Abstract CT127: Pre-operative abemaciclib in localized cisplatin-ineligible MIBC with tissue and ctDNA molecular response validation (CLONEVO)

Abstract Background: Up to 40% of patients with muscle-invasive bladder cancer (MIBC) are ineligible to receive standard-of-care neoadjuvant cisplatin-based chemotherapy, creating a significant unmet need for effective neoadjuvant therapies. Based on our prior findings of the high prevalence of somatic cell cycle alterations in MIBC, we conducted the first window-of-opportunity investigator-initiated trial of the CDK4/6 inhibitor abemaciclib (abema) followed by radical cystectomy (RC) in MIBC (CLONEVO, NCT03837821). Methods: Eligibility included MIBC appropriate for RC and cisplatin-ineligibility or refusal. Planned treatment was abema (200mg BID PO) for 4-8 weeks prior to RC. We planned to enroll 20 patients (accounting for 20% attrition). With 16 evaluable patients, this provided 80% power to detect an effect size of 0.75 (α=0.05 and r=0.5 between pairs). Planned Whole-exome (WES) and RNA sequencing of pre- and post-abema tissues and serial evaluation of ctDNA WES were performed using Caris Life Sciences assays. Results: 20 patients were enrolled and received abema for a median of 36 days. Median age was 73, 16/20 (80%) were males, and 5/20 (25%) had cT4 stage. 3 patients didn't undergo RC, and 1 withdrew consent. Abema resulted in pathologic complete response in 18.8% (3/16) and pathologic downstaging in 31.3% (5/16) of 16 evaluable patients. No unexpected safety signals were detected. Grade 3 abema-related adverse events included anemia (4/20), diarrhea (1/20), abdominal pain (1/20), neutropenia (1/20), and leukopenia (1/20). Variant allele frequency of somatic mutations significantly decreased after abema by 20.5% (p =0.04), confirming its efficacy in reducing tumor burden. Serial ctDNA showed a significant reduction in tumor fraction (TF) following abema by 11.7% (p =0.03). Post-TURBT ctDNA TF increased prior to initiating abema but rapidly decreased within 2 weeks of starting abema (19.3%), confirming that responses were driven by abema, not TURBT. Patients with CCND1 amplification had the most significant decrease in ctDNA TF (45% vs. 1.1% p=0.001). The higher response in CCND1-amplified tumors aligns with its role as a driver of CDK4/6-dependent cell cycle progression, identifying a potential response biomarker. Abema significantly downregulated the expression of MKI67, CCNA2, and PCNA proliferation markers with log-fold changes of -1.2, -0.7, and -0.6 (p=0.001). Gene set enrichment analysis of matched pre- and post-abema samples showed significant downregulation of E2F targets and G1/S transition pathways. Patients who achieved pathologic downstaging had a significant decrease in E2F target scores (-1.6 vs. -0.4, p=0.01). These data confirm that abema suppressed E2F-dependent cancer cell proliferation, validating on-target drug activity. Interestingly, abema significantly inhibited the homologous recombination pathway of double-strand DNA breaks (DSB) repair (FDR=0.001), particularly TOPBP1 and RAD51. Conclusion: This first trial of short-term pre-operative abema in MIBC demonstrated favorable efficacy and tolerability while modulating cell cycle-dependent pathways, including DSB repair. Our findings support future trials investigating sequential therapy combining abema with antibody-drug conjugates such as enfortumab vedotin, where abema's effects on DSB repair enhance treatment responses. Citation Format: Bishoy M. Faltas, Mohamed Osman, Mark G. Evans, Daniel J. Margolis, Cora N. Sternberg, Jones T. Nauseef, Ana M. Molina, David M. Nanus, Neal A. Patel, Rohit K. Jain, Amie Patel, Michael Sigouros, Jyothi Manohar, Hiranmayi Ravichandran, Amanda Reid, Majd Al Assaad, Giovanni Medico, Giorgio Inghirami, Benjamin D. Hopkins, Juan Miguel Mosquera, Philip Abbosh, Manuel Hidalgo, William F. Hooper, Nicolas Robine, Olivier Elemento, Namrata Peswani, Suzanne Cole, Douglas S. Scherr, Scott T. Tagawa. Pre-operative abemaciclib in localized cisplatin-ineligible MIBC with tissue and ctDNA molecular response validation (CLONEVO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT127.