Treatment with cisplatin-based neoadjuvant chemotherapy (NAC) and accelerated methotrexate, vinblastine, doxorubicin and cisplatin (AMVAC), followed by a risk-adapted approach to local consolidation, demonstrated an improved two-year metastasis-free survival (MFS) in patients with muscle-invasive bladder cancer (MIBC).
According to study findings published in Journal of Clinical Oncology, study authors wrote, “[These results] show that this approach, unprecedented at the time we launched this trial, is both feasible and promising.”
In addition, the primary end goal was not met. However, 17% of all enrolled patients and 48% of patients in the active surveillance (AS) group avoided cystectomy without metastatic disease.
After a median follow-up of 40 months, the two-year MFS rate for all patients was 72.9%. In the AS group, the MFS rate was 76%, and 71.1% for the remaining patients. Regarding overall survival (OS), the two-year OS rate was 84.3% in all patients, with an OS of 88% in the AS group and an OS of 82.2% for the remaining patients.
Glossary:
Metastasis-free survival (MFS): the length of time a person lives without the cancer spreading to other parts of the body.
Overall survival (OS): the length of time a person lives after a cancer diagnosis.
Intravesical: refers to the inside of the bladder.
cT0 status: clinical stage 0, indicating no evidence of a tumor after neoadjuvant chemotherapy.
cT2-T3NOMO: clinical stage of bladder cancer, indicating the tumor has grown into the muscle wall but not spread to other organs.
Sepsis: a life-threatening condition caused by the body's response to an infection.
Active surveillance: close monitoring of a cancer without immediate treatment.
Metastasis: spreading of disease.
Furthermore, eight patients (32%) in the AS group remained disease-free, while 17 (68%) experienced urothelial carcinoma recurrence (intravesical, local or distant) managed with intravesical therapy (4 patients), radiation (2 patients), cystectomy (8 patients) and or systemic therapy (7 patients). In total, 12 patients in the AS group remained metastasis-free with an intact and unradiated bladder. Out of the 17 patients who recurred, nine developed metastatic disease, and eight out of the nine patients recurred with localized disease first.
A post-hoc analysis revealed a two-year MFS rate of 76% in the per-protocol AS group and 71.1% in the remaining patients. Additionally, the two-year OS rates were 84.3%, 88% and 82.2% for the entire population, AS and non-AS groups, respectively.
“The benefit to the patients in our study was a 53% cystectomy rate in the ITT, allowing a meaningful subset of patients to avoid life-altering surgery in situations where it may have been safely avoided,” study authors wrote.
In terms of safety, 14 out of the 78 patients who received at least one dose of AMVAC experienced a grade 3 (severe) to 5 (death) treatment-related adverse effect (TRAE, side effects). Among the eight patients who began AMVAC but were replaced per protocol, four discontinued AMVAC after one cycle due to acute kidney injury. Sepsis caused one death after three cycles of AMVAC.
In this single-arm, phase 2, noninferiority trial, a total of 70 patients, with a median age of 70 years and cT2-T3N0M0 MIBC, were enrolled in the study. Thirty-three patients had a mutation of either ATM, ERCC2, FANCC and RB1, and 25 began per-protocol AS. Patients with one or more mutations and had cT0 status post-NAC, began AS. Treatment with AMVAC was administered as per the standard of care every two weeks, and dose modification and reductions were permitted to manage TRAEs.
The primary end goal of the trial was MFS at two years for the entire cohort. Secondary end goals included urothelial carcinoma recurrence in the AS cohort, OS, safety during NAC and number of patients requiring a cystectomy.
“Riding the tide of support gained among clinicians, patients, and our partners in drug and biomarker development in this space, we hope to retain that momentum with the next generation of trials that optimize all aspects of a risk-adapted approach for MIBC,” study authors concluded.
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