Andrea Necchi, MD, discusses treatment with TAR-200 by PD-L1 expression in BCG-unresponsive, high-risk non–muscle-invasive bladder cancer with carcinoma.

Dr Necchi on Responses With TAR-200 According to PD-L1 Status in NMIBC

Andrea Necchi, MD, associate professor, oncology, Vita-Salute San Raffaele University, director, Genitourinary Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, discusses treatment with TAR-200 by PD-L1 expression in patients with Bacillus Calmette-Guérin (BCG)-unresponsive, high-risk non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), as seen in an updated dataset from the phase 2 SunRISe-1 trial (NCT04640623).

 provides further insights into the efficacy of TAR-200 monotherapy and its use in combination regimens for patients with NMIBC. At the data cutoff on January 2, 2024, 85 patients had received TAR-200 monotherapy. Among the 58 efficacy-evaluable patients, the complete response (CR) rate was 83% (95% CI, 71%-91%). Notably, among 31 patients with available PD-L1 scores, CR rates of 91% were observed in patients with a combined positive score (CPS) of at least 10, and 85% in those with CPS less than 10. Overall, high clinical responses to TAR-200 monotherapy were observed in patients with NMIBC regardless of PD-L1 status.

Previously reported results had already demonstrated the clinically meaningful efficacy and favorable benefit-risk profile of TAR-200 monotherapy in this population, and the updated data both confirm and improve upon these findings, Necchi asserts. These results suggest that TAR-200, which is delivered through an intravesical system, may minimize the risk of toxicities associated with checkpoint inhibitors and improve a patient's chance of being cured, he explains.

designation to TAR-200 for the treatment of patients with Bacillus Calmette-Guérin (BCG)-unresponsive, high-risk NMIBC who are not candidates for or choose not to undergo radical cystectomy. This decision was supported by findings from the SunRISe-1 study. Accordingly, updated safety data and confirmed activity presented at the 2024 ESMO Congress reinforce the FDA's decision, highlighting TAR-200's potential as a viable alternative to more invasive treatment options for this patient population, Necchi concludes.

Dr Necchi reports receiving institutional grants/research funding from AstraZeneca, Bristol Myers Squibb, Gilead, Ipsen, and Merck; reciving consulting/advisory fees from Astellas, AstraZeneca, Bristol Myers Squibb, Catalym, Gilead, Johnson & Johnson, Samsung Bioepis, Bicycle Therapeutics, and Merck; serving in a leadership role for the Global Society of Rare Genitourinary Tumors; and serving as an Associate Editor for the Journal of Clinical Oncology.

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Andrea Necchi, MD, discusses treatment with TAR-200 by PD-L1 expression in BCG-unresponsive, high-risk non–muscle-invasive bladder cancer with CIS.

Dr Necchi on the Efficacy and Safety of TAR-200 Plus Cetrelimab in MIBC

Andrea Necchi, MD, associate professor, oncology, Vita-Salute San Raffaele University, director, Genitourinary Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, discusses 

findings from the interim analysis of the phase 2 SunRise-4 trial (NCT04919512)

 evaluating TAR-200 plus cetrelimab in patients with muscle-invasive bladder cancer (MIBC).

SunRise-4 enrolled patients with MIBC who were ineligible for or refused treatment with neoadjuvant cisplatin-based chemotherapy. Patients were randomly assigned to receive cetrelimab alone (n = 41) or in combination with TAR-200 (n = 79).

Among efficacy-evaluable patients in the TAR-200 arm (n = 53), the pathologic complete response (pCR) rate was 42% (95% CI, 28%-56%), and the pathologic overall response (pOR) rate was 60% (95% CI, 46%-74%). In the cetrelimab arm (n = 31), these respective rates were lower, at 23% (95% CI, 10%-41%) and 36% (95% CI, 19%-55%). In the subgroup of patients with clinical T2 disease who received TAR-200 plus cetrelimab (n = 40), the pCR rate was 48% (95% CI, 32%-64%), and the pOR rate was 68% (95% CI, 51%-81%).

Based on these findings, the addition of TAR-200 to cetrelimab appears to generate pCR and downstaging benefits regardless of prior trans-urethral resection of bladder tumor (TURBT) status, Necchi says. Patients with residual disease after TURBT appeared to derive the same amount of benefit from the combination as those with completely resected disease following TURBT, he notes.

Furthermore, investigators noted a positive correlation between prolonged TAR-200 exposure and improved pCR, Necchi explains. Most patients who completed 4 courses of treatment with TAR-200 benefitted from the therapy, with a pCR rate of 50% (95% CI, 32%-68%); the rate of pOR was also high in this population, he emphasizes. These findings indicate that urologic oncologists should become comfortable with administering TAR-200 to patients, he adds.

TAR-200 plus cetrelimab was also safe and associated with manageable treatment-related adverse effects (AEs), according to Necchi. In the TAR-200 arm, the rate of immune-related AEs was 6.3%, and few patients interrupted therapy because of AEs. Furthermore, no patients in the combination arm experienced a delay in time to radical cystectomy, he says. Overall, the efficacy and safety profiles of the combination support the use of this regimen in patients with bladder cancer, Necchi concludes.

Andrea Necchi, MD, discusses an analysis of the SunRise-4 trial evaluating TAR-200 plus cetrelimab in patients with muscle-invasive bladder cancer.

Dr Necchi on the Efficacy of TAR-200 Monotherapy in BCG-Unresponsive NMIBC

Andrea Necchi, MD, director, Genitourinary Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, associate professor, Vita-Salute San Raffaele University, Milan, Italy, discusses results from the phase 2b SunRISe-1 trial (NCT04640623) of TAR-200 in patients with Bacillus Calmette-Guérin (BCG)–unresponsive, high-risk, non–muscle-invasive bladder cancer (NMIBC).

The ongoing SUNRISE-1 trial assessed the efficacy of this intravesical delivery system as a monotherapy or in combination with cetrelimab in patients with BCG-unresponsive high-risk NMIBC, Necchi begins. This includes those with carcinoma in situ (CIS) with or without papillary disease, who either decline radical cystectomy or are ineligible for the procedure. The TAR-200 system was designed to deliver localized, sustained low-dose gemcitabine directly to the bladder, Necchi explains.

Findings from cohort 2 were presented at the 

, and showed that efficacy evaluable patients treated with TAR-200 monotherapy achieved a complete response (CR) rate of 76.7% (95% CI,57.7-90.1) and a comparable investigator-assessed CR rate of 80.0% (95% CI, 61.4-92.3), Necchi reports. Of these CRs, 91% were ongoing at a median follow-up of 48 weeks. At the time of analysis, the median duration of response (DOR) was not reached (range, 12-121), although 11 complete responders had a DOR of at least 6 months and 6 had a DOR of at 12 least months, Necchi states. All responses in this latter group were ongoing. Kaplan-Meier estimates for DOR rates were 93% (95% CI, 61-99) at 6 months 84% (95% CI, 49-96) at 12 months, he adds.

These data support the ongoing investigation of TAR-200 in the SUNRISE-2 trial (NCT04658862) for patients with MIBC who are radical cystectomy–ineligible or refuse to receive the surgery; SUNRISE-3 trial (NCT05714202) of patients with BCG-naive high-risk NMIBC; and SUNRISE-4 trial (NCT04919512) in the neoadjuvant MIBC setting, Necchi concludes.

Andrea Necchi, MD, discusses results from the phase 2b SunRISe-1 trial of TAR-200 in patients with Bacillus Calmette-Guérin (BCG)–unresponsive, high-risk, non–muscle-invasive bladder cancer.

Andrea Necchi, MD, director of Genitourinary Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, associate professor, Vita-Salute San Raffaele University, Milan, Italy, discusses updated analysis of cohort B in the phase 2 KEYNOTE-057 trial (NCT02625961) in non-muscle invasive bladder cancer (nMIBC).

The multicohort study evaluated the activity of pembrolizumab (Keytruda) monotherapy in patients with Bacillus Calmette-Guerin (BCG)-unresponsive nMIBC who declined or were ineligible for cystectomy, Necchi begins.

Three-year follow-up data from cohort A of the study were previously published and demonstrated that single-agent pembrolizumab produced clinically meaningful responses and was well tolerated in patients with histologically confirmed BCG-unresponsive carcinoma in situ (CIS) of the bladder, with or without papillary tumors. These findings led to the FDA approval of pembrolizumab for this population and established the regimen as a standard of care.

Subsequent analysis was conducted in a cohort of patients with high-risk, BCG-unresponsive, nMIBC without a CIS component, Necchi continues. Notably, patients in cohort B were ineligible or elected not to undergo cystectomy, he says. The study’s primary end point was 12-month disease-free survival (DFS).

Results showed that pembrolizumab monotherapy elicited a DFS rate of 43.5% in patients with high-risk disease, Necchi states. Quality of life (QOL) scores were also reported and indicated that QOL was improved or maintained over time in patients who continued treatment and did not experience disease recurrence with pembrolizumab.

Secondary end points such as overall survival (OS) and progression-free survival (PFS) were also encouraging, Necchi continues. The 1-year PFS rate was 88.2%, and the 1-year OS rate was 96.2%. Importantly, median OS was not yet reached at the 45 months of median follow-up.

No new safety signals were observed with the regimen, and its adverse effect (AE) profile is consistent with previously observed data from both cohort A of KEYNOTE-057 and several other disease settings, Necchi notes.

These findings indicate that pembrolizumab monotherapy may be a viable treatment alternative for this patient population with nMIBC, Necchi explains. Continued development of the regimen may require a comparison with a standard of care arm, according to FDA regulations, he concludes.

Dr. Necchi reports serving as a consultant or in an advisory role for AstraZeneca, Basilea Pharmaceutical, Bayer,

Squibb, Catalym, Clovis Oncology, GlaxoSmithKline, Incyte, Janssen, Merck Sharp & Dohme, Rainier Therapeutics, Roche, Seattle Genetics/Astellas; he reports receiving funding from AstraZeneca (Inst), Gilead Sciences, Ipsen, Merck Sharp & Dohme (Inst); he obtained honoraria from Astellas Pharma, AstraZeneca,

Squibb, Foundation Medicine, Janssen, Merck, Roche; he is currently employed by and has ownership interest in Bayer.

Andrea Necchi, MD, discusses updated analysis of cohort B in the phase 2 KEYNOTE-057 trial in non-muscle invasive bladder cancer.
 

 Dr. Necchi on Key Results From Cohort B of the KEYNOTE-057 Trial in MIBC

Andrea Necchi, MD, a medical oncologist at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, discusses the impact of PD-1 inhibition in bladder cancer as well as the promise with combination strategies.

It is known that treatment with pembrolizumab (Keytruda) alone, as well as other single-agent checkpoint inhibitors, will not significantly improve progression-free survival in patients with bladder cancer, explains Necchi. 

There are multiple international, phase I, II, and III combination trials being conducted in the field of bladder cancer, Necchi adds. These are combining immune checkpoint inhibitors with other checkpoint inhibitors, PD-1 agents combined with antiangiogenesis therapy, or checkpoint inhibitors combined with more personalized therapeutic approaches. These studies could provide many new possibilities for patients, and is an advantage and a positive next step for the field, he concludes. 

Andrea Necchi, MD

Articles

Dr Necchi on Responses With TAR-200 According to PD-L1 Status in NMIBC

Dr Necchi on the Efficacy and Safety of TAR-200 Plus Cetrelimab in MIBC

Dr Necchi on the Efficacy of TAR-200 Monotherapy in BCG-Unresponsive NMIBC

Dr. Necchi on Key Results From Cohort B of the KEYNOTE-057 Trial in MIBC

Dr. Necchi on Impact of PD-1 Inhibition in Bladder Cancer