In a 10 to 1 vote, the FDA’s Oncologic Drugs Advisory Committee voted to support the accelerated approval of atezolizumab for the frontline treatment of patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma.
In a 10 to 1 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted to support the accelerated approval of atezolizumab (Tecentriq) for the frontline treatment of patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma.
“Today’s positive vote reaffirms that [atezolizumab] fills a significant unmet need for people with previously untreated metastatic bladder cancer, many of whom cannot tolerate standard of care chemotherapy and need additional options,” said Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, the developer of atezolizumab. “Having now received positive ODAC recommendations in both bladder cancer and triple-negative breast cancer, we will continue to work with the FDA on next steps for [atezolizumab] in these indications.”
“We believe that the accelerated approval should be maintained while we await the final read out for the IMvigor130 trial,” said Charles Fuchs, MD, senior vice president and global head of oncology and hematology drug development at Genentech, during the hearing.
The meeting roster comprised ODAC members, Susan Halabi, PhD; Philip C. Hoffman, MD; Christopher H. Lieu, MD; David E. Mitchell, and Anthony D. Sung, MD; as well as temporary voting members Andrea B. Apolo, MD; Julie N. Graff, MD; Colette Johnston; Ravi Madan, MD; Matthew Rettig, MD; and Mohummad M. Siddiqui, MD, FACS.
Voting members Susan Halabi, PhD; Christopher H. Lieu, MD; David E. Mitchell; Anthony D. Sung, MD; Andrea B. Apolo, MD; Julie N. Graff, MD; Colette Johnston; Ravi Madan, MD; Matthew Rettig, MD; Mohummad M. Siddiqui, MD, FACS, voted for the continued accelerated approval of atezolizumab.
In explaining his decision, Madan said, “I voted yes to wait for the final results. I’m optimistic that the data will continue to support the best care for our patients with bladder cancer.”
Siddiqui added, “I voted yes as well. The interim analysis of the primary overall survival outcome of the IMvigor130 trial looks promising, so I felt it was very reasonable to wait until the final analysis comes out.”
Non-voting members included acting designated federal officer of ODAC Joyce Yu, PharmD, acting industry representative to the committee; Albert L. Kraus, PhD; and FDA participants Richard Pazdur, MD; Julia Beaver, MD; and Laleh Amiri-Kordestani, MD.
The meeting represents the second day of a 3-day public review of 6 indications for checkpoint inhibitors granted under the agency’s accelerated approval process that later failed to reach thresholds for statistical significance for key end points in confirmatory clinical trials.
With regard to atezolizumab, the PD-L1 inhibitor demonstrated an objective response rate of 23.5% in the intention-to-treat population and 28.1% in the PD-L1–high population of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma enrolled in cohort 1 of the phase 2 IMvigor210 trial. The median duration of response was 59.1 months.
Primary findings from cohort 1 of the trial served as the basis for the April 2017 accelerated approval of the agent for the frontline treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
Based on findings from cohort 2 of the IMvigor210 trial, in May 2016, atezolizumab received an accelerated approval as a treatment for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.
The continued approval of the agent was contingent on positive data from the phase 3 IMvigor211 trial. However, atezolizumab missed the trial’s primary end point of improved overall survival (OS) in the second-line treatment of patients with locally advanced or metastatic urothelial carcinoma who had high PD-L1 expression, leading to Roche’s voluntary withdrawal of the agent from the US market in the second-line setting.
Despite the withdrawal, the FDA expressed concern that not only did the phase 3 IMvigor211 not meet the primary end point of the study, but that the phase 3 IMvigor010 trial also failed to reach its primary end point of improved disease-free survival with atezolizumab as adjuvant therapy.
In June 2018, the FDA incorporated PD-L1 status into the label for atezolizumab for the existing frontline approval for cisplatin-ineligible patients with urothelial carcinoma, based on lower OS with the PD-L1 inhibitor compared with platinum-based chemotherapy for patients with PD-L1–low expressing platinum-eligible urothelial carcinoma.
Specifically, the label was restricted to cisplatin-ineligible patients with PD-L1 expression on immune cells (IC) of at least 5%. However, the label remained broad for patients who are ineligible for any platinum-based agent, unconstrained by PD-L1 status.
The FDA decision was based on an assessment conducted by a data monitoring committee for the confirmatory phase 3 IMvigor130 study, which evaluated atezolizumab alone, atezolizumab plus chemotherapy, and chemotherapy alone as frontline therapy in patients with platinum-eligible locally advanced or metastatic urothelial carcinoma.
Primary findings from the study demonstrated a median progression-free survival of 8.2 months in the atezolizumab/chemotherapy arm vs 6.3 months in the placebo/chemotherapy arm (HR, 0.82; 95% CI, 0.70-0.96; P = .007). The median OS was 16.1 months and 13.4 months, respectively (HR, 0.84; 95% CI, 0.71-1.00), failing to demonstrate significance.
The final analysis of the IMvigor130 trial is expected by the third quarter of 2022.
According to statistical design, if the final OS analysis comparing the atezolizumab plus chemotherapy and placebo plus chemotherapy arms is positive, a hierarchical OS analysis comparing the atezolizumab alone and placebo plus chemotherapy arms in the intention-to-treat and PD-L1–high populations will be performed, respectively.
If the final OS analysis of the atezolizumab/chemotherapy and placebo/chemotherapy arms is positive, atezolizumab will be granted full approval as monotherapy and in combination with chemotherapy as frontline treatment for patients with locally advanced or metastatic urothelial carcinoma, according to the FDA.
Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. April 28, 2021. Accessed April 28, 2021. https://collaboration.fda.gov/ODAC04282021?disclaimer-consent=true&proto=true.