Perioperative treatment with durvalumab (Imfinzi) plus neoadjuvant enfortumab vedotin (EV) significantly improved event-free survival (EFS) and overall survival (OS) compared with radical cystectomy in patients with muscle-invasive bladder cancer (MIBC) who can’t, or won’t, tolerate cisplatin-based chemotherapy, according to the VOLGA trial.
In the phase III study, EFS at 24 months was 63.5% with durvalumab/EV and 45.1% with surgery alone (HR 0.51, 95% CI 0.38-0.67, P<0.001), while OS at 24 months was 78.4% and 69.4%, respectively (HR 0.58, 95% CI 0.40-0.83, P=0.003), reported Thomas Powles, MD, of the Barts Cancer Center in London, at the European Society for Medical Oncology (ESMO) congress in Madrid. Results were published concurrently in the New England Journal of Medicine (NEJM).
Adding tremelimumab to the combination also significantly improved EFS (HR 0.61 for an event or death vs control, 95% CI 0.47-0.80, P<0.001), but has yet to demonstrate an improvement in OS (HR 0.77, 95% CI 0.54-1.07, P=0.12).
A complete response was observed in 45.1% of the patients in the durvalumab/EV group, 42.9% with the triplet, and 9.6% in the control group.
“Our findings support combining an immune checkpoint inhibitor with enfortumab vedotin, and may help guide the ongoing clinical discussion about treatment duration,” Powles and colleagues wrote. “The reduced risk of disease progression, recurrence, not undergoing radical cystectomy in the presence of residual disease, or death observed with perioperative durvalumab plus three cycles of neoadjuvant enfortumab vedotin may warrant consideration of this regimen as a new treatment option.”
During the ESMO presentation, Powles said that “I think it’s fair to say we’ve been on a long journey in the last 5 years, with 25 randomized phase III studies in bladder cancer. We’ve moved from patients with metastatic disease dying between 8 to 12 months to 3 years overall survival; we’ve moved these regimes into the perioperative space; we are curing a lot of patients with bladder cancer for the first time with systemic therapy; and here we show that shorter periods of systemic therapy are associated with great outcomes.”
“Cisplatin ineligible patients with muscle invasive bladder cancer have had historically poor outcomes and few opportunities to improve their prognosis,” noted ESMO invited discussant Michiel van der Heijden, MD, PhD, of the Netherlands Cancer Institute in Amsterdam.
This changed with the KEYNOTE-905 trial, which showed that perioperative EV plus pembrolizumab (Keytruda) significantly improved EFS and OS versus radical cystectomy in patients with cisplatin-ineligible MIBC, he pointed out. Those results were confirmed in the cisplatin-eligible population in the KEYNOTE B-15 trial that showed an improvement in EFS and OS for perioperative EV plus pembrolizumab compared with standard chemotherapy.
Results from the VOLGA trial “brings a new option to this disease setting and is another great day for bladder cancer patients,” he said.
The idea behind a perioperative regimen of durvalumab and tremelimumab plus neoadjuvant EV is that this cisplatin-free perioperative regimen “concentrates the delivery of enfortumab vedotin before the stress of surgery, while administering immunotherapy before and after surgery,” wrote Powles’ group in NEJM.
VOLGA was conducted at 229 sites across 25 countries in Europe, North America, South America and Asia, and included 695 patients who were randomized to:
- Arm 1: three cycles of durvalumab and EV, plus two cycles of tremelimumab prior to surgery, followed by nine cycles of durvalumab plus one cycle of tremelimumab as adjuvant therapy
- Arm 2: three cycles of durvalumab and EV prior to surgery, followed by nine cycles of durvalumab adjuvant monotherapy
- Control arm
Patients had a median age of about 72, and the majority were male. Among all patients, 47.9% had a clinical disease stage of T3-4aN0M0 and 15.1% had a clinical disease stage of T1-4aN1M0. Also, 76.1% were ineligible for cisplatin and 23.9% declined cisplatin.
Regarding safety, grade ≥3 adverse events (AEs) occurred in 71.1% of patients in the durvalumab/EV group, 79.5% of those in the durvalumab/tremelimumab/EV group, and 50.2% of those in the control group. The most common AEs were pruritus in the durvalumab treatment groups and urinary tract infection in the control group.
Powles noted that peripheral neuropathy, which is a known side effect associated with EV, was less than what was expected (grade 3/4 in <1% of patients), "and that's because peripheral neuropathy grows with time and gets worse."
“Here we’re only giving three cycles, so we’re not exposing those patients during that adjuvant phase to those adverse events,” he added. “This is therefore a patient-centric and attractive approach which maintains those OS and EFS advantages.”
In bladder cancer, all perioperative trials for checkpoint inhibition have used both a neoadjuvant and an adjuvant treatment component, van der Heijden stated, so VOLGA shows that “it is possible to have a positive result without using enfortumab vedotin in the adjuvant setting.”
Powles also suggested the trial’s AE summary may explain why the efficacy results with the triplet of durvalumab/EV and tremelimumab “were not quite as impressive as we saw with the doublet.”
For example grade 3 0r 4 immune-mediated AEs occurred in 20% of patients in the triplet arm compared with 11% with the doublet. Additionally, AEs leading to a discontinuation of EV occurred in 23% of patients in the triplet arm versus 11% in the doublet arm.
“What this suggests to me is by giving the third drug, although it may have activity, [it] may be taking away a little bit from the activity of the EV and durvalumab,” Powles said.
