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Pembrolizumab, nadofaragene firadenovec lead the charge in BCG-unresponsive NMIBC


“There is an urgent need for novel therapies in BCG-unresponsive disease. While standard cystectomy is highly curative, it is associated with a substantial risk for morbidity and non-trivial mortality,” said Arjun Balar MD.

The PD-L1 inhibitor pembrolizumab (Keytruda) and the intravesical treatment nadofaragene firadenovec are at the forefront of therapeutic advances in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC), according to Arjun Balar MD.1

Arjun Balar MD

Arjun Balar MD

“There is an urgent need for novel therapies in BCG-unresponsive disease. While standard cystectomy is highly curative, it is associated with a substantial risk for morbidity and non-trivial mortality,” Balar said in a presentation during the 38th Annual CFS meeting.

In his discussion, Balar, director, Genitourinary Medical Oncology Program, Medical Director– Clinical Trials Office, Perlmutter Cancer Center, NYU Langone Health, discussed the latest promising data for pembrolizumab and nadofaragene firadenovec in the high-risk, BCG-unresponsive NMIBC treatment paradigm.


Pembrolizumab was approved in January 2020 for the treatment of patients with BCG-unresponsive, high-risk, NMIBC with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

The approval was based on the multicenter, open-label, single-arm, multicohort, phase 2 KEYNOTE-057 trial, which enrolled 102 patients with BCG-unresponsive, high-risk, NMIBC with CIS with or without papillary tumors who were ineligible for or did not undergo cystectomy (cohort A). Cohort B consists of 130 patients with papillary disease without CIS.

Pembrolizumab was administered at 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or disease progression. Disease was assessed every 12 weeks, and those who did not have disease progression could receive treatment for up to 2 years.

Balar shared the results for cohort A, in which the median age was 73 years (range, 44-92), 83.3% of patients were male, and 16.7% of patients were female. Overall, 67.6% of patients were White, 26.5% were Asian, and race was unknown for 5.9% of patients. The ECOG performance score was 0 for 73.5% of patients and 1 for 26.5% of patients.

The median number of prior BCG instillations was 12 (range, 6-45). Regarding PD-L1 status, 38.2% of patientshad a combined positive score (CPS) ≥10, 56.9% had a CPS <10, and PD-L1 level was unknown for 4.9% of patients.

There were 96 patients in the efficacy evaluable population. In this group, the complete response rate at 3 months was 40.6% (n = 39). “This is, in my opinion, a meaningful complete response rate. What’s also important is that at the time of the study, none of the patients had progressed to stage T2 disease,” said Balar.

He added that the most significant component of the efficacy results was that the response generated by pembrolizumab was durable. The median duration of response was 16.2 months and 18 (46%) of the 39 responding patients maintained their response for 1 year or more.

Thirty-six patients at some point in time after the study underwent cystectomy. Of note, only 3 of these patients had pathological upstaging to muscle-invasive disease or higher. The remainder were organ-confined, non-muscle invasive tumors.

Immune-mediated adverse events (AEs) across all grades occurred in 20.6% of patients. There were 3 cases of grade 3/4 immune-mediated AEs: adrenal insufficiency, severe skin reaction, and type 1 diabetes mellitus.

Looking ahead, Balar said there are 3 important randomized phase 3 trials of systemic immunotherapy in NMIBC. The first is the KEYNOTE-676 trial (NCT03711032) evaluating pembrolizumab plus BCG versus BCG monotherapy in patients with high-risk NMIBC that is persistent or recurrent after BCG induction therapy.

The second study is the POTOMAC study (NCT03528694), which is accruing patients with high-risk, BCG-naïve NMIBC and randomized them to durvalumab plus BCG (induction and maintenance), durvalumab plus BCG (induction alone), or BCG alone. And the final study is the ALBAN trial (NCT03799835) exploring BCG with or without atezolizumab in patients with previously resected, BCG-naïve, high-risk NMIBC.

Nadofaragene Firadenovec

The pivotal data thus far for nadofaragene firadenovec have come from a phase 3 single-arm multicenter study of the intravesical treatment in patients with BCG-unresponsive NMIBC. Patients received nadofaragene firadenovec as 1 intravesical treatment once every 3 months.

In the study, there were 107 patients with CIS (+/- Ta/T1) tumors. The median patient age in this group was 71.2 years and 88.8% were male. Overall 90.7% of patients had an ECOG performance score of 0, and 3.7% had prior radiotherapy. The number of prior BCG courses included 1 (0.9%), 2 (42.1%), 3-8 (53.3%), and ≥9 (3.7%).

The complete response rate at 12 months was 24% among the 103 patients in the intent-to-treat population.

“What’s also important here is that there was a mandatory biopsy for patients who made it to 12 months. That’s something that was not included as part of the KEYNOTE-57 study, and I do think strengthens the interpretation and validity of this data as far as this agent is concerned,” said Balar.

Another emerging intravesical agent highlighted by Balar was vicinium, which he described as a “single-protein agent consisting of an EpCAM-specific antibody fragment fused to a pseudomonas toxin.” In the phase 3 VISTA trial (NCT02449239), vicinium demonstrated a 17% response rate at 12 months in patients with NMIBC previously treated with BCG.

In his concluding remarks, Balar stressed that developing biomarkers predictive of response is a critical unmet need in NMIBC. “Cystectomy for NMIBC is highly curative, so we should do our best to avoid ineffective therapy in patients who are not destined to respond.


1. Balar A. Recent developments in non-muscle invasive bladder cancer. Presented at: 38th Annual CFS. November 4-6, 2020.

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