On October 19, 2021 ImmunityBio, Inc. (NASDAQ: IBRX), a clinical-stage immunotherapy company, reported that Papillary disease (Cohort B), the second indication of its QUILT 3.032 Phase 2/3 study of intravesical BCG plus Anktiva in patients with BCG-unresponsive high-grade NMIBC (NCT03022825), also met its primary endpoints with disease-free survival of 57% of patients at 12 months (Press release, ImmunityBio, OCT 19, 2021, View Source [SID1234591515]). The company has previously reported that the primary endpoint of Cohort A, patients with CIS disease, has been met with a complete response of 72% (58/81).
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Non-muscle invasive bladder cancer (NMIBC) makes up 75%-85% of all bladder cancers in the U.S.; approximately 90% of NMIBC cases are papillary (stages Ta and T1). Current standard of care for high-grade papillary disease is intravesical BCG, with a 40% non-response rate.
To date, 73 patients have enrolled in Cohort B with a median follow-up of 17.3 months. The primary endpoint was met with a disease-free rate at 12-months of 57% (95% CI: 43.7%, 68.5%) and at 18-months, 53% (95% CI: 38.8%, 64.6%) by Kaplan-Meier analysis. Durable responses were noted in both cohorts and the therapy resulted in significant avoidance of cystectomy.
The safety profile of Anktiva (N-803) in Cohort B was consistent with that seen in Cohort A, which was recently presented at the American Urological Association’s 2021 Annual meeting, in which 0% SAEs, including 0% immune-related SAEs, were detected. In addition, 85% of the patients were able to avoid a cystectomy. A full analysis of efficacy and safety data for both Cohorts A (CIS) and B (Papillary) has been submitted to the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancer Symposium (ASCO GU), which is taking place in February 2022.
"Intravesical BCG has been the standard of care for more than 30 years for patients with non-invasive papillary tumors, yet, unfortunately some 40% of them don’t respond," said Patrick Soon-Shiong, M.D., Founder and Executive Chairman and Global Chief Scientific and Medical Officer of ImmunityBio. "Anktiva has demonstrated strong disease control in CIS, and based on the latest data from our study, it is showing the same effect in papillary tumors. This gives us confidence in the potential for all BCG-unresponsive NMIBC patients to benefit from this combination therapeutic."
The U.S. Patent & Trademark Office has recently allowed ImmunityBio’s patent application for a method of treating cancer, including non-muscle invasive bladder cancer, using Anktiva (N-803) in combination with Bacillus Calmette-Guerin (BCG). The new patent will extend patent life on the N-803/BCG combination therapy for bladder cancer to at least 2035.
The Urgent, Unmet Need to Treat NMIBC and Avoid Cystectomy
Bladder cancer has a high incidence worldwide; in 2020, an estimated 573,278 new cases were diagnosed and it was the cause of 212,536 deaths1. In the United States, bladder cancer is the fourth most commonly diagnosed solid malignancy in men and the twelfth for women and the American Cancer Society estimates there will be 83,730 new cases and 17,200 deaths from bladder cancer in 20212. Approximately 75–85% of patients with bladder cancer present with a disease that is confined to the mucosa [stage Ta, carcinoma in situ (CIS)] or submucosa (stage T1). These categories are grouped as non-muscle invasive bladder cancer (NMIBC). Of these, approximately 70% present as stage Ta, 20% as T1 and 10% as CIS3.
For the last 30 years, BCG immunotherapy has been the standard for treating NMIBC. However, disease recurrence and progression rates remain unacceptably high. Standard-of-care recommendations for these patients include lifetime invasive surveillance and rapid treatment of recurrences, creating a substantial financial burden and drastic impact on quality of life. Of those patients who experience recurrence, approximately 30% will progress and succumb to their disease over a 15-year period, and another 50% will undergo radical cystectomy of the bladder— a surgery to remove the entire bladder that may require removal of other surrounding organs—in an attempt to control their disease4.
Despite the advent of minimally invasive procedures and robotic techniques, the 90-day mortality and morbidity rates in patients who undergo cystectomy remain unacceptably high at 3-6% and 28-64%, respectively5 & 6. Based on this urgent need, FDA published guidance in February 2018 to address BCG unresponsive non-muscle invasive bladder cancer (NMIBC), stating that the goal of therapy in patients with BCG-unresponsive NMIBC is to avoid cystectomy.
About the Study and Breakthrough Designation
QUILT 3.032 is an open-label, three cohort, multicenter Phase 2/3 study of intravesical BCG plus Anktiva (N-803) in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) and was opened in 2017. The primary endpoint for Cohorts A (CIS with N-803+ BCG) and C (CIS with N-803 alone) of this Phase 2 study is incidence of complete response (CR) of CIS at any time and the primary endpoint for Cohort B (papillary) is 12-month disease-free rate. The FDA granted Fast Track Designation to the pivotal trial based on Phase I data. In December 2019, the FDA granted ImmunityBio Breakthrough Therapy Designation based on interim Phase 2 data indicating the primary endpoint of the trial was already met.
ImmunityBio’s IL-15 superagonist Anktiva (N-803)
The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of the natural killer (NK) and T cells. N-803 is a novel IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. Its mechanism of action is direct specific stimulation of CD8+ T cells and NK cells through beta gamma T-cell receptor binding (not alpha) while avoiding T-reg stimulation. N-803 has improved pharmacokinetic properties, longer persistence in lymphoid tissues and enhanced anti-tumor activity compared to native, non-complexed IL-15 in vivo.