Adding the PD-L1 inhibitor durvalumab to neoadjuvant cisplatin/gemcitabine (GC) chemotherapy and continuing its use as adjuvant treatment after radical surgery may improve outcomes in patients with muscle-invasive urothelial carcinoma (MIUC), according to a new study published in the Journal of Clinical Oncology.
The study demonstrated that this strategy could achieve high rates of event-free survival (EFS) and overall survival for up to 3 years. The investigators defined EFS as time from trial treatment initiation until one of the following events, whichever occurred first: recurrence of locoregional disease following surgery; development of metastases at any site; progression during neoadjuvant therapy leading to inoperability; or death from any cause.
The findings are from the open-label phase 2 international SAKK 06/17 trial, which examined the addition of neoadjuvant durvalumab to gemcitabine/cisplatin (GC) chemotherapy followed by radical surgery and adjuvant durvalumab (ClinicalTrials.gov identifier: NCT03406650). Investigators accrued patients at 11 sites within the SAKK network in Switzerland and at an additional site in Germany. This study is unique because it explored a time to event endpoint in the perioperative setting rather than pathologic complete response.
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Patients with stage cT2-T4a cN0-1 operable MIUC received neoadjuvant GC in combination with 4 cycles of durvalumab starting at GC cycle 2. After radical surgery, adjuvant durvalumab was given for 10 cycles. The study accrued 61 patients (12 female and 45 male) with a mean age of 68 years. The final analysis consisted of 57 patients, 54 (95%) with bladder cancer.
With a median follow-up of 40 months, the study met its primary endpoint. The EFS rate was 75.7% at 2 years and 73.4% at 3 years, Richard Cathomas, MD, of Cantonal Hospital Graubünden, Switzerland, and colleagues reported. The overall survival rates were 85% and 81% at 2 and 3 years, respectively. Further, 17 resected patients (33%) had a complete pathologic response and 31 (60%) had a pathologic response <ypT2 ypN0. Grade 3 treatment-related adverse events (TRAEs) during neoadjuvant treatment occurred in 42% of patients and grade 4 TRAEs occurred in 25%.
Joaquim Bellmunt, MD, PhD, director of the Bladder Cancer Center at Dana-Farber Cancer Institute in Boston, Massachusetts, said the results from this study are promising, but they still must be considered preliminary. “These findings need to be compared to the standard of care,” Dr Bellmunt said. “This approach of neoadjuvant cisplatin/gemcitabine plus durvalumab followed by adjuvant durvalumab will need to be compared to giving only chemotherapy followed by adjuvant nivolumab and see if the outcome is superior.”
In the current study, adjuvant durvalumab was started 4-12 weeks after surgery at a fixed dose of 1,500 mg intravenously over 60 minutes. It was administered once every 4 weeks for a total of 10 cycles or a maximum of 40 weeks, whichever came first. Adjuvant durvalumab was started in a timely manner in 47 patients (83%), and 30 patients (64%) completed all planned 10 cycles. Overall, 36 patients (77%) received at least 8 cycles, Durvalumab had to be delayed at least once in 18 patients (38%). Timely admission and completion of planned surgery was achieved for 51 patients (90%). One patient had delayed surgery, and another was found intraoperatively to be unresectable. The median number of lymph nodes removed was 29.
The study failed to identify any potential biomarkers of response to treatment or significant correlations with PD-L1, MTAP, or SLFN11 status.
Chad R. Ritch, MD, MBA, an associate professor and director of urology at the Desai Sethi Urology Institute, part of the University of Miami Miller School of Medicine in Florida, said the pathologic complete response rate is 30%-40% with chemotherapy alone. Increasing that rate by 10%-20% by adding immunotherapy could translate to improved cancer-specific and overall survival rates. “However, this study did not appear to demonstrate a significant improvement over what one would expect with standard neoadjuvant chemo,” he said. “Therefore, we need more trials with these combinations to better understand who will benefit from the combination therapy.”
Several phase 3 trials with cisplatin-eligible patients in the perioperative setting are underway. The NIAGARA trial (ClinicalTrials.gov identifier: NCT03732677) is testing the same regimen as in SAKK 06/17. It has completed accrual and efficacy results are expected soon. There are 2 similar trials looking at the combination of GC with pembrolizumab (KEYNOTE 866, ClinicalTrials.gov identifier: NCT03924856) and nivolumab (ENERGIZE, ClinicalTrials.gov identifier: NCT03661320).
Urologist Carissa Chu, MD, an assistant professor in the division of urologic oncology at University of California, San Francisco, said the study is most notable because it showed strong pathologic downstaging rates. “We know that downstaging is associated with improved long-term outcomes, including survival,” Dr Chu said. “Furthermore, the inclusion of higher-risk disease including node positive or locally advanced (T3-T4) shows that some patients could benefit from cystectomy who would otherwise be ineligible.”
Although the study did not show that any particular biomarker predicted response, larger randomized studies may change that. Dr Chu said it is notable that the number of serious adverse event rates was fairly high. “Now that we know adjuvant nivolumab is an option for patients with significant residual disease after cystectomy, I wonder if additional adjuvant durvalumab should only be reserved with those who did not experience pathologic downstaging to further reduce the risk of morbidity in patients in the perioperative period.”
Reference
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 online August 17, 2023. doi:10.1200/JCO.23.00363