Delacroix, Scott Edward

TPS909 Background: BCG-Exposed NMIBC (a high grade recurrence within 24 months of prior BCG, but not meeting “unresponsive” criteria) is a large patient population with a critical need for more effective treatment strategies that prevent the development of BCG unresponsive disease/progression. The current standard of care is re-treatment with BCG alone, but only ~50% of patients derive clinical benefit. While intravesical gemcitabine (with or without docetaxel) is sometimes used, multiple retrospective studies have found that GemDoce is no better than re-treatment with BCG alone for patients with BCG-exposed NMIBC. A chemoimmunotherapy strategy of intravesical Gemcitabine with BCG (GemBCG) combines the two most effective, inexpensive, and commonly used treatments for NMIBC. Based on compelling biologic rationale and preclinical data, a phase I/II (n=52) trial was initiated of GemBCG in BCG-exposed NMIBC (NCT04179162). GemBCG has minimal side effects (3.8% [2/52] with Grade 3 TRAEs (no grade 4/5 seen) with similar side effects and tolerability to BCG alone. GemBCG has a outstanding early efficacy signal (6-month complete response of 97% [28/29] in patients with CIS, compared to ~50% 6-month complete response w/ BCG alone for BCG exposed CIS). GemBCG has promising preliminary longer term efficacy (18-month HG-RFS of 76% compared to ~45-55% reported with BCG alone, GemDoce, and recombinant BCG in BCG exposed NMIBC). Correlative studies support the hypothesis that the addition of gemcitabine to BCG can favorably modulate the tumor immune microenvironment. Methods: Based on the above rationale, we initiated the “GAIN” trial (A032303/ NCT07000084), a prospective, multicenter, open-label phase III study for patients with BCG-exposed NMIBC randomized to either: re-treatment with BCG only (Arm A, SOC) or Gemcitabine + BCG (GemBCG, Arm B). BCG-exposed NMIBC is defined as a high grade NMIBC (Ta, T1, Tis/CIS) that has recurred within 24 months of prior BCG, but NOT otherwise currently meeting BCG unresponsive NMIBC. The primary objective is to compare high grade recurrence-free survival (HG-RFS) between the two treatment arms. Notable aspects of the trial include: (1) the reduced burden on investigators and research teams due to the NCI’s new streamlined data initiative, (2) liberal inclusion/exclusion criteria and pragmatic design to improve generalizability of results, and (3) Cystoscopic biopsies/TURBT at week 13/month 3 for all participants (both CIS and “papillary only”) for multiple reasons including to allow for earlier detection of BCG unresponsive disease for patient safety, increased rigor of the trial, and objectively evaluate urinary biomarkers/urinary tumor DNA. Clinical trial information: NCT04179162 .

LBA629 Background: Whether BCG strain influences clinical efficacy is unclear. BCG shortages and a reliance on a single strain may impact disease outcomes. Evidence also suggests that priming with intradermal (ID) BCG vaccination prior to intravesical (IVe) BCG enhances anti-tumor immunity and cancer clearance. Co-primary objectives address these issues. Methods: The trial design calls for 924 eligible patients with BCG naïve non-muscle invasive bladder cancer (NMIBC) (HG Ta/T1 +/- CIS or CIS alone) with negative purified protein derivative (PPD) to be randomized in a 1:1:1 ratio, to IVe TICE (Arm 1), IVe Tokyo-172 (Arm 2), or ID + IVe Tokyo-172 (Arm 3) BCG, stratifying on age group and clinical stage. IVe BCG included 6 weekly instillations (induction) and three weekly instillations (maintenance) at 3 and 6 months (mo), then every 6 mo for 3 years. Objective 1 tests whether Tokyo-172 BCG is non-inferior (NI) to TICE BCG, specifying a NI hazard ratio=1.34 (84% power). Objective 2 tests whether priming with ID prior to IVe Tokyo-172 is superior to IVe Tokyo-172 (HR=0.71, 83% power). The primary endpoint is high-grade recurrence-free survival (HG-RFS) censored at last cystoscopy, using a one-sided α=0.021 for each test. A Cox model adjusting for the stratification factors is used. Secondary endpoints include adverse events, 6-mo biopsy-proven complete response (CR) in patients with CIS +/- Ta, T1, duration of CR, PPD conversion and HG-RFS, progression-free survival (PFS) and quality of life. Max follow-up is 5 years. Results: 1000 (984 eligible) patients were enrolled from 2/17-12/20. Median (IQR) follow up is 4.6 (3.6, 5.0) yrs. Median age (range) is 70 yrs (26, 99), 17% are female, 9% are non-white, and 34% had CIS at entry. HG-RFS, CR, duration of CR at 4 yrs, and PFS were similar among arms (Table). PPD conversion occurred in 29% and was not correlated with HG-RFS. Gr 1-2 AE rate was similar (67%, 71%, and 67%) and Gr 3-4 (no Gr 5s) rate was 6%, 11%, and 14% for Arms 1,2, and 3, respectively. Conclusions: Tokyo-172 is non-inferior to TICE BCG in terms of HG RFS and CIS CR and is similar for PFS. Gr 3-4 AE rate is higher with Tokyo-172. Priming with Tokyo-172 BCG does not improve HG RFS. PPD conversion is not prognostic. Clinical trial information: NCT #03091660 . CIS Component N (eligible) 5-yr HG RFS HG RFSHR (95.8% CI) @ 5-yrPFS PFS HR(95% CI) @ CR %(95% CI) 4 yr CR duration Tice Ive 333 (330) 58% 79% 62%; 71/114(53%, 71%) 80% Tokyo Ive 332 (327) 64% *0.82(0.63, 1.08) 79% *0.99(0.70, 1.39) 60%; 66/110(50%, 69%) 83% Tokyo ID + Ive 335 (327) 63% **1.00(0.76, 1.33) 77% **1.07(0.76, 1.51) 63%; 69/109(54%, 72%) 80% 3 mo. PPD + conversionY vs. N 782 evaluable225 (29%)557 (71%) 69%67% ^HR=0.91(0.68, 1.22) * Tokyo-172 vs. Tice, ** Tokyo Priming vs. Tokyo no priming. ^conversion to PPD + vs. – @ adjusted for 2 strat factors (and arms for PPD model). PFS event = MIBC, metastasis, or death.