New List of Competition from UroTodayThis recent article from
UroToday (01 April) reveals that the
2 year CR rate for N-803 is around
36%:
"In Cohort A, complete response was noted in 59 of 83 (71%) at the primary endpoint designated 3- or 6-month time point. Impressively, more than half (52%) had durable response out to 2 years or beyond." 52% of 59 = 30 out of 83 patients = 36% This jives with Immunity Bio's announcement of their results in February:
"Indeed,
the benchmark of 30% durable response at 18 to 24 months for a clinically meaningful therapy “is likely too high and may not be realistically achievable,”3 according to recommendations published in the Journal of Clinical Oncology.
This “realistically unachievable” endpoint of 30% durable response at 18 months has in fact now been achieved and exceeded with the combination of Anktiva and BCG in this trial reported today. "
According to the list at the bottom of the following article
TLD1433 is one of 14 trials currently going on in this space.
Pembrolizumab and Beyond for BCG-Unresponsive, High-Risk, Non-Muscle Invasive Bladder Cancer Published 01 April 2022
It has now been over a year since pembrolizumab received FDA approval on January 8, 2020, for treatment for Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or who have elected to not undergo radical cystectomy. This approval was a nice step towards expanding treatment options for a patient population that harbors a clear unmet medical need. Intravesical BCG is the standard for intermediate and high-risk disease, but BCG is not adequate to prevent relapses or frank resistance in approximately 50% of patients.1 BCG-unresponsive disease includes both BCG-refractory and BCG-relapse populations. BCG-refractory refers to the presence of persistent high-grade cancer 6 months after the start of induction therapy or cancers that have progressed by either stage or grade 3 months after the initiation of induction therapy.2
BCG-relapse refers to patients with recurrence after achieving a ≥ 6-month disease-free interval after treatment.2 The standard of care for these patients generally remains radical cystectomy, but many patients are not fit enough and/or have a strong desire to retain their bladders. Intravesical valrubicin is a previously regulatory approved option for BCG-refractory carcinoma-in-situ and for those who do not find cystectomy to be a suitable option. However, valrubicin only offers a 12-month disease-free rate of 16%.2 Therefore, pembrolizumab is a welcome new addition to the arsenal.
The efficacy of pembrolizumab for BCG-unresponsive disease was established in the KEYNOTE-057 (NCT02625961) clinical trial.3 This was a multicenter, single-arm, 101 patient trial with high-risk NMIBC. Ninety-six of the patients had CIS with or without papillary tumors. Treatment with pembrolizumab 200 mg IV q3weeks continued until persistent or progressive disease, unacceptable toxicity, or 24 months without disease progression. The primary endpoint was complete response, defined by negative cystoscopic evaluations, urine cytology, and CT imaging. The complete response rate was 41% (95% CI: 31, 51%) and median response duration was 16.2 months. Toxicity was as expected from previous trials with pembrolizumab.
More recently, at the 2022 Genitourinary Cancers Symposium, the phase II/III QUILT 3.032 trial of the IL-15RalphaFc superagonist N-803 was presented.4 N-803 was combined with BCG for patients already with BCG-unresponsive non-muscle invasive bladder cancer. N-803 serves to drive proliferation and activation of NK and T cells, without binding to T regulatory cells. In combination with BCG, N-803 previously showed complete response in 9 of 9 subjects in a phase 1 trial.5 The 2022 Genitourinary Cancers Symposium presentation was focused on the presentation of two separate cohorts of data. This included Cohort A patients, who had persistent or recurrent CIS +/- recurrent Ta/T1 disease within 12 months of receiving adequate BCG and Cohort B patients, with recurrent high-grade Ta/T1 disease, without CIS, within 6 months of completing adequate BCG. Treatment was administered as intravesical BCG 50 mg plus intravesical N-803 400 ug weekly X6 induction or reinduction X 6 plus maintenance for up to 3 years. In Cohort A, complete response was noted in 59 of 83 (71%) at the primary endpoint designated 3- or 6-month time point. Impressively, more than half (52%) had durable response out to 2 years or beyond. In Cohort B, the papillary tumor group only, the primary endpoint of being disease-free at 12 months was achieved in 57% of the 77 patients enrolled. At 2 years, the disease-free survival rate was still 48%. Adverse events were minimal in grades 1-2, most commonly being dysuria (22%), pollakiuria (19%), and hematuria (18%). The above results are quite impressive, leaving the promise that we may eventually have another option for patients with BCG-unresponsive non-muscle invasive bladder cancer.
The FDA approval of pembrolizumab for this unmet disease state represents a significant advancement in the field and increased options for our patients. However, close dissection of the data reveals that the sustained pathologic T0 rate without any recurrence at one year approximates a little less than 18%. Recognizing that fact puts things into perspective. It emphasizes our need to persist in developing additional treatment options for patients with BCG-unresponsive NMIBC. In July 2018, I presented an article summarizing the ongoing immuno-oncology trials for these patients, but of course, there are many new trial options now.6 The recent 2022 Genitourinary Cancers Symposium presentation of the QUILT 3.032 trial with N-803 combined with BCG is just one promising example.
Below, I present other ongoing trials for BCG-unresponsive non-muscle invasive bladder cancer that we should continue to accrue aggressively to. Given the fact that this is a significantly large, unmet need population, with limited treatment options if radical cystectomy is not feasible or desired, the below trials may offer more options for our patients.
Accruing Trials for Patients with BCG-Unresponsive Urothelial Cancer
- Erdafitinib vs. investigator choice of intravesical chemotherapy (gemcitabine or mitomycin C) for those with FGFR mutation or fusion (NCT04172675)
- Intravesical gemcitabine plus pembrolizumab (NCT04164082)
- Durvalumab plus S-488210/S-488211 (5-peptide cancer vaccine) (NCT04106115)
- PREVERT - Avelumab plus radiation (NCT03950362)
- Intravesical TLD-1433 (photosensitizer) plus photodynamic therapy (NCT03945162)
- Intravesical durvalumab (NCT03759496)
- QUILT 3.032 - Intravesical BCG plus ALT-803 (IL-15 superagonist) (NCT03022825)
- HX008 (PD-1 antibody) (NCT04738630)
- LEGEND Study – EG-70 (non viral gene therapy encoding two RIG-1 agonists)
- ADAPT-BLADDER – durvalumab with radiation and BCG (NCT03317158)
- BOND-003 – Phase 3 trial of CG0070 (oncolytic immunotherapy) and N-dodecyl-B-D-maltoside (detergent) (NCT04452591)
- CORE-001 – CG0070 with pembrolizumab (NCT04387461)
- Sun-RISe-1 – Cetrelimab (PD-1 inhibitor), TAR-200 (continuous intravesical release gemcitabine) or combination (NCT04640623)
- CGC – Intravesical cabazitaxel, gemcitabine and cisplatin (NCT02202772)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington
References
1 Packiam VT et al. "Non-muscle-invasive bladder cancer: Intravesical treatments beyond Bacille Calmette-Gurin." Cancer. 2017. 123:390-400.
2 Kamat AM et al. "BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG." Nat Rev Urol. 2017. 14:244-55.
3 Balar AV, et al. "Pembrolizumab monotherapy for high-risk, non-muscle invasive bladder cancer." Lancet Oncol. 2021. 22:919-30.
4 Chang SS, et al. J Clin Oncol 40, no. 6_suppl 2022. 431-431.
5 Rosser CJ, et al. "Safety, Tolerability, and Long-Term Clinical Outcomes of an IL-15 analogue (N-803) Admixed with Bacillus Calmette-Gurin (BCG) for the Treatment of Bladder Cancer." Oncoimmunology. 2021. 10:e1912885.
6 Yu EY. From the desk of Evan Yu: How can I keep my bladder, Doc? The BCG refractory non-muscle invasive bladder cancer question. Urotoday Clinical Trials Portal. July 9, 2018.