Atezolizumab shows ‘meaningful’ efficacy against bladder cancer

CHICAGO — Phase 2 data from the ABACUS trial showed that neoadjuvant atezolizumab therapy was safe and demonstrated a “meaningful” benefit in patients with muscle-invasive bladder cancer who underwent a cystectomy, researchers reported at ASCO.

“These preliminary results are promising,” Thomas Powles, MBBS, MRCP, MD, professor of genitourinary oncology at Barts Cancer Institute of the Queen Mary University of London and director of Barts Cancer Center, said during a presentation. “This is an area of high unmet need.”

Cystectomy is the standard of care for patients with bladder cancer who have T2 to T4a N0 M0 disease, according to Powles. Neoadjuvant cisplatin-based chemotherapy is usually given before the procedure. The treatment is associated with a 30% to 40% pathological complete response (CR) rate. However, many patients are unable to receive neoadjuvant cisplatin-based chemotherapy due to poor renal function, Powles said.

For the ABACUS study, Powles and colleagues examined the safety and efficacy of two cycles of the PD-L1 monoclonal antibody, atezolizumab (Tecentriq, Genentech), in patients with operable muscle-invasive transitional cell carcinoma bladder cancer who were ineligible for cisplatin-based chemotherapy. Atezolizumab was administered 4 to 8 weeks before patients underwent cystectomy.

The phase 2 analysis included data from 74 patients (median age, 73 years) with T2 (73%), T3 (20%) and T4 (7%) disease. The primary endpoints were pathological CR occurring in at least 20% of patients and vigorous changes to immune parameters.

Efficacy data were available for 68 patients, including one who did not undergo cystectomy due to disease progression. Among these patients, the overall pathological CR rate was 29% (95% CI, 19-42), increasing to 40% (95% CI, 21-61) in the PD-L1-positive population. In contrast, pathological CR was 16% (95% CI, 5-34) among PD-L1-negative participants. Pathological CR occurred in 35% of patients with T2 disease and 15% of patients with the more aggressive T3 and T4 diseases.

Drug-related adverse events included fatigue (21%), transaminitis (7%), anorexia (8%), rash (7%), pyrexia (5%), diarrhea (5%) and pruritis (5%). One treatment-related death due to dyspnea was reported.

“The adverse event profile is what one would expect with two cycles of atezolizumab,” Powles said.

Further investigation revealed an upregulation of CD8 expression as well as PD-L1 positivity, which increased from 35% at baseline to 73% posttreatment. Powles said this was a “tantalizing” finding.

“We don’t know the importance of this from an outcome perspective, but it is showing the dynamic biology of the disease and underpinning the mode of action of atezolizumab in bladder cancer,” he said. “More follow-up, particularly in terms of relapsed larger samples, the role of adjuvant-type therapy and other questions require further exploration.”

In May, the FDA issued a safety alert to warn health care providers about an association between decreased survival and atezolizumab or pembrolizumab (Keytruda, Merck) monotherapy among patients with metastatic urothelial cancer and low PD-L1 expression. Interim results from two trials — KEYNOTE-361 and IMVIGOR-130 — showed patients with low PD-L1 who received monotherapy with either agent were less likely to survive than patients who received cisplatin- or carboplatin-based chemotherapy. The FDA said its warning does not apply to other approved indications for pembrolizumab or atezolizumab. – by Stephanie Viguers

Reference:

Powles T, et al. Abstract 4506. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosures: Powles reports receiving honoraria from Bristol-Myers Squibb, Merck and Roche/Genentech; consulting or advisory fees from AstraZeneca, Bristol-Myers Squibb, Merck, Novartis and Roche/Genentech; research funding from AstraZeneca, Roche/Genentech; and other financial ties with Bristol-Myers Squibb and Ipsen.