Novel Therapies Offer Hope for BCG-Unresponsive Bladder Cancer

Colin P.N. Dinney, MD

It’s well known that few treatment options exist for BCG—unresponsive, non–muscle-invasive bladder cancer (NMIBC) apart from early cystectomy. But a window of opportunity exists in which some NMIBC patients would benefit from trying novel second-line therapies prior to surgery, Colin P.N. Dinney, MD, told attendees at the 2016 LUGPA Annual Meeting in Chicago.

According to Dinney, department chair in urology at the University of Texas MD Anderson Cancer Center, 1 to 3 years of maintenance immunotherapy with bacillus Calmette-Guérin (BCG) is recommended for the estimated 20% of patients with high-risk disease. “Patients can and do move from one risk stratification to another, but the reality is that most patients eventually recur if they live long enough,” he said.

Dinney noted that BCG failure is defined as a cancer recurrence after “adequate” treatment with BCG. For those who relapse early (within 6 months after completing treatment), a clinical trial or cystectomy is recommended. Late relapse (2 or more years after treatment completion) warrants a repeat of BCG or BCG combined with interferon. Patients with refractory NMIBC who experience no tumor-free interval after induction +3 and are now defined as BCG unresponsive, he said.

“When your patient recurs despite adequate BCG treatment, that is a seminal moment,” Dinney stressed. “The conversation you have will be life-changing for the patient due to the risk of progression and death associated with relying on more intravesical therapy and the risk of comorbidity and overtreatment from cystectomy.”

Don’t expect detailed direction from American Urological Association guidelines, cautioned Dinney. “There are no good data to guide us,” he said. “That’s why we say radical cystectomy is the safest option.”

Alternatives to Cystectomy

A key question for physicians at this juncture is whether the patient has enough time for you to seek an alternative to cystectomy. “You probably have about a year to find alternatives for your patient,” Dinney said, adding that only valrubicin currently has FDA approval. Valrubicin generates a complete response (CR) of 18% at 6 months and 8% at 12 months, he noted.

One potential alternative is the immunotherapy MCNA being developed Telesta Therapeutics. An FDA advisory panel voted against approval of MCNA in November 2015, noting that an additional phase III clinical trial was needed to adequately evaluate the agent in this setting.

Additionally, the SWOG S0353 phase II trial examined intravesical gemcitabine for BCG failures. Those data show a recurrence-free survival of 20% at 12 months which, Dinney noted, is still better than valrubicin’s results.¹

Checkpoint Inhibitors in NMIBC

Interest is growing regarding possible checkpoint inhibitor therapy for NMIBC, with companies currently running trials, Dinney said. “But who should lead these trials?” he asked. “Urologists should have a seat at the table because there are key safety concerns in this patient population, and we are used to taking care of them.” He added that two phase III trials with durvalumab are on hold due to bleeding events.

He also believes urologists are well-equipped to help answer two key questions: Could checkpoint inhibitors cause a delay or change in patients’ operative plans? And is an agent’s toxicity commensurate with the disease’s lethality?

Dinney mentioned a planned phase II trial under the auspices of SWOG that will examine how well the PD-L1 inhibitor atezolizumab (Tecentriq) works in treating patients with recurrent NMIBC that has not responded to treatment with BCG.² The agent received an accelerated approval from the FDA in May as a treatment for patients with locally advanced or metastatic urothelial carcinoma (mUC) whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.

Meanwhile, Dinney’s own lab has focused on intravesical gene therapy. “The bladder is an ideal organ for gene therapy because there is direct contact between the vector and the tumor,” he said. Urine and tissue samples are easily accessed to monitor the effect and perform correlative studies, and animal models are available to optimize therapy. Nonetheless, early trials have been disappointing, he said, noting that gene delivery remains a challenge.

The researcher is also working on interferon gene therapy in the form of an adenoviral intravesical interferon α (Ad-IFNa) gene medicine technology. In preclinical studies, Ad-IFNa formulated in the excipient Syn3 induced the regression of human bladder cancer growing in athymic nude mice. Researchers attained sustained high IFNa levels with redosing at 90 days. The agent has been active against IFNa—sensitive and IFNa–resistant cells and has a direct and a bystander effect. Rodent and primate studies have revealed no major toxicities.

Dinney recounted a phase II trial of Ad-IFNa/Syn 3 sponsored by the Society of Urologic Oncology Clinical Trials Consortium, Inc. (SUO-CTC). He is a past president of this clinical research network that connects academic and community-based urologists to run industry-sponsored trials, as well as its current bladder organ site committee chair.

In this trial, 40 patients were randomized to receive Ad-IFNa/Syn3 at 1 or 3 x 10¹¹ vp/mL every 3 months for 12 months as long as CR continued. The median time to recurrence in the low-dose group was 4 months and 12 months for the high-dose group. Responses were maintained for up to 36 months.

Dinney concluded by summarizing SUO-CTC’s interactions with the FDA from earlier this year. Given the natural history of NMIBC, a single-arm trial with a mixed population is still a viable proposition and FDA approval will be for the indication of carcinoma in situ. The label could be extended to include prophylaxis of papillary disease, however. The FDA is conscious of the importance of assembling an appropriate review panel, added Dinney, meaning that urologists’ involvement is likely. Finally, it will be up to the investigators to define the metrics for the registration trial.

References:

1. Skinner EC, Goldman B, Sakr WA, 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. 2-13;190(4):1200-1204.
2. Clinicaltrials.gov. NCT02844816: Atezolizumab in Treating Patients With Recurrent BCG-Unresponsive Non-muscle Invasive Bladder Cancer.

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