Approximately 40% of MIBC patients are ineligible to receive standard neoadjuvant cisplatin-based chemotherapy creating a significant unmet need. 

VERZENIO (abemaciclib), a CDK4/6 inhibitor  was chosen in this setting owing to  the high prevalence of cycle D1 amplification events (roughly 70%) within extra extrachromosomal DNA in patients with (published in Nature end of last year).  The CLONEVO trial was a “window of opportunity”, which means investigators gave muscle-invasive bladder cancer (MIBC) patients the drug without trying to delay their definitive treatment which is cystectomy. Overall, 20 patients received VERZENIO 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. 

VERZENIO resulted in pathologic complete response in 18.8% (n = 3/16) and a 31% (n= 5/16) pathologic downstaging in this patient population. Additionally, circulating tumor DNA (ctDNA) levels decreased in 69% of patients with detectable baseline levels. Importantly, amplification and protein overexpression of the CCND1 gene were found to predict response to therapy, suggesting a potential biomarker for patient selection. 

The study also showed that VERZENIO inhibits DNA repair processes by reducing retinoblastoma phosphorylation and the expression of key repair proteins, providing a rationale for combining it with DNA-damaging agents.

KOL insights – 

“This was a window of opportunity to study 20 patients who had histologically confirmed MIBC who were ineligible or declined neoadjuvant platinum-based chemotherapy. The patients had to be medically fit for TRBT and radical cystectomy. Some of the results that we found promising were that three out of 16 patients which were the number of patients, invaluable for a pathological response. Three out of 16 patients had a complete clear pathological response. Five out of 16 patients had downstaging.” – Expert Opinion

Conclusion – 

The mainstay of Cisplatin-eligible MIBC treatment remains platinum-based neoadjuvant chemotherapy (such as MVAC: Methotrexate, Vinblastine, Doxorubicin, Cisplatin) followed by radical cystectomy. For patients ineligible for cisplatin, alternative regimens or direct surgery are standard, but outcomes are generally inferior. The CLONEVO trial is a single-arm, window-of-opportunity study specifically investigating neoadjuvant VERZENIO in patients with resectable MIBC who are ineligible for platinum-based chemotherapy. This is the first trial of “short-term preoperative” VERZENIO in cisplatin-ineligible patients with MIBC. The study supports future trials combining VERZENIO with agents like antibody-drug conjugates (ADCs), including PADCEV (enfortumab vedotin-ejfv), which induces double-strand DNA breaks. Preclinical data indicate that PADCEV  followed by VERZENIO results in significantly greater tumor growth inhibition than PADCEV alone, positioning this sequential strategy as a promising avenue for enhancing therapeutic efficacy in bladder cancer.