Four weeks of once-daily oral JNJ-56136379 (JNJ-6379; 25, 75, 150 or 250 mg), a class-N capsid assembly modulator (CAM-N), was well tolerated with potent antiviral activity in treatment-naïve, chronic hepatitis B e antigen-positive and hepatitis B e antigen-negative patients (NCT02662712). Hepatitis B virus (HBV) genome sequence analysis, using HBV DNA next-generation sequence technology, was performed, and impact of substitutions on efficacy was assessed. Analyses focused on HBV core protein amino acid positions associated with JNJ-6379 and/or other CAMs in vitro resistance, and those within the CAM-binding pocket. 31/57 patients had ≥ 1 polymorphism at any of the core amino acid positions of interest, most frequently at positions 38 (32%), 105 (23%) and 109 (14%). None of these polymorphisms are known to reduce JNJ-6379 in vitro activity (fold change [FC] in 50% effective concentration <3.0). Two JNJ-6379-treated patients carried a Y118F baseline core polymorphism known to reduce JNJ-6379 activity in vitro (FC = 6.6) and had HBV DNA declines of 2.77 (75 mg) and 2.19 log 10 IU/mL (150 mg) at the end of treatment. One 75 mg JNJ-6379-treated patient had an emerging T109S substitution (FC = 1.8; HBV DNA decline 3.18 log 10 IU/mL). A 25 mg JNJ-6379-treated patient had on-treatment enrichment of Y118F variant (HBV DNA decline 2.13 log 10 IU/mL). In conclusion, baseline polymorphisms and enrichment of substitutions reducing JNJ-6379 in vitro activity were rare, with no consistent impact on virological response during a 4-week phase 1b study. Emergence of resistance to longer treatments of JNJ-6379 will be evaluated in phase 2 studies.

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TPS596 Background: Radical cystectomy (RC) without neoadjuvant chemotherapy remains SOC for cis-ineligible pts (and those refusing cis) with MIBC and T1-T4aN1 disease. Yet, many pts progress to incurable, metastatic disease. Preventing disease recurrence for these pts remains an unmet need. Immune checkpoint inhibitors (ICIs) are approved in Bacillus Calmette-Guérin-unresponsive carcinoma in situ, in the adjuvant and metastatic urothelial cancer (UC) settings, and are being actively explored in the perioperative setting. In phase 2 single-arm trials, neoadjuvant ICIs showed promising pathologic complete response (pCR) rates (approximately 30%–40%). The phase 3 CheckMate 274 study showed improved disease-free survival with adjuvant NIVO vs placebo in MIBC. BEMPEG, an immunostimulatory interleukin-2 (IL-2) cytokine prodrug, is engineered to deliver a controlled, sustained, and preferential signal to the clinically validated IL-2 pathway. Preferential binding of BEMPEG to the IL-2 heterodimeric receptor (IL-2Rβγ) activates and expands CD8+ T cells and natural killer cells over immunosuppressive regulatory T cells. The combination of BEMPEG + NIVO demonstrated deep responses and a tolerable safety profile in pts with metastatic UC in the phase 1/2 PIVOT-02 trial and is being further explored in the phase 2 PIVOT-10 (NCT03785925) study. The PIVOT IO 009 study, presented here, aims to evaluate the hypothesis that perioperative treatment with BEMPEG + NIVO will provide higher pCR and longer event-free survival (EFS) vs SOC in cis-ineligible pts with MIBC and T1-T4aN1 disease. Methods: PIVOT IO 009 (NCT04209114) is an open-label, phase 3 trial of 540 cis-ineligible pts with MIBC and T1-4aN1 disease, who will be randomized 1:1:1 to receive SOC, neoadjuvant and adjuvant BEMPEG + NIVO, or neoadjuvant and adjuvant NIVO alone. Stratification factors include clinical stage (T2N0 vs T3-T4aN0 vs T1-T4aN1) and tumor cell PD-L1 status. Key inclusion criteria: adults with MIBC and T1-T4aN1 disease deemed eligible for RC and ECOG PS 0–1. Cis-ineligibility is defined as one of the following: glomerular filtration rate ≥30 but < 60 mL/min, or ≥grade 2 hearing loss or peripheral neuropathy. Key exclusion criteria: clinical evidence of ≥N2 or metastatic disease or UC in the upper urinary tract; prior systemic therapy, radiation therapy, or prior surgery for bladder cancer other than TURBT or biopsies. Primary endpoints: pCR rate (pT0N0) of neoadjuvant BEMPEG + NIVO vs no neoadjuvant therapy (SOC), and EFS of neoadjuvant and adjuvant BEMPEG + NIVO vs SOC. Secondary endpoints: pCR rate of neoadjuvant NIVO vs SOC; EFS of neoadjuvant and adjuvant NIVO vs SOC; overall survival and safety in each treatment arm vs SOC. The study is currently recruiting pts. Clinical trial information: NCT04209114.

TPS403 Background: The current standard of care for advanced RCC (aRCC) utilizes immune checkpoint inhibitors (ICIs) and targeted agents. Novel combinations of these agents, such as NIVO + TKIs, have demonstrated clinical benefit over TKI monotherapy. In CheckMate 9ER, NIVO + cabozantinib (CABO) in aRCC demonstrated clinically meaningful efficacy results and a favorable safety profile, and was FDA approved (01/2021). High-dose interleukin-2 (IL-2) was used historically for durable responses in mRCC but had unfavorable toxicity with complex inpatient treatment regimens. BEMPEG, an immunostimulatory IL-2 cytokine prodrug, is engineered to deliver a controlled, sustained, and preferential signal to the clinically validated IL-2 pathway. Preferential binding of BEMPEG to the IL-2 heterodimeric receptor (IL-2Rβγ) activates and expands CD8+ T cells and NK cells over immunosuppressive Tregs. In the phase 1/2 PIVOT-02 study, BEMPEG + NIVO displayed encouraging antitumor activity in pts with mRCC, with a tolerable safety profile. The clinical activity and the manageable, non-overlapping toxicity profiles of the individual agents in this combination warrants exploration of triplet regimens in previously untreated aRCC. Methods: PIVOT IO 011 (NCT04540705) is a 2-part, phase 1/2, randomized, open-label study assessing the safety and efficacy of BEMPEG + NIVO + TKI triplet in pts with untreated aRCC or mRCC. In Part 1, pts will receive BEMPEG + NIVO + TKI (Part 1A: axitinib [AXI] or Part 1B: CABO; n≈6–24 pts in each TKI arm). While BEMPEG + NIVO dosing will remain consistent across phases, each TKI will have 2 doses evaluated in Part 1, and results will determine the recommended phase 2 dose for AXI/CABO in Part 2. In Part 2, pts will be randomized 1:1 to receive either BEMPEG + NIVO + CABO or NIVO + CABO (N≈250), stratified by IMDC prognostic score and prior nephrectomy status. If the CABO triplet has an unacceptable toxicity profile, Part 2 may be amended to use the AXI triplet. Key inclusion criteria: aRCC or mRCC with clear cell component; no prior systemic therapy for RCC, except 1 prior adjuvant/neoadjuvant therapy for completely resectable RCC (must have included an anti–VEGF agent with recurrence ≥6 months after last dose); and Karnofsky PS ≥70%. Key exclusion criteria: active CNS brain/leptomeningeal metastases; active, known, or suspected autoimmune disease; and inadequately treated adrenal insufficiency. Primary endpoints in Part 1: dose-limiting toxicities and safety; and in Part 2: overall response rate per RECIST v1.1 by investigator. Secondary endpoints in Part 2: progression-free survival, overall survival, safety. Duration of BEMPEG + NIVO will be ≤2 years, and treatment with TKI will continue until disease progression. The study is currently recruiting. Clinical trial information: NCT04540705.