Atezolizumab in Urothelial Cancer: Ushering in a New Standard of Care


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Jean Hoffman-Censits, MD

It is a challenge to treat patients who have progressed on platinum. Atezolizumab has the potential to change the standard of care for metastatic urothelial cancer.

—Jean Hoffman-Censits, MD

Atezolizumab achieved excellent results in a cohort of patients with platinum-resistant urothelial cancer enrolled in a large phase II trial known as IMvigor 210.1 Overall response rates were greatly improved over those with historical controls, and responses were durable. Although expression of the programmed cell death ligand 1 (PD-L1) was correlated with the magnitude of response, responses were observed in patients with very low levels of PD-L1 expression. These results are particularly encouraging, because patients who progress on platinum therapy have no treatment options with overall survival benefit.

“It is a challenge to treat patients who have progressed on platinum. This group of patients desperately needs new treatments,” said lead investigator Jean Hoffman-Censits, MD, of The Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, who presented these findings at the 2016 Genitourinary Cancers Symposium.

“Atezolizumab has the potential to change the standard of care for metastatic urothelial cancer. Response rates are higher than the 10% seen with historical controls in second-line trials. Higher PD-L1 status was associated with higher overall response rate, but low PD-L1 expression did not preclude response. Median duration of response has not been reached in any predefined PD-L1 or poor prognostic subgroup,” she stated.

Study Details

IMvigor 210 was a multicenter, open-label, single-arm phase II study conducted at 70 centers in Europe and North America. The study was designed to evaluate the safety and efficacy of atezolizumab (an anti–PD-L1 monoclonal antibody designed to put the brakes on PD-L1) in patients with locally advanced or metastatic urothelial cancer. All comers were enrolled on the trial, and PD-L1 testing on tumor-infiltrating immune cells was performed during screening. Patients and investigators were blinded to these results.

There were two cohorts of patients: Cohort 1 included patients who were platinum ineligible, and cohort 2 included patients with disease progression during or following previous treatment with platinum-based chemotherapy. Results from the primary analysis were presented at the 2015 European Cancer Congress. The data from the 2016 Genitourinary Cancers Symposium represent an updated analysis of cohort 2, and data for cohort 1 will be presented at a later date.

Of the 486 patients screened, 310 received treatment with atezolizumab at 1,200 mg intravenously every 3 weeks until loss of benefit, as determined by investigator.

PD-L1 expression was evaluated using the Ventana SP142 assay, with stratification of endpoints by PD-L1 tumor-infiltrating immune cell (IC) status. A score of IC 2/3 was considered medium-to-high PD-L1 expression, whereas a score of IC 0/1 was considered low PD-L1 expression.

Median age of patients was 66 years, and 78% were male. Almost three-quarters of the patients had bladder cancer, and more than 40% were treated with third-line and beyond.

Response Rates

“Higher overall response rate was reported with higher PD-L1 expression, but responses were seen at all levels. Surprisingly, complete responses were seen, which is not typical for this group of patients,” Dr. Hoffman-Censits told listeners.

Overall response rate was 26% in IC 2/3 patients and 18% in patients with any expression of PD-L1; overall response rate was 15% in all patients in an intent-to-treat analysis. Complete response was observed in 11%, 6%, and 5%, respectively.

“These response tables give us a partial picture of response to atezolizumab,” she continued. “Waterfall plots show a reduction in tumor burden associated with IC status.” In IC 2/3 patients, 61% achieved reduction in tumor burden, compared with 45% in the IC 1 patients and 30% in IC 0 patients.

Responses were durable. Median duration of response was not yet reached in any subgroup of PD-L1 expression or poor prognostic patients. “Eighty-four percent of responding patients were still in response at data cutoff of 11.7 months,” stated Dr. Hoffman-Censits.

In a subgroup analysis, the most heavily pretreated patients who had four or more lines of previous therapy (comprising 10% of the entire cohort), overall response rate was 20% in IC 2/3 patients, with a complete response of 10%; in all patients in this subgroup, overall response rate was 8%, and the complete response rate was 4%.

Practice-Changing Results From IMvigor 210 Trial?

■ Atezolizumab had encouraging response rates and durability of response in advanced metastatic urothelial cancers that progressed on prior platinumbased therapy, primarily bladder cancer, and represents a possibly new treatment paradigm in advanced urothelial cancer. ■ Responses were durable and were seen at any level of PD-L1 expression as well as in very poor prognosis subgroups.■ Phase III trials are ongoing with this agent in metastatic urothelial cancer.

Survival and Toxicity

Progression-free survival was similar at all levels of PD-L1 expression, about 2.2 months. Median overall survival, presented for the first time at the 2016 Genitourinary Cancers Symposium, was 11.4 months for IC 2/3 patients, 6.7 months for IC 0/1 patients, and 7.9 months for all patients. Twelve-month overall survival was 48%, 30%, and 36%, respectively.

“Median overall survival appears longer in patients with higher PD-L1 status,” she commented.

Atezolizumab was well tolerated; 97% of patients experienced any grade adverse event; 11% experienced serious treatment-related adverse events. Fatigue is the most commonly reported adverse event. Five percent of patients had a grade 3 or 4 immune-related event. ■

Disclosure: The study was sponsored by F. Hoffman-La Roche Ltd. Dr. Hoffman-Censits has received honoraria from and consulted for Roche/Genentech and received research funding from Sanofi.

Reference

  1. Hoffman-Censits JH, Grivas P, Van Der Heijden MS, et al: IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma. 2016 Genitourinary Cancers Symposium. Abstract 355. Presented January 8, 2016.

 


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