ODAC Says Yes to Continued Approval of Atezolizumab for Cisplatin-Ineligible Locally Advanced or Metastatic UC

The FDA’s Oncologic Drug Advisory Committee voted 10 to 1 to continue the accelerated approval of atezolizumab for the frontline treatment of patients with urothelial cancer who are ineligible for cisplatin.

The FDA’s Oncologic Drug Advisory Committee voted 10 to 1 to continue the accelerated approval of atezolizumab (Tecentriq) for the frontline treatment of patients with urothelial cancer who are ineligible for cisplatin.1

“In my personal opinion, the positive vote by ODAC to maintain the accelerated approval for both checkpoint inhibitors (pembrolizumab [Keytruda] and atezolizumab) likely reflects the lack of standard of care for unfit patients with chemotherapy-ineligible metastatic bladder cancer. Although it remains unclear if we will ever see a confirmatory trial demonstrating OS benefit to either agent in that particular setting, having the opportunity to receive one of these agents at present time is critically important for those patients in need of treatments outside chemotherapy,” Jorge A. Garcia, MD, FACP, a non-voting ODAC member and chief, Division of Solid Tumor Oncology; interim chief, Divisions of Hematology/Hematologic Malignancies; George and Edith Richman Distinguished Scientist Chair; professor of medicine and urology; and director, GU Oncology Program, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center; told Targeted Oncology in an interview.

In April 2017, atezolizumab was granted accelerated approval for this indication based on the achievement of durable responses in patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma (UC) treated with 1200 mg of the agent in the phase 3 IMvigor210 clinical trial (NCT02108652).

One hundred thirteen patients were dosed with atezolizumab in the IMvigor210 out of 123 patients enrolled. At a median follow-up of 17.2 months, the objective response rate (ORR) observed was 23% (95% CI, 16%-31%), which included complete responses (CRs) in 9% of patients. The median duration of response (DOR) was not reached in the study. Finally, the ORR benefit was seen across the PD-L1 and poor prognostic factor subgroups evaluated in the study.1,2

IMvigor210 also demonstrated favorable survival outcomes and tolerability for patients with cisplatin-ineligible locally advanced or metastatic UC. The median progression-free survival (PFS) observed was 2.7 months (95% CI, 2.1-4.2). The median overall survival (OS) was 15.9 months (95% CI, 10.4 to not estimable).

The tolerability of atezolizumab in the study was determined by the incidence of treatment-related adverse events (TRAEs). The most common TRAEs included fatigue (30%), diarrhea (12%), and pruritus (11%). There was 1 treatment-related death in the study and 9 treatment discontinuations due to TRAEs.

Although IMvigor210 was positive and led an accelerated approval, the FDA required a confirmatory phase 3 trial to continue the approval. To meet the FDA requirement, atezolizumab was further evaluated as treatment of patients with cisplatin-ineligible locally advanced or metastatic UC in the phase 3, multicenter, randomized IMvigor130 trial (NCT02807636).1

Exploring the primary end points of PFS and OS, the IMvigor130 study did in fact show improvement in PFS in the interim analysis, but the OS result did not meet the threshold for statistical significance.

IMvigor130 enrolled 1230 patients who were randomized 1:1:1 to received either atezolizumab plus chemotherapy, atezolizumab alone, or placebo plus chemotherapy. The cohorts were stratified by PD-L1 expression, risk factor score, and choice of platinum-based chemotherapy. Treatment in the study was continued until disease progression or unacceptable toxicity.1,3

The median PFS in the atezolizumab plus chemotherapy arm was 8.2 months (95% CI, 6.5-8.3) versus 6.3 months (95% CI, 6.2-7.0) in the placebo plus chemotherapy arm (HR, 0.82; 95% CI, 0.70-0.96; P = .007). The median OS was 16.1 months (95% CI, 14.2-18.8) in the atezolizumab combination arm compared with 13.4 months (95% CI, 11.9-15.2) in the placebo plus chemotherapy arm (HR, 0.84; 95% CI, 0.71-1.00). The final OS data for the study remain immature.

During the open hearing portions of the ODAC meeting, Sumanta Kumar Pal, MD, explained his reason for supporting continued approval of atezolizumab for the indication in question.

“What we don’t often acknowledge is that when we look a response rate and PFS, we don't acknowledge the fact that amongst those individuals who garner benefit, the benefits [are] very substantial, and I can attest to many patients who have eligible disease receiving doing well for extended durations of time, often measured in years. And I can assure you that this wouldn't be the case with platinum-based chemotherapy,” commented Pal, clinical professor, Department of Medical Oncology & Therapeutics Research and co-director, Kidney Cancer Program, City of Hope.

The FDA proposed the question of whether the indication for atezolizumab for the first-line treatment of cisplatin-ineligible patients with advanced/metastatic UC should be maintained pending final OS results from IMvigor130, considering the fact that the benefit of this agent was not shown in a confirmatory trial, or if it should be verified in the second-line metastatic setting with the indication withdrawn. The FDA also wanted the voting attendees to consider that the adjuvant trial did not meet its primary end point, and that since the initial approval, the treatment landscape has expanded to include another checkpoint inhibitor that can provide OS benefit in the maintenance setting.

Speaking to both the decision on atezolizumab and the FDA vote earlier in the day to continue approval of pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy, Garcia stated: “I believe that both pembrolizumab and atezolizumab continue to meet most of the accelerated approval requirements posted by the FDA. Metastatic bladder cancer is a serious and life-threatening disease; there is long-term safety and clinical efficacy data with these [checkpoint inhibitors]; the end points used on the trials for accelerated approval (ORR and DOR) do predict some degree of clinical benefit over any other available therapeutic options. We certainly await final results from IMvigor130 that could cement the role of atezolizumab for patients with metastatic bladder cancer.”

“Lastly, as newer regimens (monotherapy or combinations) move earlier in the natural history of bladder cancer, it is conceivable that we could change this accelerated approval in the near future. That would mean that we have newer and better agents to offer our patients with metastatic bladder cancer,” Garcia concluded in the interview with Targeted Oncology.


1. April 27-29, 2021: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement. FDA website. Accessed April 28, 2021.

2. 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. doi:10.1016/S0140-6736(16)32455-2

3. Galsky MD, Arija JA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-1557. doi:10.1016/S0140-6736(20)30230-0