Trial Results of Microparticle Docetaxel for High-Risk NMIBC

Might there be a new delivery mechanism available to administer intravesical docetaxel? According to a recently published study in the Journal of Urology by Dr. Max Kates et al from the James Buchanan Brady Urological Institute at Johns Hopkins, there is reason to be excited.¹ The standard of care for treatment of patients with non-muscle-invasive bladder cancer (NMIBC) is transurethral resection of bladder tumor (TURBT) followed by intravesical bacille Calmette-Guérin (BCG), but 50% of patients will experience a recurrence in 2 years.²

Additionally, there is a need for optimization of intravesical chemotherapy for patients who are not responsive to BCG. Kates et al explain large surface area microparticle docetaxel (LSAM-DTX) as “docetaxel microparticles formulated for tissue entrapment and sustained local drug release” that “is engineered using a precipitation with compressed antisolvent process that employs fluid state carbon dioxide held at or above its critical temperature and pressure (supercritical) and acetone to generate pure docetaxel microparticles with well-characterized particle size distribution and large surface area.”³

Studying the Safety of LSAM-DTX

An earlier report investigating the potential benefit of higher concentrations of docetaxel for a longer time with a significant immune reaction and intratumoral injection of LSAM-DTX demonstrated significant tumor reduction.⁵ Additionally, investigators using a mouse model to study intratumoral LSAM-DTX in combination with systemic anti-cytotoxic T lymphocyte antigen-4 for metastatic breast cancer reported a reduction in tumor progression and metastatic disease with detection of significant changes to effector immune cells⁴. This led Kates et al to investigate the safety and tolerability of LSAM-DTX for the management of high-risk NMIBC.

Eligibility criteria included high-grade T1, recurrent high-grade Ta, high-grade Ta >3 cm, high-grade Ta multifocal disease, carcinoma in situ, variant histology, and lymphovascular invasion, including high-grade prostatic urethral involvement. Enrolled patients also had a life expectancy of >6 months and adequate marrow, liver, and renal function. Patients were excluded if they had evidence of metastatic disease, a history of other malignancies besides nonmelanoma skin cancer within 12 months, intravesical therapy within 4 weeks prior to consent, a resection surface >8 cm², bladder perforation during TURBT, or upper tract and urethral disease within 18 months.

The authors note that LSAM-DTX has not yet been approved by the US Food and Drug Administration. LSAM-DTX was prepared as a saline suspension and was administered via injection into the tumor resection bed immediately following TURBT. Within 2 hours of injection, patients underwent intravesical instillation of LSAM-DTX for 30 minutes. After ≥4 weeks, patients underwent a weekly intravesical induction course for 6 weeks, followed by 6 weeks of rest, and 3 weeks of maintenance. Cytology and cystoscopic surveillance were conducted before induction, and then at 12 and 24 weeks after induction initiation.

A total of 19 patients were enrolled between 2019 and 2020; the population comprised mostly white men with a median age of 72 years. The median time from diagnosis to the start of treatment was 17 months. A total of 74% of patients had received BCG, and 84% had undergone multiple TURBTs in the past. All tumors were high grade and included 37% Ta, 42% Tis, and 21% T1. The researchers administered 4 different concentrations (3-15 mg) of LSAM-DTX as the direct injection, and there was a dose escalation for the intravesical instillation. Both direct injection and intravesical instillation of LSAM-DTX were well tolerated, and there were no drug-related systemic or local serious adverse events (AEs) observed. There were 31 grade 1 or 2 local AEs reported (including hematuria, dysuria, or urinary tract infection). There also were 5 grade 1 systemic AEs in 1 patient (including diarrhea, fatigue, and elevated liver enzymes).

In the 3 lowest dose cohorts, follow-up was 8.6 months and 90% of patients developed recurrence (median time to recurrence, 5.4 months). The estimated recurrence-free survival (RFS) rate was 90% at 3 months and 40% at 6 months. For the high-dose and expansion cohorts, median follow-up was logged at 12.2 months, and 56% of patients developed recurrence. Estimated RFS was 100% at 3 months, 78% at 6 months, and 50% at 12 months. After univariate analysis, there was a significant increase in RFS for the high-dose escalation and expansion cohorts compared with those that received lower doses. Multiplex immunofluorescence analysis was performed on 5 tissue samples from biopsies performed before and after LSAM-DTX treatment. The researchers found important increases in immune cellular profiles and concluded that “although these results are limited due to sample availability, they demonstrated favorable antitumor immune cell changes.”

LSAM-DTX Study Review

The authors began their discussion by highlighting that intratumoral treatment may significantly impact disease progression and reduce systemic toxicities associated with systemic therapies. This has been studied conceptually in other malignancies, including pancreatic cancer,⁶ and is currently under investigation in phase 1 and phase 2 ongoing clinical trials.^7,8 This is important to consider in patients with high-risk NMIBC, where TURBT and intravesical chemotherapy (gemcitabine/ docetaxel) is associated with RFS rates of 89%, 85%, and 82% at 6, 12, and 24 months, respectively.⁹ The study reported that individuals who received high doses of LSAM-DTX had RFS rates of 78% at 6 months and 50% at 1 year. On a cellular level, there was an increase in tumor microenvironment immunogenicity, “including increases in adaptive T cells and innate NK effector cells.” The authors note that while the immune analysis in this study was limited, “immune checkpoint receptor expression was increased across all cell types evaluated, including T cells, macrophages, and PanCK+ cells.”

This suggests the possibility that adding an immune checkpoint inhibitor to LSAM-DTX may improve progression-free survival. The authors’ findings support the hypothesis that local LSAM-DTX has cytotoxic effects and acts as a stimulant for effector immune cells, leading to tumor cell death.

Limitations of the study included small sample size, heterogenous tumor stage, range of previous TURBT procedures, limited immune analysis, a short maintenance period, and a short follow-up. However, the results lend evidence to support that LSAM-DTX has a positive safety profile and “has the potential to overcome the limitations of conventional intravenous chemotherapy.” Further studies addressing the limitations of conventional treatment are warranted.

The authors concluded that the treatment was well tolerated with a seemingly low AE profile and that the “preliminary efficacy data suggesting that post-TURBT direct injection and intravesical therapy of high dose LSAM-DTX may provide therapeutic benefits to patients with high risk NMIBC. Furthermore, findings suggest that LSAM-DTX has the potential for enhanced sensitivity to checkpoint inhibitors.” The outcomes support the need for further research to identify the optimal patient and therapeutic regimen to improve RFS in patients with high-risk NMIBC.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

References

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2. Kates M, Matoso A, Choi W, et al. Adaptive immune resistance to intravesical BCG in Non-muscle invasive bladder cancer: implications for prospective BCG-unresponsive trials. Clin Cancer Res. 2020;26(4):882-891. doi: 10.1158/1078-0432.CCR-19-1920.
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5. Maulhardt HA, Hylle L, Frost MV, et al. Local injection of submicron particle docetaxel is associated with tumor eradication, reduced systemic toxicity and an immunologic response in uro-oncologic xenografts. Cancers (Basel). 2019;11(4):577. doi: 10.3390/ cancers11040577.
6. Sharma N, Othman M, Mendoza-Ladd A, et al. EUS-guided injection of intratumoral submicron particle paclitaxel (SPP) for the treatment of locally advanced pancreatic adenocarcinoma (LAPC): phase 2 study. Gastrointest Endosc. 2020;91(6 suppl):AB238. Poster abstract Sa2006. doi: 10.1016/j.gie.2020.03.1781.
7. Williamson SK, Johnson GA, Maulhardt HA, et al. A phase I study of intraperitoneal nanoparticulate paclitaxel (Nanotax®) in patients with peritoneal malignancies. Cancer Chemother Pharmacol. 2015;75(5):1075-1087. doi: 10.1007/s00280-015-2737-4.
8. Mullany S, Miller DS, Robison K, et al. Phase II study of intraperitoneal submicron particle paclitaxel (SPP) plus IV carboplatin and paclitaxel in patients with epithelial ovarian cancer surgery. Gynecol Oncol Rep. 2020;34:100627. doi: 10.1016/j.gore.2020.100627.
9. McElree IM, Steinberg RL, Martin AC, et al. Sequential intravesical gemcitabine and docetaxel for bacillus Calmette-Guérin-naïve high-risk nonmuscle-invasive bladder cancer. J Urol. 2022;208(3):589-599. doi: 10.1097/JU.0000000000002740.