Atezolizumab shows promise for advanced, metastatic urothelial cancer

Atezolizumab demonstrated efficacy and tolerability for patients with advanced and metastatic urothelial cancer who progressed following platinum-based chemotherapy, according to the results of a single-arm, phase 2 study.

Increased programmed death ligand 1 (PD-L1) expression levels on immune cells appeared associated with increased patient response, results showed.

Few treatment options exist for patients with urothelial cancer who experience failure after treatment with platinum chemotherapy, according to study background. However, studies have suggested that immune checkpoint inhibitors are more active in tumors with high mutation rates, and data from The Cancer Genome Atlas suggests urothelial carcinoma has the third highest mutation rate of studied cancers.

Jonathan E. Rosenberg, MD, Enno W. Ercklentz Chair of genitourinary oncology service at Memorial Sloan Kettering Cancer Center, and colleagues evaluated the efficacy of atezolizumab (MPDL3280A, Genentech/Roche) — a monoclonal antibody that selectively binds to PD-L1 — among patients with metastatic and advanced urothelial cancer.

The analysis included data from 310 patients (median age, 66 years; range, 32-91) who received 1,200 mg of IV atezolizumab every 3 weeks.

Objective response rate (ORR) by RECIST criteria — assessed by independent review and the investigators — served as the primary endpoint.

The researchers measured PD-L1 expression on tumor-infiltrating immune cells by immunohistochemistry and defined expression status in the tumor microenvironment by the percentage of PD-L1–positive immune cells as IC0 (< 1%), IC1 ( 1% but < 5%) or IC2/3 ( 5%).

Compared with a historical control ORR of 10%, atezolizumab significantly increased ORR for each prespecified subgroup (IC2/3: 27%; 95% CI, 19-37; IC1/2/3: 18%; 95% CI, 13-24), as well as for the entire cohort (15%; 95% CI, 11-20).

The independent review confirmed an ORR for the entire cohort of 15% (95% CI, 11-19). The independently reviewed ORR was 26% (95% CI, 18-36) for patients in the IC2/3 group and 18% (95% CI, 13-24) in the IC1/2/3 group.

After a median follow-up of 11.7 months (95% CI, 11.4-12.2), ongoing responses continued in 84% (n = 38 of 45) of responding patients.

The median time to response was 2.1 months (95% CI, 2-2.2). Median duration of response had not been reached at the time of reporting (range, 2-13.7).

Median PFS in all patients was 2.1 months (95% CI, 2.1-2.1) and median OS was 7.9 months (95% CI, 6.6-9.3).

Exploratory analyses showed The Cancer Genome Atlas subtypes (luminal vs. basal) and mutation load independently predicted atezolizumab response. A significantly greater proportion of patients with the luminal cluster II subtype responded to treatment (34%) than patients with other subtypes (subtype I, 10%; subtype III, 16%; subtype IV, 20%; P = .0017). Further, responding patients had a significantly greater mutation load (12.4 per megabase vs. 6.4 per megabase; P .0001).

Sixteen percent of patients (n = 50) experienced grade 3 or grade 4 treatment-related adverse events, including fatigue (n = 5), anemia (n = 3), hypertension (n = 3) and decreased appetite (n = 2).

Five percent of patients (n = 15) experienced grade 3 or grade 4 immune-mediated adverse events, including pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash and dyspnea.

No treatment-related deaths occurred.

“In conclusion, we report that targeting PD-L1 with atezolizumab is effective in heavily pretreated patients with locally advanced or metastatic urothelial cancer, and that responses are more common in patients with higher levels of PD-L1 expression on immune cells than in those with lower expression,” Rosenberg and colleagues wrote. “The efficacy seems to be driven by underlying genomic, molecular and immunological factors.”

Although these study results are encouraging, more research is required to maximize the potential for immune checkpoint inhibition in this patient population, George J. Netto, MD, professor of pathology, urology and oncology and director of surgical pathology molecular diagnostics at Johns Hopkins School of Medicine, wrote in an accompanying editorial.

“Although Rosenberg and colleagues’ findings are encouraging, especially in the subset of patients with higher immune cell PD-L1 expression levels, the fact that in the overall cohort the improvement in overall response remained incremental (15% compared with the 10% historical control rate) and the median OS was a modest 7.9 months highlights the importance of future efforts to identify, validate and standardize biomarkers of response,” Netto wrote.

“Existing assessment of immunohistochemistry-based immune checkpoint biomarkers suffers from substantial variability in antibody performance characteristics and cutoff points among assays using different anti–PD-L1 antibodies,” Netto continued. “The findings by Rosenberg and colleagues can soon be contrasted with those of several ongoing phase 3 trials assessing the OS benefit of anti–PD-L1 and other immune checkpoint inhibitors compared with chemotherapy and pembrolizumab [Keytruda, Merck].” – by Cameron Kelsall

Disclosure: Genentech/Roche funded this study. Rosenberg reports nonfinancial support from Genentech/Roche, as well as consultant fees from Agensys, Eli Lilly, Oncogenex and Sanofi. Please see the full study for a list of all other researchers’ relevant financial disclosures. Netto reports no relevant financial disclosures.