In January 2020 the FDA voted 9 to 4 to approve pembrolizumab as a treatment for BCG-unresponsive, high-risk NMIBC with CIS, with or without papillary disease for patients who are ineligible for or refuse early radical cystectomy (ERC). The durable complete response rate at one year was 20% - far lower than the FDA's own recommended rate.
According to a March 2020 study by Drs. Wettstein, Jewett, and Kulkarni (the PI of our phase 2 trial at UHN), even the FDA recommended rate of 30% CR at one year is an inadequate threshold for approval.
The study used a supercomputer and a discrete event simulation framework to determine what efficacy rate would be required for a novel therapy for BCG-unresponsive NMIBC to be competitive with early radical cystectomy in terms of quality adjusted life expectancy.
The study concluded that the current efficacy recommendations are too low and propose that they be increased to 45%-55% at 6 months and 35% at one year.
I think Theralase will easily hit those efficacy targets and may even achieve 67% CR at one year in 20-25 patients, allowing for accelerated approval.
Required efficacy for novel therapies in BCGunresponsive nonmuscle invasive bladder cancer: Do current recommendations really reflect clinically meaningful outcomes? 1 INTRODUCTION
Patients with nonmuscle invasive bladder cancer (NMIBC) unresponsive to intravesical Bacillus CalmetteGurin (BCG) immunotherapy pose a clinical dilemma1: On the one hand, surgical tumor extirpation before progression to muscleinvasive disease (ie, early radical cystectomy; ERC) is the sole standard therapy.1, 2 However, this procedure is not only associated with considerable perioperative mortality and morbidity3 but also leads in most patients to a substantial decrease in quality of life.4 On the other hand, several bladdersparing novel therapies ranging from systemic immune checkpoint blockade to photodynamic therapy have been proposed during the last years.1 Although these modalities can potentially delay or even avoid ERC and hence preserve quality of life, they all come at the cost of inferior cancer control.
Considering the infeasibility of a randomized controlled trial comparing a specific novel therapy to ERC, the unavailability of an effective comparator arm besides ERC, and the fact that it is unethical to use placebo controls in this setting, the United States Food and Drug Administration (FDA) currently allows singlearm phase II trials for the assessment and registration of novel therapies in BCGunresponsive NMIBC.5 Two recommendations regarding clinically meaningful outcomes of such singlearm trials have been published so far: The International Bladder Cancer Group (IBCG) considers complete response rates (carcinoma in situ; CIS) and recurrencefree rates (papillary tumors) of 50% at 6 months, 30% at 12 months, and 25% at 18 months as clinically meaningful6 while a public workshop of the FDA and the American Urological Association (AUA) proposed 40%50% at 6 months and 30% at 1824 months (regardless if CIS or papillary tumor).7 Although both recommendations are products of intensive discussions among renowned experts, they are not purely based on quantitative evidence. Therefore, the aim of this study was to quantitatively verify the two recommendations using a decisionanalytic approach. Specifically, we used a simulation framework in combination with the infrastructure of a supercomputer to find the required efficacy at which a novel therapy can compete with ERC when it comes to qualityadjusted life expectancy.
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4 DISCUSSION
In this simulation study, we quantitatively verified if current recommendations regarding clinically meaningful outcomes in singlearm trials evaluating novel therapies in BCGunresponsive NMIBC translate into meaningful outcomes from an integrative healthcare perspective. We therefore compared three different types of novel therapies against ERC as the standard of care. Our work not only showed that there is a low probability that the recommendation of the IBCG (50% at 6 months, 30% at 12 months, and 25% at 18 months) or the one of the FDA/AUA (40%50% at 6 months and 30% at 1824 months) would make any novel therapies a real competitor to ERC but also that these recommendations need to be increased by at least 10% (IBCG) and 5% (FDA/AUA). Thus, we feel that an appropriate recommendation should suggest an efficacy threshold of at the minimum 45%55% at 6 months and 35% at 1824 months (complete response rate/recurrencefree survival).