Neoadjuvant durvalumab feasible in muscle-invasive bladder Ca

Durvalumab (IMFINZI) appears to be feasible as neoadjuvant therapy with preliminary evidence of antitumor activity in patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy.

From cohort 1 of a single-center sequential multicohort trial, all 10 patients who entered completed all three doses of durvalumab per protocol and proceeded to radical cystectomy, with only one patient experiencing a grade 3 treatment-related adverse event ([TRAE] anemia), reported Guru P. Sonpavde, MD, and colleagues at the Genitourinary Cancers Symposium in San Francisco.

Eight of the 10 patients had at least 12 weeks of follow-up at the most recent analysis in October 2019. Of the eight, two (25%) had a pathologic response, defined as less than pT2N0 disease, and one (12.5%) had a pathologic complete response (pCR), defined as pT0 disease.

There is no established neoadjuvant therapy for patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy preceding radical cystectomy. Prospective data with PD-1/PD-L1 inhibitors, including pembrolizumab (Keytruda) and atezolizumab (Tecentriq), are encouraging, indicating safety and activity in this setting, said Dr. Sonpavde, director of the Bladder Cancer Program, Dana-Farber Cancer Institute, Boston.

Durvalumab is a PD-L1 inhibitor approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma following platinum-based chemotherapy, but its performance in the neoadjuvant setting had not been tested previously.

“The goal in this phase I trial was primarily to demonstrate feasibility and safety of using durvalumab before radical cystectomy for muscle-invasive bladder cancer. Achieving pCR was a secondary endpoint, which needs to be evaluated in a larger trial employing and powering the trial for pCR as the primary endpoint,” Dr. Sonpavde told Urology Times.

The data presented here were from cohort 1 of the study, which assessed durvalumab at a dosage of 750 mg intravenously (IV) every 2 weeks for three cycles followed by radical cystectomy 2 to 4 weeks after the last durvalumab dose in patients who were ineligible for or declined chemotherapy.

“Population pharmacokinetic modeling of durvalumab supports the switch from the 10 mg/kg IV every 2 weeks schedule to a flat-dosing regimen of 750 mg IV every 2 weeks, or a regimen of 1,500 mg every 4 weeks IV,” said Dr. Sonpavde.

Cohort 2 is examining durvalumab plus oleclumab, a CD73 antagonist monoclonal antibody that enhances the immune response, in 10 patients with cT2 to T4a N0M0 muscle-invasive bladder cancer.

Patients in cohort 1 were a median age of 67 years, 80% were men, and 100% were Caucasian. Eight had clinical stage T2 disease at baseline, one had stage T3, and one had stage T4. Five were not eligible for cisplatin due to grade >1 hearing loss, three due to creatinine clearance level <60 mL/min, and one due to both grade >1 hearing loss and low creatinine clearance. One patient declined chemotherapy.

No dose-limiting toxicities were observed and no TRAEs led to treatment discontinuation. The most frequent TRAEs of any grade were fatigue (n=3), an increase in lipase (n=2), and dry skin (n=2), all of which were grade 1 or 2. Six of the eight patients (75%) who proceeded to surgery underwent cystoprostatectomy; one underwent cystectomy plus hysterectomy, bilateral salpingo-oophorectomy, and anterior vaginectomy; and one underwent cystectomy plus anterior pelvic exenteration.

“While it is reasonable to hypothesize that pCR with PD1/L1 inhibitors translates into prolonged survival (similar to the neoadjuvant chemotherapy setting), validation is required,” Dr. Sonpavde said.

AstraZeneca provided funding for the study. For full disclosures, see bit.ly/abstract507.