Targeted Therapies, Multidrug Regimens, and Standardized Drug Development Efforts Needed in Nonmuscle-Invasive Bladder Cancer

James M. McKiernan, MD

Editor’s Note: This article was developed as a result of a collaboration between members of the Division of Urologic Oncology at Columbia University Medical Center, James F. McKiernan, MD, and Jennifer Ahn, MD, and our freelance writer, Barbara L. Jones.

Management of nonmuscle-invasive bladder cancer (NMIBC) remains difficult, with high rates of recurrence and disease progression despite strict surveillance, local resection, and intravesical therapy. About 50% of patients experience disease recurrence within 5 years even with the most effective current treatment—intravesical bacillus Calmette-Guérin (BCG).

In a featured presentation at the 2012 Society of Urologic Oncology annual meeting in Bethesda, Maryland, James M. McKiernan, MD, director of Urologic Oncology at Columbia University in New York City, reviewed treatment alternatives under study for NMIBC, but pointed to a context characterized by nonstandardized study frameworks and a lack of creative collaborations that could result in truly novel treatments capable of producing better outcomes for patients.

Also, the heterogeneous nature of BCG failure makes it difficult to assess efficacy of new drugs. Study populations are often mixed, consisting of patients differing by timing of the BCG failure, presence or absence of carcinoma in situ, lymphovascular invasion, micropapillary features, and tumor stage.

Definitions of failure have been proposed, depending on the initial response to BCG and timing of recurrence, McKiernan said. But these have yet to be uniformly adopted into practice.

At present, however, multiple intravesical agents are under investigation, primarily for patients who have failed BCG therapy.

One strategy to address recurrence after BCG is the intravesical use of chemotherapeutic agents, which are used systemically for urothelial cancer:

• Intravesical gemcitabine has been shown to be well tolerated, and results of a recent phase II study (SWOG S0353) showed moderate efficacy with 13/47 (28%) patients showing no evidence of disease at 12 months follow-up.¹ This study enrolled patients with at least two prior courses of BCG and kept patients who responded after 6 weeks on monthly maintenance up to 12 months.
• Intravesical taxanes have also shown similar efficacy, particularly with added drug delivery technology, including binding paclitaxel to hyaluronic acid (ONCOFID-P-B) or albumin.² A phase I study of ONCOFID-P-B demonstrated a 60% (9/16) response rate in patients with BCG-refractory carcinoma in situ.³

Jennifer Ahn, MD

An ongoing phase II study of nanoparticle albumin-bound paclitaxel (Abraxane) currently has a complete response rate of 27% (7/26) at 11 months follow-up, similar to gemcitabine. An alternative strategy is to employ a multidrug regimen, as is standard with systemic chemotherapy.

• The combination of gemcitabine and mitomycin C has resulted in a 3-month complete response rate of 60% (6/10).⁴
• Combining mitomycin C, doxorubicin, and cisplatin has also been reported.⁵ This approach is promising, said Jennifer Ahn, MD, postdoctoral residency fellow in urology at Columbia University, New York City, as patients may have an increased chance of responding to at least one of the agents in the multidrug regimen, improving the overall response rate. However, further research in this area is certainly needed, and Ahn and McKiernan are currently collaborating to develop a novel new strategy to deliver multiple new compounds intravesically in humans.

BCG is not a chemotherapeutic agent, but an immunotherapy. Therefore, multiple agents have been developed to adopt this mechanism.

• Mycobacterial cell wall DNA complex (MCC) uses elements of BCG to elicit an immune response but does not contain live vaccine, thus reducing infectious and inflammatory complications. MCC is well tolerated, and has exhibited a 46% complete response rate at 26 weeks in a phase II trial.⁶ (A phase III randomized trial was recently closed due to poor accrual.)
• Oportuzumab monatox is a treatment employing Pseudomonas exotoxin A to induce cell death, aided by fusion to the anti-EpCAM antibody, which enables preferential binding to urothelial cells. A recently published phase II study exhibited a complete response rate of 16% at 24 months.⁷
• Another targeted therapy, CG-0070, uses an adenovirus that targets retinoblastoma (Rb) defective cells, a common mutation in urothelial carcinoma, and transfects granulocyte- macrophage colony-stimulating factor (GM-CSF), causing local cytotoxicity. Patients with Rb mutations exhibited an 80% response rate, compared with 49% overall.⁸

As more is understood regarding pathogenetic changes of bladder cancer, McKiernan and Ahn predict that targeted therapies and multidrug regimens will likely be a robust area of research and development. Still, at this time no agent is reliably superior to the rest. And, McKiernan noted that small cohorts, heterogeneous study populations, and various response rates complicate the interpretation.

Collaborative and standardized efforts to develop and evaluate novel drugs are necessary to ultimately provide effective long-term treatment for this high-risk, complicated population.

References

1. Skinner EC, Goldman B, Sakr WA, et al. 1666 SWOG S0353 phase II trial of intravesical gemcitabine in patients with non-muscle invasive bladder cancer who recurred following at least two prior courses of BCG. J Urol. 2012;187(4, Supplement):e673.
2. McKiernan JM, Barlow LJ, Laudano MA, et al. A phase I trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer. J Urol. 2011;186(2):448-451.
3. Tringali G, Lisi L, Bettella F, et al. The in vitro rabbit whole bladder as a model to investigate the urothelial transport of anticancer agents: the ONCOFID-P paradigm. Pharmacol Res. 2008;58 (5-6):340-343.
4. Breyer BN, Whitson JM, Carroll PR, Konety BR. Sequential intravesical gemcitabine and mitomycin C chemotherapy regimen in patients with non-muscle invasive bladder cancer. Urol Oncol. 2010;28(5):510-514.
5. Chen CH, Yang HJ, Shun CT, et al. A cocktail regimen of intravesical mitomycin-C, doxorubicin, and cisplatin for non-muscle-invasive bladder cancer. Urol Oncol. 2012;30(4):421-427.
6. Morales A, Phadke K, Steinhoff G. Intravesical mycobacterial cell wall-DNA complex in the treatment of carcinoma in situ of the bladder after standard intravesical therapy has failed. J Urol. 2009;181(3):1040-1045.
7. Kowalski M, Guindon J, Brazas L, et al. A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guérin. J Urol. 2012;188(5):1712-1718.
8. Burke JM, Lamm DL, Meng MV, et al. A first in human phase I study of CG0070, a GMCSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. J Urol. 2012;188(6):2391-2397.