A single-arm trial induced high event-free and overall survival with the addition of durvalumab to standard of care before radical surgery in patients with muscle-invasive urothelial carcinoma.
The addition of durvalumab (Imfinzi) to neoadjuvant chemotherapy followed by radical surgery and adjuvant checkpoint inhibition yielded high event-free (EFS) and overall survival (OS) in patients with muscle-invasive urothelial carcinoma (MIUC), according to the primary analysis of the phase 2 SAKK 06/17 trial (NCT03406650).1
“The results of our trial, SAKK 06/17, demonstrate that perioperative multimodality treatment with neoadjuvant [gemcitabine/cisplatin] plus durvalumab followed by surgery and adjuvant durvalumab is feasible and achieves promising EFS and OS rates. The outcome of several ongoing phase 3 trials will inform us if this kind of treatment can become standard of care for patients with localized MIUC,” the investigators wrote.
After a median follow-up 40 months, the EFS rate at 2 years was 75.7% (95% CI, 61.8%-85.1%), meeting the trial’s primary end point. Further, the EFS rate at 3 years was 73.4% (95% CI, 59.2%-83.4%). Median EFS has not been reached.
Of the 52 patients who underwent resection, 17 patients (33%) experienced complete pathologic response, while 31 (60%) had pathologic response <ypT2 ypN0.
At 2 and 3 years, the OS rates were 85.0% (95% CI, 72.3%-92.2%) and 80.8% (95% CI, 67.2%-89.2%).
Recurrence-free survival (RFS) for patients with R0 resection was 83.4% (95% CI, 69.5%-91.3%) at 2 years, and 80.9% (95% CI, 66.5%-89.6%) at 3 years following surgery.
In resected patients, 31 achieved a pathologic response for a rate of 59.6% (95% CI, 45.1%-73.0%), and 17 experienced a pathologic complete response for a rate of 32.7% (95% CI, 20.3%-47.1%).
During neoadjuvant therapy, 42% and 25% of patients, respectively, experienced either grade 3 or 4 treatment-related adverse events (TRAEs). During adjuvant therapy, grade 3 and 4 TRAEs occurred in 11% and 4% of patients, respectively.
“Neoadjuvant chemo-immunotherapy studies in muscle invasive bladder cancer have demonstrated consistent clinical activity. This study is unique in exploring a time to event end point in the perioperative setting, rather than pathologic complete response. Phase 3 trials are ongoing which should inform us on options for localized muscle invasive bladder cancer,” wrote Michael Anthony Carducci, MD, AEGON professor in Prostate Cancer Research, Johns Hopkins University School of Medicine, associate cancer center director for clinical research, Johns Hopkins Kimmel Cancer Center, and regional research director, National Capital Region for the Kimmel Cancer Center, who provided the relevance section of the study.
In the international, investigator-initiated, open-label, single-arm phase 2 trial, 61 patients with stage cT2-T4a, cN0-1 operable MIUC received 4 cycles of 1,000 mg/m2 gemcitabine over 30 minutes intravenously on day 1 and day 8 of each cycle, 70 mg/m2 cisplatin over 1 to 2 hours intravenously on day 1 of each cycle, and 1,500 mg durvalumab intravenously over 60 minutes starting on day 22 of each cycle, followed by radical surgery. Patients then went on to receive adjuvant durvalumab at 1,500 mg every 4 weeks for 10 cycles or 40 weeks, whichever occurred first.
EFS at 2 years served as the primary end point of the trial. “Although the achievement of non–muscle-invasive disease (<ypT2) or pCR with neoadjuvant treatment is an important milestone and has been correlated with improved outcomes, it is clear, however, that only time-to-event end points such as EFS or OS are true measurements for the benefit of such treatments. This is especially true in case of combined use of neoadjuvant and adjuvant systemic treatment,” explained the investigators.
Secondary end points included EFS, OS, RFS after R0 resection, quality of resection, pathologic complete response (ypT0), pathologic response rate (defined by pathologic downstaging to <ypT2 N0 M0), pattern of recurrence, treatment feasibility, and AEs.
Eligibility criteria included histologically proven urothelial carcinoma of the bladder, urethra, or upper urinary tract with clinical stage T2-T4a and ≤N1 (defined as a solitary lymph node ≤2 cm in the greatest dimension); no evidence of distant metastases; and positive urine cytology and tumor mass documented by urography for those with upper tract disease. Further, patients had to be considered suitable for curative multimodality treatment and have an estimated glomerular filtration rate of >50 mL/min/1.73 m2, according to the Chronic Kidney Disease Epidemiology Collaboration formula.
The full analysis set consisted of 57 patients, including 54 (95%) who had bladder cancer. Of the patients who underwent resection, median age was 67 years (range, 33-81), and the majority of these patients were male (77%). Further, 73% of patients presented with cT2 stage disease, 85% with cN0, and 79% presented with not otherwise specified histology.
The investigators acknowledged that the trial is a single-arm, phase 2 trial with a small number of patients, which may limit its interpretation and clinical impact. “The field is, however, moving fast since several phase 3 trials for cisplatin-eligible patients in the perioperative setting are underway,” they added.
In particular, they made note of the phase 3 NIAGARA trial (NCT03732677) of neoadjuvant gemcitabine/cisplatin plus durvalumab, which has completed accrual and expecting efficacy results; the KEYNOTE 866 trial (NCT03924856) of neoadjuvant gemcitabine/cisplatin plus pembrolizumab (Keytruda); the ENERGIZE trial (NCT03661320) of neoadjuvant gemcitabine/cisplatin plus nivolumab (Opdivo); the EV-304 trial (NCT04700124) of neoadjuvant enfortumab vedotin (Padcev) in combination with pembrolizumab; and the VOLGA trial (NCT04960709) of neoadjuvant enfortumab vedotin plus durvalumab or tremelimumab (Imjudo).
Cathomas R, Rothschild SI, Hayoz S, et al. Perioperative chemoimmunotherapy with durvalumab for muscle-invasive urothelial carcinoma: Primary analysis of the single-arm phase II trial SAKK 06/17. Published August 17, 2023. J Clin Oncol. doi:10.1200/JCO.23.00363.