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Roche has withdrawn atezolizumab from the US market for the treatment of patients with metastatic urothelial carcinoma who had previously received platinum-based therapy.
Roche has withdrawn atezolizumab (Tecentriq) from the US market for the treatment of patients with metastatic urothelial carcinoma who had previously received platinum-based therapy, according to announcement from the pharmaceutical company.1
In May 2016, the FDA granted an accelerated approval of atezolizumab for use in patients with locally advanced or metastatic urothelial carcinoma whose disease had progressed during, or after, platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.
The regulatory decision was based on data from the phase 2 IMvigor210 trial (NCT02302807), in which the PD-L1 inhibitor elicited an overall response rate (ORR) of 14.8% (95% CI, 11.1-19.3; n = 46/310) in patients with locally advanced or metastatic urothelial carcinoma, irrespective of PD-L1 expression.2 However, the ORR was even higher in those with a PD-L1 expression of 5% or higher, at 26% (95% CI, 17.7-35.7; n = 26/100).
The continued approval of the agent was contingent on positive data from the phase 3 IMvigor211 trial (NCT02302807). However, atezolizumab missed the trial’s primary end point of improving overall survival (OS) in the second-line treatment of patients with locally advanced or metastatic urothelial carcinoma who had high PD-L1 expression.3
The regulatory agency subsequently designated the phase 3 IMvigor130 trial (NCT02807636) as the post-marketing requirement. Although the trial will continue on to the final analysis, Roche is voluntarily withdrawing the indication in recognition of the principles of the Accelerated Approval Program, as the treatment landscape in the second-line setting has rapidly evolved with the emergence of new therapeutic options.
“The Accelerated Approval Program allows people with difficult-to-treat cancers to receive certain new therapies earlier,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, stated in a press release. “While the withdrawal of [atezolizumab] for prior-platinum treated bladder cancer is disappointing, [atezolizumab] continues to demonstrate benefits across multiple cancer types and therefore remains a meaningful treatment option for many patients.”
The IMVigor210 enrolled a total of 316 patients with inoperable locally advanced or metastatic urothelial carcinoma. Among 310 patients for whom data were available, the mean patient age was 66 years, the majority (78%) were male, and more than half (62%) of patients had an ECOG performance status of 1. Seventy-five percent of patients had the bladder as their primary tumor site. Metastasis to viscera was reported in 78% of patients and to the liver in 31% of patients.
All participants had progressed during or after platinum-based chemotherapy. The population was heavily pretreated, with 40% of patients having undergone 2 or more previous systemic regimens in the metastatic setting and 74% having previously received cisplatin-based chemotherapy.
In the trial, patients received the PD-L1 inhibitor at an intravenous dose of 1200 mg on the first day of each 21-day cycle until no further clinical benefit was observed. The median treatment duration was 12 weeks.
The co-primary end points of the trial included ORR per central review and investigator assessment as well as in accordance with RECIST v1.1 criteria. Key secondary end points comprised duration of response (DOR), progression-free survival (PFS), OS, and safety.
Additional results showed that in patients with a PD-L1 expression of less than 5%, the ORR was 9.5% (95% CI, 5.9-14.3; n = 20/210). In 59 patients who had progressed on neoadjuvant or adjuvant platinum-based chemotherapy, the ORR was 22% (95% CI, 12.3-34.7). The median DOR was 12.7 months (range, 2.1+ to 12.7) in the patients who had a high PD-L1 expression; it had not yet been reached in the overall study population and those with a lower PD-L1 expression.
The IMvigor211 trial included 931 patients with previously treated metastatic urothelial carcinoma who progressed during or following a platinum-based regimen. Here, patients were randomized to receive either atezolizumab or investigator’s choice of chemotherapy, which comprised either vinflunine, paclitaxel, or docetaxel. Treatment was given every 3 weeks in both arms. To be eligible for enrollment, patient had to have an ECOG performance status of either 0 or 1 and evaluable tumor samples for PD-L1 testing.
In April 2017, the FDA granted an accelerated approval to atezolizumab for use as a frontline treatment for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma based on data from the phase 2 IMvigor210 trial. In a cohort of 119 cisplatin-ineligible, treatment-naïve patients, the ORR with the agent was 23.5% (95% CI, 16.2-32.2; n = 28), which included a complete response (CR) rate of 6.7%.4
Of 123 patients, 119 received at least 1 dose of atezolizumab. The median PFS was 2.7 months (95% CI, 2.1-4.2), while the median OS was 15.9 months (95% CI, 10.4–not estimable). The median DOR had not yet been reached. In the 32 patients with PD-L1 expression of 5% or higher, the ORR was 28.1% (95% CI, 13.8-46.8%), which included a CR rate of 6.3%. In those with a PD-L1 expression of less than 5%, the ORR was slightly lower, at 21.8% (95% CI, 13.7-32.0), with a 6.9% CR rate.
Lastly, data from IMvigor130 showed that the addition of atezolizumab to platinum-based chemotherapy resulted in a significant improvement in PFS in patients with previously treated, locally advanced or metastatic urothelial carcinoma.5 A positive trend in OS was also noted at the interim analysis. No new safety signals were reported with the combination vs historical data.