Presentation Authors: Nima Almassi*, Eugene Pietzak, Nikolaus Schultz, Aleksandra Walasek, Hikmat Al-Ahmadie, Min Yuen Teo, Samuel Funt, Dean Bajorin, Jonathan Rosenberg, Gopa Iyer, Guido Dalbagni, Bernard Bochner, David Solit, New York, NY
Introduction: Actionable genomic alterations include somatic mutations and structural alterations that predict response to targeted drug therapy. Defining the landscape of actionable alterations in bladder cancer may identify therapeutic targets and inform targeted therapy trials in patients with disease unresponsive to Bacillus Calmette-Guerin (BCG) or neoadjuvant chemotherapy (NAC). In this study we describe the prevalence of actionable alterations and the corresponding evidence supporting the alteration as predictive of response to targeted therapy in primary bladder tumors that underwent next-generation sequencing.
Methods: Bladder tumors that underwent next-generation sequencing were identified from our prospectively-maintained institutional database. Actionable alterations were identified, stratified by level of evidence using OncoKB, and reported for non-muscle-invasive tumors and muscle invasive tumors (MIBC) responsive or refractory to BCG and NAC, respectively.
Results: A total of 506 tumors from 491 patients were sequenced. One or more actionable alterations were identified in 366 samples (72.3%), including 89% of BCG-unresponsive NMIBC and 52% of chemorefractory MIBC tumors. Of 639 total alterationss, 80 (12.5%) had level 2B evidence, reflecting alterations predictive of response to an FDA-approved drug in another indication, thereby representing rational targets for future trials. TSC1 mutations (11.4% of cohort) and ERBB2 amplification (9% of cohort) were the most common level 2B alterations in BCG-unresponsive NMIBC and chemorefractory MIBC, respectively (figure). An additional 380 alterations (59.5%) were level 3A/3B, supported by compelling clinical evidence, and 179 (28%) were level 4 supported by compelling biologic evidence for response to targeted therapy.
Conclusions: The majority of BCG-unresponsive NMIBC and chemorefractory MIBC tumors harbor at least one actionable alteration, highlighting opportunity for targeted therapy clinical trials in patients with localized bladder cancer refractory to standard therapy.
Source of Funding: This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, the Michael and Zena Wiener for Therapeutics Program in Bladder Cancer, Pin Down Bladder Cancer, Cycle for Survival, the Marie-Josee and Henry R. Kravis Center for Mole