo were performed on archival tumor specimens from mUC pts (NCT02108652 cohort 2). PD-L1 expression in tumor samples was assessed by IHC (SP142 assay) and associated with response as determined by RECIST v1.1 (central review). Gene expression was quantified by RNA-seq (Illumina TruSeq RNA Access; n = 195); molecular subtypes were assigned as per TCGA. Mutations were detected by genomic profiling (FoundationOne 315-cancer gene panel; n = 150) to estimate overall load. Results: PD-L1 tumor-infiltrating immune cell (IC) status was associated with CD8+ T effector (Teff) gene expression levels (P < 0.0001). Notably, response to atezo was associated with high expression of CXCL9 (P = 0.0057) and CXCL10 (P = 0.0079). Evaluable samples were classified into luminal (n = 73) and basal (n = 122) TCGA subtypes. PD-L1 IC prevalence was enriched in basal (60%) vs luminal (23%) samples (P < 0.0001); elevated tumor cell PD-L1 was mostly restricted to the basal subtype (39% basal vs 4% luminal, P < 0.0001) and did not correlate with ORR. Teff expression was elevated in luminal cluster II and basal III/IV and not in luminal I. Responses occurred in all subtypes, but ORR was significantly higher in luminal II samples: 34% (P = 0.0017). While median mutational load was significantly increased in responders (12.4/Mb) vs non-responders (6.4/Mb; P < 0.0001) and correlated with both PFS (P = 0.003) and OS (P = 0.014), these associations were independent of TCGA subtype. Conclusions: PD-L1 expression on IC was associated with response to atezo. Intrinsic TCGA subtype and mutational load each added predictive value. Simultaneous classification by these characteristics in mUC pts treated with atezo further defines the drivers of immune responsiveness and may suggest potential combination strategies. Clinical trial information: NCT02108652.