Cretostimogene Grenadenorepvec Shows High CR Rate in BCG-Unresponsive NMIBC

Mark D. Tyson, II, MD, MPH

Cretostimogene grenadenorepvec showed sustained and durable complete responses (CR) over 12 months with a CR rate of 75.2% when used for the treatment of patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), according to findings from the phase 3 BOND-003 trial (NCT04452591).¹

The single-arm, open-label, phase 3 BOND-003 study was developed to assess and confirm the clinical activity of cretostimogene grenadenorepvec in this patient population. A total of 112 patients with high-risk BCG-unresponsive NMIBC were enrolled. Patients with BCG-unresponsive, high-risk NMIBC were enrolled across North America and the Asia-Pacific regions. Patients were required to be aged 18 years and older, have pathologically confirmed high-risk NMIBC with CIS +/- Ta/T1 that is unresponsive to BCG treatment, and an ECOG performance status of 0 to 2.

Investigators explored the primary end point of the rate of CRs reached at any time, and the secondary end points were CR rate at 12 months, duration of response, progression-free survival, cystectomy-free survival, and safety.

In addition to the promising efficacy data, there were no grade 3 or higher treatment-related adverse events (TRAEs) or deaths observed. There were 2 patients (1.8%) with serious TRAEs that were deemed grade 2, and 94.5% of patients completed all expected treatments. Seventy patients (62.5%) had a TRAE, and as of January 31, 2024, the safety cutoff date, the most frequently observed TRAEs (≥10%) included bladder spasm, pollakiuria, dysuria, micturition urgency, and hematuria.

In an interview with Targeted Oncology^TM, Mark D. Tyson, II, MD, MPH, a urologic oncologist at Mayo Clinic in Phoenix, Arizona, delved into the findings from BOND-003 and the rationale for using cretostimogene grenadenorepvec for the treatment of patients with high-risk BCG-unresponsive NMIBC with CIS.

Targeted Oncology: What is cretostimogene grenadenorepvec?

Tyson: 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.

After binding the [chimeric antigen] receptor, [cretostimogene] 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. This leads us to BOND-003 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.

Bladder Cancer, Urinary Bladder Image: © reineg - stock.adobe.com

Who was included in the study? What were the end points?

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 nonresponders 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.

In total, 112 patients enrolled in BOND-003, and the data presented here are up to a cutoff date of April 1, 2024. In terms of baseline characteristics, most patients were White, male, and Medicare age. Eighteen percent of patients did have concomitant papillary disease, and as expected, the cohort was heavily pretreated with the median number of prior BCG instillations of 12, with several other patients also having received pembrolizumab [Keytruda].

Can you discuss the efficacy findings from the study?

In terms of the efficacy analysis, the complete response rate at any time point for all patients based upon central path review was 75.2%, with the confidence interval indicating a range of plausible CRs between 65% and 83%. The key observation worth noting is that 54% of patients who did not respond to the initial induction course of cretostimogene responded to the second induction course of cretostimogene, with several patients whose response was durable to beyond 12 months. This speaks to the oncolytic immunotherapeutic mechanism of action, whereby the immune system switches from innate to adaptive, as seen with the second induction course of BCG.

Secondly, of the 35 patients who hit the 12-month time point, 29, or 83%, have maintained a duration of response of greater than 12 months with 22 complete responders still pending. Lastly, 92% of patients had not required a cystectomy at the 1-year time point.

What about the safety results?

In terms of tolerability, cretostimogene has generally been well tolerated. There were no grade 3 treatment-related adverse events and no deaths. There were 2 grade 2 adverse events, and 1 patient did discontinue the trial, but this was due to an unrelated adverse event. Ninety-four and a half percent of patients completed all expected treatments.

In terms of the instillation process itself, cretostimogene administration is a familiar and convenient workflow. It can be administered by nurses or medical assistants, and the favorable tolerability profile lends itself to high patient compliance. This is evidenced by the fact that no patient in the BOND-003 trial was unable to tolerate the instillation.

What are the main takeaways from this study?

Recognizing that it is difficult to compare across studies due to underlying differences in the population, cretostimogene would at least appear to compare favorably to the current nonsurgical co-standards of care. The 75% response rate observed for cretostimogene monotherapy compares favorably to the 62% observed for the N-803 [Anktiva] combination therapy with BCG, to the 51% for nadofaragene [firadenovec; Adstiladrin], and to the 41% for pembrolizumab. Similarly, the duration of complete response for cretostimogene monotherapy compares favorably with 83% of responders at a 12-month time point having a duration of response greater than 12 months, vs 58% for N-803, and 46% both for nadofaragene and pembrolizumab. Toxicity data compares favorably as well with no grade 3s observed in BOND-003.

Based upon the strength of these data, the FDA has granted CG Oncology fast track and breakthrough designations for the development of cretostimogene grenadenorepvec for the treatment of BCG-unresponsive non-muscle invasive bladder cancer. Two substantial amendments have been implemented. The first is a treatment extension phase for those who get to the end of the protocol in complete response. These patients can now get maintenance therapy every 6 months in years 2 and 3. And second is the addition of a papillary-only cohort called cohort P. These patients have papillary only BCG-unresponsive non-muscle invasive bladder cancer and receive the same dosing schedule as cohort C.

REFERENCE:

Tyson M, Uchio E, Nam J, et al. Pivotal results from BOND-003: a phase 3, single-arm study of intravesical cretostimogene grenadenorepvec for the treatment of high risk, BCG-unresponsive non-muscle invasive bladder cancer. Presented at: 2024 American Urological Association Meeting; May 3-6, 2024; San Antonio, TX.