Dr Li on Safety Data Derived From the CORE-001 Trial in BCG-Unresponsive NMIBC

Roger Li, MD, genitourinary oncologist, Moffitt Cancer Center, discusses safety data from the final analysis of the phase 2 CORE-001 trial (NCT04387461) investigating cretostimogene grenadenorepvec plus pembrolizumab (Keytruda) in patients with bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS). He also highlights the clinical implications of the data.

, Li and colleagues presented findings from the open-label trial, which demonstrated that patients with BCG-unresponsive CIS with or without papillary disease in the intention-to-treat population (n = 35) had a 12-month complete response (CR) rate of 57.1% (95% CI, 39.5%-73.2%). The rate of CR observed at any time during the study was 82.9%. Both these rates were notably higher than the CR rate achieved with pembrolizumab monotherapy in the phase 2 KEYNOTE-057 trial (NCT02625961).

In CORE-001, cretostimogene grenadenorepvec was administered intravesically as a 6-week induction regimen, which was followed by 3 weekly maintenance doses at months 3, 6, 9, 12, and 18. Patients who exhibited high-grade or persistent CIS at the 3-month assessment had the option for reinduction. Pembrolizumab was administered intravenously every six 6 weeks for up to 24 months. The primary end point for the first quarter of the trial was CR at 12 months.

The safety data from the study importantly demonstrate that there was no synergistic toxicity observed with the agents in the combination regimen, Li begins. The safety profile aligns closely with what has been reported in previous pembrolizumab monotherapy trials, indicating no unexpected adverse effects (AEs), he reports. Overall, the treatment was well tolerated, with an approximate 14.3% incidence of grade 3 serious AEs, Li adds.

This combination regimen is exciting, as it has generated efficacy extending out to 2 years and potentially even beyond, he continues. This combination may represent a new treatment option for patients with BCG-unresponsive NMIBC with CIS, Li notes. Li concludes by stating that he is enthusiastic about these results and eager to see what the future holds for this treatment approach.

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Roger Li, MD, discusses safety data from the final analysis of the CORE-001 trial in BCG-unresponsive non–muscle-invasive bladder cancer.

Dr Li on Cretostimogene Grenadenorepvec Plus Pembrolizumab in BCG-Unresponsive NMIBC

Roger Li, MD, genitourinary oncologist, Moffitt Cancer Center, discusses findings from the final analysis of the phase 2 CORE-001 trial (NCT04387461) investigating cretostimogene grenadenorepvec plus pembrolizumab (Keytruda) in patients with bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS).

. The primary end point of CORE-001 was 12-month complete response (CR) rate, and investigators aimed to improve upon response rates seen with pembrolizumab monotherapy in the phase 2 KEYNOTE-057 trial (NCT02625961), Li begins. In cohort A of KEYNOTE-057, which consisted of patients with high-risk, BCG-unresponsive NMIBC with CIS, the 12-month CR rate was 46%. In CORE-001, the 12-month CR rate with the combination (n = 35) was 57.1% (95% CI, 39.5%-73.2%). Overall, 82.9% of patients achieved a CR at any time.

Additionally, responses in CORE-001 were durable, Li says. A total of 54.3% (95% CI, 36.9%-70.8%) of patients had a CR at 24 months, and 95.1% of the patients who achieved a CR at 12 months continued to have a CR at 24 months. The Kaplan Meier recurrence-free survival (RFS) rates in the combination arm were 77.3% (95% CI, 58.1%-88.5%) at 12 months and 69.6% (95% CI, 49.4%-83.0%) at 24 months. The median duration of response (DOR) was not reached but was at least 21 months. The 12-month DOR rate was 81.6% (95% CI, 61.3%-91.9%), and the 24-month DOR rate was 77.3% (95% CI, 56.2%-89.1%).

Importantly, no patients developed MIBC or metastatic urothelial cancer during treatment with the combination, including patients who underwent radical cystectomy, Li emphasizes. Therefore, cretostimogene grenadenorepvec plus pembrolizumab is an ideal regimen to offer to patients who want to prevent their disease from progressing to MIBC or metastatic disease and who can tolerate the minimal amount of adverse effects that were observed in CORE-001, Li explains. However, these findings need to be validated in larger studies, he concludes.

Roger Li, MD, discusses the final analysis of the CORE-001 trial of cretostimogene grenadenorepvec plus pembrolizumab in BCG-unresponsive NMIBC with CIS.

Dr Li on the Clinical Implications of a Post Hoc Analysis of KEYNOTE-057 in BCG-Unresponsive NMIBC

Roger Li, MD, genitourinary oncologist, Moffitt Cancer Center, discusses the clinical implications of findings from a post hoc analysis of patients with Bacillus Calmette-Guérin (BCG)–unresponsive, high-risk non–muscle-invasive bladder cancer (NMIBC) who did not respond to treatment with pembrolizumab (Keytruda) on the phase 2 KEYNOTE-057 trial (NCT02625961).

Previously, investigators shared data from the KEYNOTE-057 trial, which demonstrated superiority with pembrolizumab as a bladder-sparing treatment option for patients with high-risk NMIBC unresponsive to BCG. At the 

, investigators shared insights from a post hoc analysis that was conducted to evaluate the clinical outcomes of patients from KEYNOTE-057 who either proceeded with radical cystectomy or received other bladder-sparing treatments following progression on pembrolizumab. 

analysis showed that oncologic outcomes were comparable

 between patients treated with bladder-sparing therapies vs radical cystectomy after pembrolizumab nonresponse, indicating that patients were not adversely affected by bladder-sparing therapy following pembrolizumab.

The clinical implications of these findings are significant, particularly in the context of treating patients with BCG-unresponsive bladder cancer, Li begins. The absence of notable differences in clinical outcomes among the 3 groups studied indicates that it is safe to continue treating patients even after they have developed BCG-unresponsive disease during their initial salvage therapy, he explains. This is a crucial insight because it underscores the possibility of prolonging bladder preservation strategies rather than immediately resorting to radical cystectomy, he states.

In recent years, several new agents have been approved by the FDA for use in this specific setting, offering more treatment options for patients, Li continues. The findings from this post hoc analysis support the notion that these treatments can be safely administered following progression on pembrolizumab without compromising patient outcomes, he adds. For oncologists, this evidence reinforces the viability of bladder-sparing approaches, providing reassurance that delaying more invasive procedures like cystectomy can be a safe and effective strategy for managing BCG-unresponsive bladder cancer, Li concludes.

Roger Li, MD, discusses the implications of a post hoc analysis of the KEYNOTE-057 trial in BCG-unresponsive, high-risk non–muscle-invasive bladder cancer.

Dr Li on the Rationale for a Post Hoc Analysis of KEYNOTE-057 in BCG-Unresponsive NMIBC

Roger Li, MD, genitourinary oncologist, Moffitt Cancer Center, discusses results from the phase 2 KEYNOTE-057 trial (NCT02625961) that have been previously reported, detailing 

 of patients with Bacillus Calmette-Guérin (BCG)–unresponsive, high-risk non–muscle-invasive bladder cancer (NMIBC) who did not respond to treatment with pembrolizumab (Keytruda) on the study.

KEYNOTE-057 was the first study that evaluated pembrolizumab in patients with BCG-unresponsive NMIBC, Li begins. The trial was structured into 2 cohorts; cohort A included patients with carcinoma in situ (CIS)–containing tumors, and cohort B consisted of patients with papillary-only tumors. The study assessed the efficacy of pembrolizumab in these disease settings, he explains.

For cohort A, the primary end point was the complete response (CR) rate at 3 months, which was found to be 41%, Li reports. This result demonstrated a significant level of effectiveness for pembrolizumab in patients with CIS-containing tumors, according to Li. For cohort B, the primary end point was the 12-month disease-free survival rate, which was reported in 2023 as 43.5%, he explains. These findings were crucial in securing 

use in patients with BCG-unresponsive NMIBC

, making it a new therapeutic option for patients with limited treatment alternatives, Li notes.

The rationale for conducting a post hoc analysis of KEYNOTE-057 stemmed from the observation that, despite pembrolizumab’s FDA approval, many patients still experience disease recurrence after treatment, he continues. These patients are often elderly and frail, making radical cystectomy, the standard treatment for nonresponse, a less viable option due to its associated risks and impact on quality of life, Li emphasizes. The purpose of the post hoc analysis was to determine whether patients who continued on a bladder-sparing therapeutic strategy, rather than undergoing immediate radical cystectomy, faced poorer outcomes after developing a nonresponse to pembrolizumab, Li states. This analysis provided insights into the potential benefits of less aggressive treatment approaches for this vulnerable patient population, he concludes.

Roger Li, MD, details a post hoc analysis of patients with BCG-unresponsive non–muscle-invasive bladder cancer who did not respond to pembrolizumab.

Dr Li on Unmet Needs in High-Risk MIBC

Roger Li, MD, genitourinary oncologist, Moffitt Cancer Center, discusses persisting unmet needs and potential avenues of research for patients with high-risk, muscle-invasive bladder cancer (MIBC).

Li begins by explaining that patients with Bacillus Calmette­–Guérin (BCG)–unresponsive, high-risk, non–muscle-invasive bladder cancer (NMIBC) have historically been a difficult population to treat. However, FDA-approved agents have entered this treatment space to give this patient population additional options, he says.

the FDA approved nogapendekin alfa inbakicept-pmln (Anktiva; N-803)

 in combination with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with carcinoma in situ with or without papillary tumors. As agents such as nogapendekin alfa inbakicept enter the BCG-unresponsive NMIBC space, Li ponders if therapies used in this setting could also have an application for patients with MIBC.

Currently, the standard of care for MIBC centers around surgical removal of the bladder via radical cystectomy combined with pelvic lymph node dissection, Li says. Although this surgical approach is effective, it represents a highly invasive technique that significantly impacts a patient's quality of life due to the removal of the bladder, Li emphasizes. A persisting unmet need in this patient population is the development of efficacious and safe therapeutic regimens that could offer bladder preservation as a viable alternative to surgery, he says.

Li notes the possibility and challenge of adapting these treatments to a more aggressive disease setting such as MIBC; however, he underscores the importance of conducting robust clinical trials to evaluate the efficacy and safety of these regimens in patients with MIBC. Such trials are essential to determine whether these therapies could provide disease control comparable with radical cystectomy and offer potential bladder preservation.

Furthermore, bladder-preserving strategies would represent a significant paradigm shift in the management of MIBC, as such strategies could potentially improve survival outcomes and enhance QOL for patients by avoiding the removal of the bladder, Li concludes.

Roger Li, MD, discusses persisting unmet needs in high-risk, muscle-invasive bladder cancer.

Roger Li, MD, discusses patient outcomes from the KEYNOTE-057 trial BCG–unresponsive, high-risk non–muscle-invasive bladder cancer.

Dr Li on Patient Outcomes From the KEYNOTE-057 Trial in BCG-Unresponsive NMIBC

Roger Li, MD, genitourinary oncologist, Moffitt Cancer Center, discusses results from a post-hoc analysis of patients with Bacillus Calmette-Guérin (BCG)–unresponsive, high-risk non–muscle-invasive bladder cancer (NMIBC) who did not respond to treatment with pembrolizumab (Keytruda) in the phase 2 KEYNOTE-057 trial (NCT02625961).

Primary results from KEYNOTE-057 demonstrated that pembrolizumab can serve as a bladder-sparing option for patients with high-risk NMIBC who are BCG-unresponsive and are unable or unwilling to undergo radical cystectomy. However, the outcomes of patients who do not respond to bladder-sparing therapies, including pembrolizumab, are of concern. Accordingly, Li and colleagues conducted a post hoc analysis of the KEYNOTE-057 trial to assess the clinical outcomes of patients who experienced persistent or recurrent high-risk NMIBC despite pembrolizumab therapy and subsequently received either radical cystectomy or other bladder-sparing therapies.

The analysis focused on progression-free survival (PFS), metastasis-free survival (MFS), and overall survival (OS), Li says. Patients with BCG-unresponsive carcinoma in situ (CIS) and/or papillary-only tumors who had nonresponse during treatment with pembrolizumab were divided into 3 different groups based on the timing of their radical cystectomy after non-response to pembrolizumab, using the 4-month mark as a categorization point, he explains. These groups included patients who underwent immediate radical cystectomy within the first 4 months, those who had late radical cystectomy after 4 months, and those who did not undergo radical cystectomy at all, opting instead for other bladder-sparing therapies, Li details.

Key findings from this analysis were presented at the 

, and revealed no significant differences in PFS, MFS, or OS among these 3 groups, Li reports. Additionally, a comparison of patients who underwent radical cystectomy within the first 4 months vs those who had it after 4 months showed no difference in the distribution of pathological staging. These findings suggest that the timing of radical cystectomy following non-response to pembrolizumab does not impact key survival outcomes and that patients may have flexible options for managing persistent or recurrent high-risk NMIBC after pembrolizumab therapy, he concludes.

Roger Li, MD, discusses patient outcomes from the KEYNOTE-057 trial in BCG–unresponsive, high-risk non–muscle-invasive bladder cancer.

Dr Li on Patient Outcomes From the KEYNOTE-057 Trial in BCG-Unresponsive NMIBC  

Roger Li, MD, discusses the rationale of the phase 3 MoonRISe-1 trial (NCT06319820).

Dr Li on the Rationale of the MoonRISe-1 Trial in NMIBC

Roger Li, MD, a genitourinary oncologist at Moffitt Cancer Center, discusses the rationale of the phase 3 MoonRISe-1 trial (NCT06319820) examining TAR-210 vs intravesical chemotherapy in patients with non–muscle-invasive bladder cancer.

Roger Li, MD, genitourinary oncologist, Moffitt Cancer Center, expands on the mechanism of action for the combination of CG0070 (cretostimogene grenadenorepvec) and pembrolizumab (Keytruda), detailing the rationale for investigating the regimen's synergy in patients with Bacillus Calmette-Guérin (BCG)–unresponsive, carcinoma in situ-containing non–muscle invasive bladder cancer (NMIBC).

There is currently a substantial lack of effective treatment options for patients with BCG-unresponsive NMIBC that allow patients to preserve their bladder function, Li begins. Although radical cystectomy remains the standard-of-care in this setting, many patients that are elderly and frail are not good candidates for this procedure, he adds.

CG0070 contains a human E2F promoter that allows it to specifically attach to cancer cells that are defective in the retinoblastoma protein pathway, Li explains. This pathway is responsible for increases in E2F expression. The virus replicates in these cancer cells, and leads to cell lysis, Li says. During lysis, CG0070 also releases cancer-specific neoantigens into the tumor microenvironment. These neoantigens recruit immune cells to the tumor site to mount an immunogenic attack, Li details.

Prior studies have shown the efficacy of the cancer-selective oncolytic adenovirus CG0070 and pembrolizumab as single agents in BCG-unresponsive MIBC, Li continues. Additionally, pembrolizumab has been shown to reinvigorate lymphocytes that may become exhausted over time, he notes.

Accordingly, it was hypothesized that administering these treatments incombination could be synergistic, thereby producing more durable responses, Li states. 

Therefore the phase 2 CORE-001 trial (NCT04387461) was created to evaluate this hypothesis

 Demonstrating that the combination elicited a high overall response rate that was maintained at the 12-month time point. Although the regimen did show synergistic activity, no clear evidence of synergistic toxicity was observed, and the regimen’s adverse effect profile was generally consistent with prior studies of each agent alone.

Roger Li, MD, expands on the mechanism of action for the combination of CG0070 and pembrolizumab, and discusses the rationale for investigating the regimen's synergy in patients with non–muscle invasive bladder cancer who are unresponsive to Bacillus Calmette-Guérin.

Dr Li on the Rationale for Evaluating CG0070 Plus Pembrolizumab in BCG-Unresponsive NMIBC

Roger Li, MD, genitourinary oncologist, Moffitt Cancer Center, discusses phase 2 data with the combination of CG0070 (cretostimogene grenadenorepvec) and pembrolizumab (Keytruda) in patients with non–muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG).

The phase 2 CORE-001 trial (NCT04387461) has fully accrued a total of 35 patients with BCG-unresponsive carcinoma in situ (CIS)–containing NMIBC, and 25 patients had 12-month response data available at the time of data cutoff, Li says. The primary end point of the trial was the 12-month complete response (CR) rate evaluated with random bladder biopsies, cystoscopy, and urine cytology. Results showed that 68% of patients achieved a CR at 1 year, demonstrating the durability of response with the combination, Li says. Additionally, there was little additive toxicity with the addition of CG0070. Notably, immune-related adverse effects were transient and resolved after treatment completion.

Both pembrolizumab and nadofaragene firadenovec-vncg (Adstiladrin) are approved for the treatment of adult patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors. However, the 1-year CR rates with these agents range from 20% to 25%, leaving most patients vulnerable to disease recurrence and need for subsequent therapy, Li explains. As such, the CR rate reported in this trial is encouraging and worthy of further exploration, according to Li.

To that end, investigators will continue to follow patients in 6-month intervals after year 2. Moreover, the single-arm phase 3 BOND-003 trial (NCT04452591) has been launched, and will investigate CG0070 monotherapy in 110 patients with high-risk, BCG-unresponsive, CIS-containing NMIBC. The primary end point of this trial is CR at any time. Additionally, the phase 3 PIVOT-001 trial is planning to evaluate CG0070 in combination with checkpoint inhibition in the same population.

Roger Li, MD, discusses phase 2 data with the combination of CG0070 and pembrolizumab in patients with non–muscle invasive bladder cancer unresponsive to Bacillus Calmette-Guérin.

Roger Li, MD

Articles

Dr Li on Safety Data Derived From the CORE-001 Trial in BCG-Unresponsive NMIBC

Dr Li on Cretostimogene Grenadenorepvec Plus Pembrolizumab in BCG-Unresponsive NMIBC

Dr Li on the Clinical Implications of a Post Hoc Analysis of KEYNOTE-057 in BCG-Unresponsive NMIBC

Dr Li on the Rationale for a Post Hoc Analysis of KEYNOTE-057 in BCG-Unresponsive NMIBC

Dr Li on Unmet Needs in High-Risk MIBC

Dr Li on Patient Outcomes From the KEYNOTE-057 Trial in BCG-Unresponsive NMIBC

Dr Li on the Rationale of the MoonRISe-1 Trial in NMIBC

Dr Li on the Rationale for Evaluating CG0070 Plus Pembrolizumab in BCG-Unresponsive NMIBC

Dr Li on the Use of CG0070 Plus Pembrolizumab in BCG-Unresponsive Non–muscle Invasive Bladder Cancer