(UroToday.com) The 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between January 25th and 27th was host to a urothelial carcinoma trials in progress poster session. Dr. Sumana Veeravelli presented a phase 1 study of IO102-IO103 vaccine plus pembrolizumab in patients with BCG-intolerant or unresponsive non-muscle invasive bladder cancer (NMIBC).
Intravesical BCG is the mainstay of treatment for intermediate- and high-risk NMIBC. However, up 30% of patients with high-risk disease recur within one year, and nearly 20% have evidence of disease progression.1 Radical cystectomy is a potentially curative option in these patients. However, radical cystectomy is a highly morbid procedure, and the 2-year recurrence rate may be as high as 22%.2 Intravesical chemotherapy generally has a low recurrence-free survival and up to 35% of patients ultimately require cystectomy within two years.3,4 Pembrolizumab is also approved for high-risk BCG-unresponsive NMIBC, with a modest complete response (CR) rate of 41% at 3 months, and a median CR duration of 16.2 months.5 Nadofaragene firadenovec is another recently approved recombinant adenovirus vector encoding the IFN-alpha-2b gene and has achieved CR rates of up to 53% at 3 months, with 12 month recurrence-free survival rates of 44%.6
IO102-IO103 is an investigational therapeutic cancer vaccine designed to kill both tumor cells and immune-suppressive cells in the tumor microenvironment (TME), via the stimulation, activation, and expansion of T-cells against indoleamine-2,3-dioxygenase 1 (IDO1) and/or PD-L1 positive cells, translating to potentiated antitumor activity. IDO1 is an immuno-regulatory enzyme expressed by tumor, endothelial, dendritic cells, and macrophages within the tumor microenvironment. IO102 is an IDO1-derived peptide vaccine. IO103 is a PD-L1-derived peptide vaccine designed to activate PD-L1 specific T-cells against tumor cells and regulatory T-cells to enhance the immune response against tumor cells.
The combination of IDO and PD-L1 vaccines with checkpoint inhibitors demonstrated clinical activity in patients with metastatic melanoma. Given this rationale, within known immune profile similarities between melanoma and NMIBC, Dr. Veeravelli and colleagues initiated a single arm, single center phase 1 study of a IO102-103 vaccine in combination with pembrolizumab for patients with NMIBC.
The key eligibility criteria are as follows:
- High-risk NMIBC defined as T1, high-grade Ta, or CIS/Tis, with predominantly urothelial cell histology.
- Patients attempted two induction courses of BCG and were either unresponsive or intolerant
- Patients with known active autoimmune disorders requiring immunosuppressive therapy or prior checkpoint inhibitor therapy are excluded from the study.
- Ineligible for or have declined cystectomy
- ECOG performance status 0-2, hematologic function, and end organ function.
The study protocol is as follows:
- Eligible patients will be treated with pembrolizumab 200 mg IV on Day 1, and IO102-IO103 vaccine 85 mcg subcutaneously on days 1 and 8 of a 21-day cycle for the first two cycles
- For cycle 3 and beyond. IO102-IO103 and pembrolizumab will be given once every three weeks
- Patients will be treated for up to two years.
The study endpoints are as follows:
- The primary endpoints of feasibility, safety, and toxicity will be evaluated by CTCAE v5.0 criteria and will be met if ≥10 patients out of 12 are able to complete the first cycle without experiencing pre-specified treatment-limiting toxicities.
- Key secondary endpoints include:
- CR rate at 3 months
- Median duration of response
- Cystectomy-free survival at 18 months.
- Biopsy specimens and serial urine and blood samples will be analyzed to evaluate potential biomarkers of response and mechanisms of response and resistance.
- Samples will be evaluated for T cell clonality, immune cell subsets, and immune-related gene expression profile
- Measurements of the tryptophan to kynurenine ratio as a surrogate for IDO activity will be collected
- The systemic immune phenotype and tumor mutational burden will be analyzed for correlation with treatment response
This phase 1 study evaluating the investigational therapeutic cancer vaccine IO102-IO103 in combination with pembrolizumab for patients with BCG-unresponsive or intolerant high-risk NMIBC is currently enrolling patients, with two patients enrolled to date.
Presented by: Sumana Veeravelli, MD, Fellow, Department of Hematology and Oncology, University of California, Davis Comprehensive Cancer Center
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024
References:1. Cambier S, et al. EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-specific and Overall Survival in Non-Muscle-invasive Stage Ta-T1 Urothelial Bladder Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guérin. Eur Urol. 2016;69(1):60-9.
2. Fritsche HM, et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. Eur Urol. 2010;57(2):300-9.
3. Dinney CPN, et al. Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin. Urol Oncol. 2013;31(8):1635-4. Skinner EC, et al. SWOG S0353: Phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette-Guérin. J Urol. 2013;190(4):1200-4.
5. Balar AV, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): An open-label, single-arm, multicenter, phase 2 study. Lancet Oncol. 2021;22(7):919-30.
6. Boorjian SA, , et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: A single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2020:S1470-2045(20)30540-4.