Response to Lammers and Witjes article: new developments in intravesical therapy for non-muscle-invasive bladder cancer

Abstract

Response to: Lammers RJM, Witjes JA. Developments in intravesical therapy for non-muscle-invasive bladder cancer. Expert Rev. Anticancer Ther. 10(12), 1903–1916 (2010).

In the December 2010 issue of Expert Review of Anticancer Therapy, Lammers and Witjes provided an excellent review on intravesical therapy for non-muscle-invasive bladder cancer (NMIBC), including the challenges of dealing with bacillus Calmette–Guérin (BCG) failure because of inefficacy or intolerance [1]. In addition to addressing conventional therapy, such as immediate postoperative single-instillation chemotherapy, the authors gave thoughtful consideration to a variety of new developments in the treatment of NMIBC. They also discussed the investigational bioreductive drug apaziquone, currently in Phase II/III studies, combination immunotherapy with BCG and IFN-α, and device-assisted chemotherapy to aid bladder wall uptake of mitomycin C. With regard to patients who fail BCG immunotherapy, they discussed induction therapy with investigational chemotherapeutics, such as intravesical gemcitabine or docetaxel, as well as valrubicin, which is approved by the US FDA for the treatment of BCG-refractory patients with carcinoma in situ (CIS) who are not candidates for cystectomy [2]. However, the article failed to include mycobacterial cell wall–DNA complex (MCC) suspension, which is currently in Phase III trials for the treatment of BCG-refractory NMIBC.

Mycobacterial cell wall–DNA complex, prepared from Mycobacterium phlei, contains cell walls with complexed mycobacterial DNA. Because MCC contains no viable mycobacteria, it is expected to have improved safety over BCG, which has an extensive toxicity profile [3]. Furthermore, MCC has a unique dual mechanism of action, involving both an immunomodulatory effect and direct inhibition of cell proliferation, which may be advantageous in treating NMIBC [4,5].

Mycobacterial cell wall–DNA complex formulated as an emulsion (4- or 8-mg doses) was effective and well tolerated in a Phase II open-label study in 55 patients with CIS and no muscle-invasive disease [6]. In the intent-to-treat population, the complete response rate was 27% (4 mg) and 46% (8 mg) when evaluated at both weeks 12 and 26. At month 12, the complete response rate was 32% (4 mg) and 25% (8 mg), and at month 18 it was 23% (4 mg) and 29% (8 mg). In the efficacy-evaluable population, complete response rates ranged from 27 to 62% at weeks 12 and 26, and 27 to 73% at months 12 and 18. Importantly, complete response rates were similar in patients who had and who had not received previous BCG therapy. Adverse events were generally mild to moderate in severity.

Two Phase III trials (ClinicalTrials.gov identifiers: NCT00406068 and NCT01200992 [101]) are currently in progress to evaluate the efficacy and safety of MCC suspension in patients who have failed adequate BCG therapy. The first of these is an open-label trial of MCC (8 mg) in patients with NMIBC at high risk of progression who are refractory to therapy with BCG. Patients received 6-weekly instillations followed by 3-weekly maintenance instillations at 3, 6, 12, 18 and 24 months. The results of the interim analysis of data obtained from 129 enrolled patients at 12 months was presented at the American Urologic Association and European Urologic Association annual meetings in Spring [7,8]. The second is a recently initiated randomized, active-controlled, open-label trial of the efficacy and safety of MCC (8 mg) versus mitomycin C alone in patients with BCG-recurrent or -refractory NMIBC. The results of these trials will help to determine whether MCC is a viable alternative to cystectomy in patients after BCG failure. For longer-term clinical development, there is the possibility that MCC may be a good alternative to BCG immunotherapy for the treatment of newly diagnosed NMIBC.

Financial & competing interests disclosure

Gary D Steinberg discloses conflicts of interest with Abbott, Adolor, Bioniche, Covidien, Endo Pharmaceuticals, GE Healthcare, Spectrum/Allergan and Tengion. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Editorial assistance, including medical writing, was provided by Nicole Strangman (PhD) and Kris Schuler (MS) of Complete Healthcare Communications, Inc., and was funded by Endo Pharmaceuticals Inc.