Durvalumab Plus Vaccine Therapy Elicits ‘Encouraging’ DFS in BCG-Unresponsive NMIBC

The addition of durvalumab (Imfinzi) to S-488210/S-488211 vaccine therapy demonstrated evidence of preliminary antitumor activity without substantial additive toxicity in patients with Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC), according to findings from the phase 1b portion of the phase 1b/2 DURANCE trial (NCT04106115) presented at the 2024 ESMO Asia Congress.1

As of the data cutoff date of October 21, 2024, the 3- and 6-month disease-free survival (DFS) rates were 71% and 57%, respectively. Additionally, 8 patients––2 of 6 with baseline carcinoma in situ (CIS), 5 of 6 with baseline T1 tumors, and 1 of 2 with baseline Ta tumors––were disease free at the 24-week assessment following the end of treatment.

“Durvalumab plus S-488210/S-488211 is a well-tolerated treatment for BCG-unresponsive high-risk NMIBC patients. The safety profile looks similar to checkpoint inhibitor monotherapy with the addition of injection site reactions,” lead study author Gianmarco Leone, PhD student and clinical research fellow at University College London, stated in the presentation.

NMIBC represents between 75% and 80% of all newly diagnosed bladder cancers. Standard frontline therapy consists of transurethral resection of bladder tumor plus BCG, but between 40% and 50% of patients will develop recurrent disease for which second-line options remain limited.

“For these patients, radical cystectomy is curative but is associated with a 30% morbidity rate and 90-day mortality rate close to 5%. Alternatively, patients could undergo endoscopic surveillance and repeated resections, but even this approach is accompanied with a non-negligible risk of progression and death,” Leone said.

In addition to mitomycin C, hyperthermic intravesical chemotherapy (HIVEC), as well as clinical trials evaluating drugs such as nadofaragene firadenovec-vncg (Adstiladrin) and TAR-200, pembrolizumab (Keytruda) is a systemic option for patients with BCG-unresponsive disease. However, the 36-month DFS rate hovers at just shy of 35% (34.9%; 95% CI, 26.4%-43.4%).2

To better understand the activity of checkpoint inhibition in combination with vaccine therapy, investigators launched DURANCE.1 “We designed the phase 1b/2 clinical trial, which enrolled patients with BCG-unresponsive disease to receive durvalumab with subcutaneous injection of two different compounds for a total of five immunogenic peptides,” Leone explained.

Eligible patients included those over 18 years of age with a World Health Organization performance status of 0 or 1 with recurrent, high-risk NMIBC that was unresponsive or intolerant to prior BCG therapy. Prior treatment with an immune checkpoint inhibitor was not allowed.

“The trial treatment was administered over the course of 6 months, with the vaccine being administered weekly for the first 6 weeks and every other week for the remaining time,” Leone stated. “Durvalumab was administered at the standard monthly dose of 1500 mg. Patients underwent cystoscopy every third month as well as mandated field biopsies at baseline, 6 months, and 1 year, and an annual CT scan.”

The primary end points were safety in phase 1b and the 1-year DFS rate in phase 2. Secondary end points included the 1-year DFS rate stratified by HLA-A*02:01 status, 5-year overall survival rate, and quality of life. Biomarkers were evaluated as part of an exploratory analysis.

A total of 15 patients were enrolled in phase 1b between March 2022 and March 2024 across 4 sites in the United Kingdom––14 started treatment. The median patient age was 70 years (range, 57-86) and most were male (93%). Patients were staged as having either Ta (14%) or T1 (43%) tumors, or CIS with or without papillary lesions (43%). The median number of BCG doses received was 15 (range, 6-36), and other prior treatments included mitomycin C (14%) and HIVEC (7%).

In terms of safety, adverse effects (AEs) included hypertension (any grade, 100%), injection site reaction (78%), hyperglycemia (64%, hypophosphatemia (57%), hematuria (50%), increased blood lactate dehydrogenase levels (50%), eosinophilia (43%), increased blood bicarbonate levels (43%), lymphocytopenia (43%), increased fibrinogen levels (43%), pruritus (43%), erythrocytopenia (43%), monocytosis (36%), and increased creatinine levels (36%). Grade 3/4 AEs included hypertension (50%), injection site reaction (7%), and hematuria (7%).

Treatment-related AEs included injection site reaction (grade 1, n = 9; grade 2, n = 1; grade 3, n = 1), pruritus (grade 1, n = 6), thyroid dysfunction (grade 1, n = 4), increased liver enzymes (grade 1, n = 1; grade 2, n = 1; grade 3, n = 1), renal dysfunction (grade 1, n = 3), diarrhea (grade 1, n = 2), fatigue (grade 1, n = 1; grade 2, n = 1), myalgia (grade 1, n = 1; grade 2, n = 1), pneumonitis (grade 2, n = 1), hyperglycemia (grade 2, n = 1), and lymphadenopathy (grade 2, n = 1).

Serious AEs––hematuria and lung infection––occurred in 2 patients but were not treatment related, and no patients had to discontinue treatment because of AEs.

“Recruitment in phase 2 is ongoing, and biomarker analyses including PD-1, HLA, and urinary cell free DNA assessments will be performed,” Leone concluded.

Disclosures: Dr Leone had no conflicts of interest to disclose.

References

1. DURANCE: a phase Ib/II study to assess the safety and activity of durvalumab (MEDI4736) in combination with S-488210/S-488211 vaccine in non-muscle invasive bladder cancer. Ann Oncol. 2024;35(suppl 4):S1509-S1510. doi:10.1016/j.annonc.2024.10.293
2. Necchi A, Roumiguié M, Kamat AM, et al. Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2024;25(6):720-730. doi:10.1016/S1470-2045(24)00178-5