FDA Issues a Complete Response Letter for Vicineum for High-Risk, BCG-Unresponsive NMIBC


The FDA has issued a complete response letter to Sesen Bio regarding its biologics license application for Vicineum for the treatment of patients with Bacillus Calmette-Guérin–unresponsive non–muscle invasive bladder cancer.

The FDA has issued a complete response letter (CRL) to Sesen Bio regarding its biologics license application (BLA) for Vicineum (oportuzumab monatox-qqrs) for the treatment of patients with Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle invasive bladder cancer (NMIBC).1

The regulatory agency has determined that it cannot give the green light to the application in its present form and has issued recommendations that are specific to clinical/statistical data and analyses, as well as product quality. Moreover, they have cited Chemistry, Manufacturing and Controls issues noted during a pre-approval inspection.

“We are deeply disappointed by this unexpected result, and it is an unfortunate day for patients suffering from BCG-unresponsive NMIBC,” Thomas R. Cannell, DVM, president and chief executive officer of Sesen Bio, stated in a press release. “We remain dedicated to our mission to save and improve the lives of patients by bringing new treatment options to patients, and we intend to work closely with the FDA to understand next steps.”

A recombinant fusion protein, Vicineum was designed to target epithelial cell adhesion molecule–specific antigens on the surface of tumor cells to deliver Pseudomonas Exotoxin A, which is a potent inhibitor of protein synthesis.

The agent is under evaluation in patients with NMIBC who had previously received standard-of-care BCG as part of the open-label, multicenter, single-arm, phase 3 VISTA trial (NCT024492339).2

For the trial, investigators enrolled patients with disease that was either refractory or relapsed after BCG treatment. To be eligible for enrollment, patients were required to have a Karnofsky performance status of 60 or higher and adequate organ function.3 Notably, patients who were pregnant or breastfeeding, had evidence of urethral tract transitional cell carcinoma within the 2 years before treatment, had hydronephrosis, received any intravesicular or other chemotherapy treatment within 2 weeks or an investigational agent 4 weeks prior to the initial dose of the study drug, were excluded.

The primary efficacy end points of the trial included complete response (CR) rate and duration of response (DOR) for patients in cohort 1. Secondary end points comprised time to disease recurrence for patients in cohort 3, as well as time to cystectomy, progression-free survival, event-free survival, and overall survival (OS) for patients across all cohorts.

Among a total of 89 patients with carcinoma in situ, with or without papillary disease that was refractory or recurred less than 11 months following their last course of BCG, Vicineum induced a CR rate of 40% (95% CI, 33%-51%) at 3 months. At 6 months, 9 months, and 12 months, the CR rates experienced with the agent were 28% (95% CI, 19%-39%), 21% (95% CI, 13%-31%), and 17% (95% CI, 10%-26%), respectively.

Cohort 1 was comprised of patients who had carcinoma in situ with or without papillary disease that was refractory or recurred within 6 months of their last course of BCG (n = 82). These patients reported CR rates of 39%, 26%, 20%, and 17% with Vicineum at 3 months, 6 months, 9 months, and 12 months, respectively.

Cohort 2 comprised patients with carcinoma in situ with or without papillary disease that was refractory or recurred after 6 months, but less than or equal to 11 months, following their last course of BCG. At 3 months, the CR rate achieved with the agent was 57% in this subgroup; at 6 months, 9 months, and 12 months, these rates were 57%, 43%, and 14%, respectively.

Patients in cohort 1 reported a median DOR of 273 days (95% CI, 122–not applicable [NA]) per the Kaplan-Meier method. Moreover, an ad-hoc analysis of pooled data for 93 patients in either cohort 1 or 2 revealed that among those who responded to Vicineum at the 3-month time point, 52% had a CR that persisted for 12 months or longer following the start of treatment.

Additionally, patients with high-risk papillary disease were found to experience higher rates of disease progression and recurrence. The median time to recurrence in 40 patients who were included in cohort 3 was 402 days (95% CI, 170–NA).

Of all the patients who were given the product (n = 133), over 75% were estimated to continue to be cystectomy free at 2.5 years. Data from an ad-hoc analysis that looked at responders vs non-responders on the trial showed that 88% of responders were estimated to remain cystectomy free at 3 years. Additionally, 90% of all patients who received Vicineum are estimated to be progression free at 2 years or longer, and 29% were estimated to remain event free at 1 year. Lastly, 96% of patients were estimated to experience an OS of 2 years or longer.

Most adverse effects (AE) experienced by patients across the trial cohorts were noted to be low grade. The most common toxicities experienced with the agent included dysuria (14%), hematuria (13%), and urinary tract infection (12%). AEs were manageable and reversible.

Only 4 patients discontinued treatment with Vicineum because of toxicities. Fourteen percent of patients experienced serious AEs (SAEs), irrespective of treatment attribution. Specifically, 4 SAEs were reported in 3 patients, and those included grade 3 acute kidney injury, grade 2 pyrexia, grade 4 cholestatic hepatitis, and grade 5 renal failure. The news of the CRL follows a Late-Cycle meeting that was held between representatives from Sesen Bio and the FDA in July 2021.4 During the meeting, the 2 parties discussed the BLA for Vicineum in this population and covered remaining questions pertaining to the inspection of manufacturing facilities, product quality data requests, and additional information on the chemistry, manufacturing, and controls.

The 2 parties had agreed on a timeline for submission of any supporting information. No Discipline Review letters were administered, and no issues linked with risk management had been raised at the meeting.

The late-stage clinical company shared plans to request a Type A meeting as soon as possible with the FDA to review the next steps required prior to approval of the BLA.


  1. Sesen Bio receives complete response letter from FDA for Vicineum (oportuzumab monatox-qqrs). News release. Sesen Bio. August 13, 2021. Accessed August 16, 2021. https://bit.ly/3xR0Y5u
  2. Sesen Bio reports positive, preliminary data update from phase 3 VISTA trial for high-risk non-muscle invasive bladder cancer. News release. Sensen Bio. August 8, 2019. Accessed August 16, 2021. http://bit.ly/3bj7Q2i
  3. Vicinium treatment for subjects with non-muscle invasive bladder cancer previously treated with BCG. ClinicalTrials.gov. Updated October 14, 2020. Accessed August 16, 2021. https://clinicaltrials.gov/ct2/show/NCT02449239
  4. Sesen Bio announces productive Late-Cycle Meeting with the FDA for Vicineum. News release. Sesen Bio. July 14, 2021. Accessed August 16, 2021. https://bwnews.pr/3z4FfIn
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