Neoadjuvant TAR-200/Cetrelimab Combo Shows Activity in Muscle-Invasive Bladder Cancer

Andrea Necchi, MD

TAR-200 plus cetrelimab elicited responses and had a manageable toxicity profile when administered as neoadjuvant treatment in patients with muscle-invasive bladder cancer who are not eligible or refuse to receive neoadjuvant cisplatin-based chemotherapy, according to data from an interim analysis of the phase 2 SunRISe-4 study (NCT04919512) presented during the 2024 ESMO Congress.¹

TAR-200 plus cetrelimab (n = 53) led to a pathologic complete response (pCR) rate of 42% (95% CI, 28%-56%) and a pathologic overall response (pOR) rate of 60% (95% CI, 46%-74%) in the efficacy-evaluable population of patients with cT2 to CT4a disease. Cetrelimab monotherapy (n = 31), which was also evaluated, led to respective pCR and pOR rates of 23% (95% CI, 10%-41%) and 36% (95% CI, 19%-55%).

“SunRISe-4 demonstrates for the first time a benefit of the addition of TAR-200, an intravesical targeted releasing system, to checkpoint inhibition as neoadjuvant treatment in patients with MIBC,” Andrea Necchi, MD, of IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, in Milan, Italy, said in a late-breaking oral presentation of the data.

For patients with MIBC who have T2 to T4a N0M0 disease, the standard-of-care treatment approach is to undergo radical cystectomy with or without neoadjuvant cisplatin-based chemotherapy but up to half of patients are eligible for chemotherapy. Moreover, about 50% of patients who undergo radical cystectomy will recur within 2 years; after the procedure, 5-year survival rates are still low, at about 50%, Necchi said.

“Also, in patients with MIBC undergoing radical cystectomy, we know that pathological stage is prognostic for survival,” he added. With the procedure alone, pCR rates range from 10% to 15%; with neoadjuvant chemotherapy, pCR rate rises to approximately 30%; and with neoadjuvant checkpoint inhibition, pCR rates fall between 31% and 39%. Achievement of pCR in patients who have received neoadjuvant chemotherapy has been linked with a 55% lower risk of death and an 81% lower recurrence risk vs those who have residual disease. “There is a high unmet need for more tolerable treatment options for patients with MIBC who are candidates for radical cystectomy, but not candidates for or who refuse neoadjuvant chemotherapy,” he underscored.

A gemcitabine intravesical releasing system, TAR-200 was designed to deliver continued gemcitabine within the bladder; it is placed using a urinary placement catheter as part of an office procedure that takes under 5 minutes. Phase 1 data have demonstrated TAR-200’s clinical activity in patients with MIBC. “Cetrelimab is an anti–PD-1 agent that has been investigated also in bladder cancer with the SunRISe platform, Necchi said. “In particular, we have data in from SunRISe-1 [NCT04640623]² with cetrelimab in patients with [Bacillus Calmette-Guérin–unresponsive, high risk] non–muscle-invasive disease and the clinical complete response rates are in the range of the rates provided by other checkpoint inhibitors.”

The ongoing, randomized, phase 2 SunRISe-4 trial was designed to understand the antitumor activity of TAR-200 plus cetrelimab and single-agent cetrelimab, as well as to show the contribution of components of the combination.¹ Investigators hypothesized that a side-by-side descriptive summary of efficacy with the approaches will elucidate the contribution of TAR-200 to the efficacy of the combinatorial approach.

The trial enrolled patients with histologically confirmed MIBC who had cT2 to CT4a N0M0 disease and predominant urothelial carcinoma histology, who were scheduled for radical cystectomy and were ineligible for or refused neoadjuvant chemotherapy. Patients were required to be at least 18 years of age and have an ECOG performance status of 0 or 1.

They were randomly assigned 5:3 to cohort 1 (n = 79), where they received TAR-200 plus 225 mg of gemcitabine every 3 weeks (indwelling) 12 weeks plus intravenous (IV) cetrelimab for 12 weeks; or cohort 2 (n = 41), where they received IV cetrelimab alone for 12 weeks. Patients were stratified by visible residual disease at transurethral resection of bladder tumor (TURBT; complete vs incomplete or ≤3 cm) and tumor stage at time of MIBC diagnosis (cT2 vs cT3 to cT4a).

Treatment was given for 4 total cycles and then they went on to radical cystectomy. Follow-up was done every 4 weeks after surgery until week 12 and then every 12 weeks until week 108 after surgery. The primary end point was pCR (ypT0N0), and secondary end points included recurrence-free survival and safety. Exploratory end points included pOR (≤ypT1N0), overall survival, time to symptomatic progression, quality of life per FACT-BI, pharmacokinetics, and biomarker analysis.

The interim analysis 2, which was slated to be performed after approximately 80 patients completed radical cystectomy, was shared at the congress. The data cutoff date for the analysis was May 31, 2024.

A total of 122 patients were randomized; 80 patients comprised cohort 1 and 42 comprised cohort 2; 98.8% and 97.6% of patients, respectively, received treatment. A total of 53 patients in cohort 1 and 31 patients in cohort 2 were determined evaluable for efficacy.

Necchi said that the main baseline characteristics between the arms were “pretty well balanced.” Regarding neoadjuvant chemotherapy, 39.2% of those in the combination arm were ineligible and 60.8% refused it; in the monotherapy arm, these respective rates were 36.6% and 63.4%. Moreover, 20.3% of patients in cohort 1 had visible residual disease before starting therapy; this was also true for 14.6% of those in cohort 2. With regard to tumor stage in cohort 1, 78.5% had cT2 disease and 21.5% had cT3-cT4a disease; these rates were 85.4% and 14.6%, respectively, in cohort 2. Further, 20.3% and 26.8% of patients had urothelial carcinoma with variant histology. “There are [also] a few patients with a history of intravesical therapy, in general meaning, a history of previous non–muscle-invasive disease progressing to muscle-invasive disease,” Necchi said.

Investigators also evaluated efficacy by clinical stage and completeness of TURBT in cohorts 1 and 2. In cohort 1, those with cT2 disease (n = 40) experienced a pCR rate of 48% (95% CI, 32%-64%) with the combination; the pOR rate was 68% (95% CI, 51%-81%). In those with cT3 to cT4a disease (n = 13), the pCR rate was 23% (95% CI, 5%-54%) with TAR-200 plus cetrelimab and the pOR rate was 39% (95% CI, 14%-68%. Moreover, in those with incomplete TURBT (n = 9), the pCR rate with the combination was 56% (95% CI, 21%-86%) and the pOR rate was 67% (95% CI, 30%-93%); in those with complete TURBT (n = 44), these respective rates were 39% (95% CI, 24%-55%) and 59% (95% CI, 43%-74%).

“Results seem to be consistent, regardless of the radicality of the completeness of the TURBT, although we should acknowledge that that proportion and sample size in patients with incomplete TURBT is still preliminary,” Necchi said.

In cohort 2, those with cT2 disease (n = 26), experienced a pCR rate of 23% (95% CI, 9%-44%) with cetrelimab alone and a pOR rate of 31% (95% CI, 14%-52%). In those with cT3 to cT4a disease (n = 5), these rates were 20% (95% CI, 1%-72%) and 60% (95% CI, 15%-95%), respectively. In those with incomplete TURBT (n = 4), no pCRs were experienced. In those with complete TURBT (n = 27), the pCR rate with the monotherapy was 26% (95% CI, 11%-46%) and the pOR rate was 41% (95% CI, 22%-61%).

Necchi and colleagues also examined efficacy by TAR-200 dose exposure in the efficacy-evaluable population. In the subset of patients who received 1 to 2 doses (n = 11), the pCR was 27% (95% CI, 6%-61%) and the pOR was 46% (95% CI, 17%-77%). In those who received 3 doses (n = 10), pCR and pOR rates climbed to 30% (95% CI, 7%-65%) and 50% (95% CI, 19%-81%), respectively. Those who received 4 doses (n = 32), experienced the highest pCR and pOR rates, at 50% (95% CI, 32%-68%) and 69% (95% CI, 50%-84%), respectively.

With regard to safety, at least 1 any-grade treatment-related adverse effect (TRAE) was experienced by 72.2% of those in cohort 1 and 43.9% of those in cohort 2. The most common TRAEs in these respective arms were dysuria (27.8%; 18.3%), pollakiuria (27.8%; 18.3%), micturition urgency (15.2%; 10.0%), and hematuria (13.9%; 9.2%). TRAEs that were grade 3 or higher were reported in 11.4% of those in cohort 1 and 4.9% of those in cohort 2. Serious TRAEs occurred in 11.4% of those in the combination arm and 2.4% of those in the monotherapy arm. TRAEs led to discontinuation of TAR-200 in 8.9% of patients and cetrelimab discontinuation in 7.6% of patients—all in cohort 1. One patient in cohort 2 experienced a TRAE that proved fatal.

Grade 3 or higher immune-related toxicities were experienced by 6.3% of those in cohort 1 and 4.9% of those in cohort 2. The median time to radical cystectomy in the respective cohorts was 13.7 weeks and 12.6 weeks.

Disclosures: Dr Necchi disclosed having received grants or research funding (institutional) from AstraZeneca, Bristol Myers Squibb, Gilead, Ipsen, and Merck; and receipt of consulting or advisory fees from Astellas, AstraZeneca, Bristol Myers Squibb, Catalym, Gilead, Johnson & Johnson, Samsung Bioepis, Bicycle Therapeutics, and Merck. He also serves in a leadership role for the Global Society of Rare Genitourinary Tumors and serves as associate editor for the Journal of Clinical Oncology.

References

1. Necchi A, Guerrero-Ramos F, Crispen PL, et al. TAR-200 plus cetrelimab or cetrelimab alone as neoadjuvant therapy in patients with muscle-invasive bladder cancer who are ineligible for or refuse neoadjuvant cisplatin-based chemotherapy: interim analysis of SunRISe-4. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation LBA84.
2. van der Heijden MS, Simone G, Bögemann M, et al. TAR-200 +/- cetrelimab and cetrelimab alone in patients with Bacillus Calmette-Guérin–unresponsive high-risk non–muscle-invasive bladder cancer: Updated results from SunRISe-1. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation LBA85.