(UroToday.com) The 2025 ASCO annual meeting featured a urothelial carcinoma rapid oral abstract session and a presentation by Dr. Bishoy Faltas discussing preoperative abemaciclib for cisplatin ineligible muscle invasive bladder cancer with molecular response assessment in the CLONEVO trial.
Unfortunately, up to 40% of muscle invasive bladder cancer patients are ineligible to receive standard neoadjuvant cisplatin-based chemotherapy creating a significant unmet need. Of note, 70% of CCND1 amplifications in bladder cancer occur within extrachromosomal DNA:
Based on prior findings of frequent cell cycle alterations, Dr. Faltas and colleagues conducted the first window-of-opportunity, investigator-initiated trial of the CDK4/6 inhibitor abemaciclib followed by radical cystectomy in muscle invasive bladder cancer.
Eligibility was muscle invasive bladder cancer appropriate for radical cystectomy and cisplatin-ineligibility or refusal. Patients had planned treatment with abemaciclib (200mg BID PO) for 4-8 weeks prior to radical cystectomy. The investigators planned to enroll 20 patients (accounting for 20% attrition), with 16 evaluable patients providing 80% power to detect 0.75 effect size (α = 0.05, r = 0.5 between pairs). Whole-exome (WES) and RNA sequencing of pre- and post-abemaciclib tissues and serial evaluation of ctDNA WES were performed on Caris Life Sciences' platform. The trial design for CLONEVO is as follows:
No unexpected safety signals were detected. Grade 3 abemaciclib-related adverse events included anemia (4/20), abdominal pain (1/20) and diarrhea (1/20):
Overall, 20 patients received abemaciclib for a median of 36 days. The median age was 73 years, 16/20 patients were males, and 5/20 had cT4 disease. There were 3 patients that did not undergo radical cystectomy, and 1 withdrew consent from the trial. Abemaciclib resulted in pathologic complete response in 18.8% (3/16) and downstaging occurred in 31.3% (5/16):
Imaging mass cytometry of pre- and post-abemaciclib tissues showed a significant reduction in RB1 phosphorylation after abemaciclib confirming on-target activity:
Serial ctDNA showed a significant reduction in tumor fraction following abemaciclib by 28.6%. Post-TURBT pre-abemaciclib tumor fraction increased but rapidly decreased within 2 weeks of abemaciclib (19.36%), confirming tumor fraction reduction was driven by abemaciclib not TURBT:
Patients with CCND1 amplification had the most significant decrease in tumor fraction (63.8%) highlighting CCND1 as a potential response biomarker:
Abemaciclib significantly downregulated MKI67, CCNA2, and PCNA proliferation markers with log-fold changes of -1.2, -0.7, and -0.6. Gene set enrichment analysis showed significant downregulation of E2F targets and G1/S transition pathways. Patients who achieved pathologic downstaging had significant decrease in E2F pathway activity (-1.6 versus -0.4, p = 0.01) confirming that abemaciclib suppressed E2F-dependent cell proliferation:
Interestingly, abemaciclib significantly inhibited homologous recombination repair of double-strand DNA break (FDR = 0.001), particularly TOPBP1 and RAD51
A key question is whether abemaciclib enhances the efficacy of DNA damaging chemotherapies and antibody drug conjugates:
Dr. Faltas concluded his presentation discussing preoperative abemaciclib for cisplatin ineligible muscle invasive bladder cancer with molecular response assessment in the CLONEVO trial with the following take-home points:
- CLONEVO is this first trial of short-term preoperative abemaciclib in cisplatin-ineligible patients with muscle-invasive bladder cancer
- 4 weeks of abemaciclib demonstrated promising efficacy with 31% pathologic downstaging
- CCND1 genomic amplification and protein expression predict response to abemaciclib
- Abemaciclib significantly inhibited Rb phosphorylation, Ki67, and DNA repair proteins
- These findings support future trials investigating sequential abemaciclib with antibody-drug conjugates such as enfortumab vedotin, where abemaciclib's effects on double-strand DNA break repair augment treatment response
Presented by: Bishoy M. Faltas, MD, Weill Cornell Medicine, New York, NY
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting, Chicago, IL, Fri, May 30 – Tues, Jun 3, 2025.
Related content: CLONEVO Study: Targeting Cyclin D1 Amplifications in Bladder Cancer with Abemaciclib - Bishoy Faltas