Background, Methods, and Design of BOND-003 in NMIBC

Mark D. Tyson, II, MD, MPH, a urologic oncologist at Mayo Clinic in Phoenix, Arizona, discusses the rationale behind studying cretostimogene grenadenorepvec for the treatment of patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) in the the phase 3 BOND-003 trial (NCT04452591).

Cretostimogene grenadenorepvec is a serotype 5 adenovirus which was made to express granulocyte-macrophage colony-stimulating factor (GM-CSF). The agent can replicate in cells with mutated or deficient retinoblastoma, and leads to response rates of approximately 45% in patients with recurrent NMIBC after receiving BCG.

BOND-003 is an open-label, single-arm, phase 3 study which enrolled patients with BCG-unresponsive, high-risk NMIBC across North America and the Asia-Pacific regions. Patients were eligible for enrollment if aged 18 years and older with pathologically confirmed high-risk NMIBC with CIS +/- Ta/T1 that is unresponsive to BCG treatment and an ECOG performance status of 0-2.

The primary end point being evaluated in the trial is the rate of complete responses (CRs) reached at any time. Investigators are also evaluating the secondary end points of CR rate at 12 months, duration of response, progression-free survival, cystectomy-free survival, and safety.

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0:09 | My name is Mark Tyson, and I am delighted to present the pivotal results of BOND-003, a single-arm, open-label, phase 3, registrational study evaluating cretostimogene grenadenorepvec monotherapy for BCG-unresponsive non-muscle invasive bladder cancer. I have no conflicts of interest with CG Oncology.

0:31 | So what is cretostimogene grenadenorepvec? Cretostimogene is a conditionally replicating oncolytic serotype 5 adenovirus that has been designed to preferentially replicate in and kill cancer cells. The E2F1 promoter drives the expression of essential viral genes while restricting replication to RB-pathway deficient tumor cells, thereby sparing normal tissue. Cretostimogene also encodes the complementary DNA for GM-CSF, which is a potent cytokine inducer of antitumor immunity in animal models. The primary receptor for Cretostimogene is the Coxsackie and adenovirus receptor, which is expressed in all stages of bladder cancer.

1:15 | After binding the CAR receptor credo enters the malignant cell, where viral replication leads to tumor cell lysis and releases viral and tumor specific antigens. These antigens are picked up by dendritic cells and presented to T cells, which initiate the local antitumor immune response, thereby potentially getting the immunotherapeutic effect.

1:36 | This leads us to BOND-003 three cohort C, a phase 3 study of Cretostimogene in patients with BCG-unresponsive CIS, according to the strict definition laid out by the FDA in their 2018 guidance. Concomitant papillary disease was allowed, but this had to be completely resected prior to the initiation of treatment. Importantly, patients underwent mandatory biopsies at 12 months, which included 5 regions of the bladder as well as the prostatic urethra in men. Patients underwent 6 sequential weekly installations of Cretostimogene, followed by a repeat induction for non responders and maintenance for responders. The primary end point was complete response at any time point. Key secondary end points include durability of response, as well as recurrence-free, progression-free, and cystectomy-free survival.