Introduction:

Vicinium is a recombinant fusion protein comprised of an anti-Epithelial Cell Adhesion Molecule (EpCAM) single chain antibody fragment genetically linked to a truncated form of Pseudomonas exotoxin A (ETA).  Evidence to date is supportive of a dual mechanism of action.  After intravesical dosing, Vicinium is internalized via EpCAM binding and the release of ETA into the cytosol results in inhibition of protein synthesis and ultimately apoptotic cell death.  As a second mechanism, nonclinical studies have demonstrated that cells killed by Vicinium display immunogenic cell death signals that are known to promote the development of an adaptive T-cell mediated anti-tumor response.  Results from the Phase 3 Vicinium trial, VISTA, in BCG-unresponsive NMIBC patients are presented.

Methods:

BCG-unresponsive NMIBC patients defined as refractory or relapsing within 6 months (n = 126) and relapsing within 11 months (n = 7) after adequate BCG were accrued in a Phase 3 single-arm multicenter registrational trial (NCT02449239).  During the induction phase, Vicinium (30 mg diluted in 50 mL PBS) was instilled for 2 hours twice weekly for 6 weeks, then weekly for 6 weeks.  Patients who were disease-free at 3 months received maintenance every 2 weeks for up to 2 years.  Evaluations were performed every 13 weeks.  Treatment success was defined as negative cytology along with normal cystoscopy or negative or low-grade Ta disease on biopsy.  Primary endpoints were complete response (CR) rate and duration of response (DoR) for CIS patients and time to recurrence for papillary patients.

Results:

Of the evaluable CIS patients (n = 89), the overall 3-month CR rate was 40% and the median DoR was 9.4 months (95% CI, 5.1-NE).  Subgroup analysis showed the median DoR was not reached for patients that had received only two courses of BCG prior to enrollment (n = 42) vs. 5.1 months in those who have received more than 2 courses of BCG (n=51).  Of the evaluable papillary patients (n = 38), the recurrence-free rate at 3 months was 71% and median time to recurrence was 13.2 months (95% CI, 5.6-NE).  On average, responders disease-free at 3 months remained cystectomy-free for 34.0 months vs. 20.7 months for non-responders (p ≤ 0.001).  Vicinium was well tolerated; approximately 50% of the patients (66 of 133) had treatment-related adverse events with the most common being dysuria (14%), hematuria (13%), urinary tract infection (12%), pollakiuria (11%), micturition urgency (11%) and fatigue (8%).  A total of 4 treatment-related severe adverse events were reported in 3 patients and included grade 4 cholestatic hepatitis, grade 5 renal failure, grade 3 acute kidney injury and grade 2 pyrexia.  Only 3% of the patients discontinued treatment due to adverse events.

Conclusion:

This Phase 3 study established that Vicinium was well-tolerated, demonstrated clinically meaningful anti-tumor activity and may both delay and/or prevent radical cystectomy.

Funding: Sesen Bio