Atezolizumab Misses Primary Endpoint in Phase III Bladder Cancer Trial

Sandra Horning, MD

Sandra Horning, MD

Atezolizumab failed to meet the primary endpoint of improving overall survival in the second-line setting for patients with locally advanced or metastatic urothelial carcinoma (mUC) in the phase III IMvigor211 trial, according to Genentech, the manufacturer of the PD-L1 inhibitor.

The IMvigor211 study was intended to confirm the findings of the phase II IMvigor210 study, on which the FDA based its May 2016 accelerated approval of atezolizumab as a treatment for patients with locally advanced or mUC whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.

Last month, atezolizumab received a second accelerated approval in bladder cancer, this time as a frontline treatment for cisplatin-ineligible patients with locally advanced or mUC. This indication was based on a different cohort from the IMvigor210 study than the initial second-line approval. The ongoing phase IMvigor130 study (NCT02807636) in this population is intended to support this accelerated approval.

The news of the phase III IMvigor211 findings comes amid second-line bladder cancer approvals this month of 2 other PD-L1 inhibitors, avelumab and durvalumab.

“While these results are not what we had expected, we believe that Tecentriq will continue to play an important role in the treatment of people with advanced bladder cancer,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a statement. “We are committed to helping people with advanced bladder cancer and will discuss these data with health authorities.”

The phase III IMvigor211 study included 931 patients with previously treated mUC who progressed during or following a platinum-based regimen. Patients were randomized to atezolizumab or investigator’s choice of chemotherapy, which included vinflunine, paclitaxel, or docetaxel. Treatment in both arms was administered every 3 weeks. Patients were required to have an ECOG performance status of 0 or 1 and evaluable tumor samples for PD-L1 testing. Genentech reported in a statement that full results from the study will be presented at some point this year.

The IMvigor 210 cohort on which the accelerated approval of second-line atezolizumab was based included an all-comer population of 316 patients with inoperable locally advanced or mUC who progressed after receiving platinum-based chemotherapy.¹Data from 310 patients were evaluable. The patients had been heavily pretreated, with 40% of patients undergoing 2 or more prior systemic regimens in the metastatic setting and 74% of patients receiving previous cisplatin-based chemotherapy.

At a median follow-up of 14.4 months, the overall response rate (ORR) was 14.8% (95% CI, 11.1-19.3; n = 46/310) in all comers, 26% (95% CI, 17.7-35.7; n = 26/100) in patients with PD-L1 expression &ge;5%, and 9.5% (95% CI, 5.9-14.3; n = 20/210) in those with PD-L1 expression <5%. In a subgroup of 59 patients from the IMvigor 210 study who progressed after neoadjuvant or adjuvant platinum-based chemotherapy, the ORR was 22% (95% CI, 12.3-34.7).

Complete response (CR) rates in the overall, higher—PD-L1, and lower&ndash;PD-L1 groups were 5.5%, 12%, and 2.4%, respectively. Partial response rates were 9.4%, 14%, and 7.1%, respectively. The median duration of response was 12.7 months (range, 2.1+ to 12.7) in the lower PD-L1 population, and had not yet been reached in either the overall group or the higher PD-L1 cohort.

The accelerated approval of atezolizumab as a frontline treatment was based on a separate IMvigor 210 cohort of 119 cisplatin-ineligible patients with locally advanced or mUC.²The ORR with atezolizumab was 23.5% (n = 28; 95% CI, 16.2-32.2), including a CR rate of 6.7%. There was an association between tumor mutation load and response.

The median progression-free survival and OS were 2.7 months (95% CI, 2.1-4.2) and 15.9 months (95% CI, 10.4 to not estimable), respectively. The median duration of response was not yet reached. Among patients with PD-L1 expression &ge;5% (n = 32), the ORR was 28.1% (95% CI, 13.8-46.8), including a CR rate of 6.3%. In patients with PD-L1 expression <5%, the corresponding rates were 21.8% (95% CI, 13.7-32.0) and 6.9%, respectively.

References:

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 (mUC).J Clin Oncol34, 2016 (suppl 2S; abstr 355).
2. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.Lancet.2017;389(10064):67-76.