(UroToday.com) To finish out the session on Innovations and Multi-disciplinary Care in Early and Late-Stage Urothelial Cancer, Dr. Geynisman presented results of the RETAIN Trial, a phase II trial of risk-enabled therapy after initiating neoadjuvant chemotherapy for bladder cancer.
As he notes in his background slide, cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy or chemoradiation is the standard of care for urothelial carcinoma (UC) patients with MIBC. Both cystectomy and chemoradiation have short and long-term toxicity and QOL implications. About 30-40% of patients have a complete response (ypT0N0) response to NAC.
But, TURBT missed about 50% of MIBC post-NAC and conventional imaging is not adequate.
Concurrently, mutations in DNA damage repair/response genes are associated with pathologic downstaging after NAC – specifically ATM, RB1, FANCC (Miron et al. EU Oncology 2020) and ERCC2
(Liu et al. JAMA Oncology 2016) have been demonstrated to be associated with a strong response to NAC.
Therefore, they asked the question and hypothesized that a combination of biomarker selection and clinical staging would identify patients prospectively for a cystectomy or chemoradiation avoidance algorithm. Specifically, they wanted to see if they could appropriately select MIBC patients who do not need cystectomy or CRT and simultaneously preserve oncologic outcomes?
They conducted a a single-arm, phase II, non-inferiority trial (NCT02710734) to evaluate a risk-adapted approach for MIBC.
Eligible patients included those with cT2-T3N0M0 UC who underwent NAC with accelerated MVAC.
Pre-NAC TURBT specimens were sequenced (Caris) for mutations in ATM, ERCC2, FANCC or RB1. Patients with ≥ 1 mutation and no clinical evidence of disease by restaging TUR, urine cytology and imaging post-NAC began pre-defined active surveillance (AS). The remaining patients underwent bladder-directed therapy.
The full trial protocol is seen below:
The AS protocol is listed below:
Again, he made clear, this is NOT a randomized trial. This is an allocation trial.
The primary endpoint was metastasis-free survival (MFS) at 2 years for the entire cohort. The risk-adapted approach would be declared non-inferior to the standard of care if the lower bound of an exact 1-sided 95% CI for MFS was > 64%. The study required 70 patients with a 4.5% type I error and 81.6% power.
From 4 academic centers, 102 (ITT) patients were enrolled over 33 months at four academic centers. But, ultimately, the ITT cohort was 71 patients. Consort diagram below demonstrates the attrition reasons:
33 patients were mutation positive.
Demographics of the ITT cohort are seen below:
Median age was 70 years (47-83), 74% were male, 92% Caucasian, 81% ECOG PS 0 and 79% cT2. 90% completed 3 cycles of MVAC with 17% grade 3-4 TRAEs.
He initially described the outcomes of the 37 patients who were mutation negative – most went on to cystectomy, though 2 did opt for AS, 6 for CRT and 3 BCG.
In the ITT population, 33 (46%) had a relevant mutation and 26 (37%) began AS. The full treatment of the patients with mutation positive disease is summarized below:
With a median follow-up of 41 months, 47 patients (66%) are metastasis-free (CI 54%-77%). The 2-year MFS for the ITT patients (primary endpoint) was 72% (lower bound exact 1-sided 95% CI=62%). Unfortunately, this did not meet predefined cutoff for significance. Hence, they cannot declare the risk-adapted approach non-inferior.
On post hoc analysis, the 2-year MFS was 76.9% in the AS group and 70.5% in the remaining patients (no significant difference).
The 2-year OS is 84.3% and 88.5% in the ITT and AS groups, respectively. There was no difference between the AS and non-AS groups.
In the AS group, 18 patients (69%) had some UC recurrence, 8 had a cystectomy, 2 chemoradiation, and 12 (46%) are metastasis-free with an intact bladder. Of the 10 patients (38%) on AS who developed metastatic disease, 9 recurred with localized disease first – and had they gotten early cystectomy, may have remained metastases free. Associations between mutation presence and MFS or UC recurrence were not observed.
The 72% 2-year MFS rate in this MIBC cohort treated with a risk-adapted approach did not satisfy the pre-specified non-inferiority condition. 38% of AS patients developed metastatic disease, with most patients first recurring locally in the bladder. With a median follow-up of 41 months, although 50% of AS patients have been able to avoid cystectomy without metastatic disease, further refinement of this approach is necessary.
To this effect, there are two ongoing trials that are building on this already - the RETAIN-2 trial and the Alliance A031701 trial.
Presented by: Daniel M. Geynisman, MD, Fox Chase Cancer Center
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Associate Professor of Urology, University of California, Davis @tchandra_uromd on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.