FDA approval of bladder cancer drug

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Roche has announced that the US Food and Drug Administration (FDA) has granted accelerated approval to Tecentriq (atezolizumab) for the treatment of people with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-based chemotherapy, or whose disease has worsened within 12 months of receiving platinum-based chemotherapy before surgery (neoadjuvant) or after surgery (adjuvant).

Urothelial carcinoma accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter and urethra.

“Tecentriq is a new medicine that can work with the immune system to treat people with a type of bladder cancer that progressed after platinum-based chemotherapy,” said Dr Sandra Horning, chief medical officer and head of global product development. “We thank the scientists, doctors, patients and their families who made it possible to bring Tecentriq to people with advanced urothelial carcinoma.”

The FDA’s Accelerated Approval Programme allows conditional approval of a medicine that fills an unmet medical need for a serious condition, based on early evidence suggesting clinical benefit. The indication for Tecentriq is approved under accelerated approval based on tumour response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. This approval of Tecentriq is based on the phase II IMvigor 210 study.

Roche is also evaluating Tecentriq in a confirmatory phase III study (IMvigor 211), which compares Tecentriq to chemotherapy in people whose bladder cancer has progressed on at least one prior platinum-containing regimen. IMvigor 210 is an open-label, multicentre, two-cohort Phase II study that evaluated the safety and efficacy of Tecentriq in people with locally advanced or mUC, regardless of PD-L1 expression. People in a cohort of the study whose disease had progressed during or following previous treatment with a platinum-based chemotherapy regimen, or who had disease progression within 12 months of treatment with a platinum-based neoadjuvant or adjuvant chemotherapy regimen (n=310) received a 1200-mg intravenous dose of Tecentriq on day one of 21-day cycles until unacceptable toxicity or either radiographic or clinical progression. The primary endpoint of the study was objective response rate (ORR) as assessed by an independent review facility (IRF) using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Secondary endpoints included duration of response (DOR). A summary of the efficacy and safety data from the IMvigor 210 study that supports this accelerated approval is included below. The median follow-up time for this cohort was 14.4 months.

In a subset of people in the IMvigor 210 study with disease progression following neoadjuvant or adjuvant platinum-containing therapy (n=59), Tecentriq shrank tumours (ORR) in 22.0% (95% CI: 12.3, 34.7) of people. The most common Grade 3-4 adverse reactions (≥ 2%) were: urinary tract infection (9$), anaemia (8%), fatigue (6%), dehydration, intestinal obstruction (partial or complete blockage of the bowel), urinary obstruction, haematuria (blood in the urine; 3%), dyspnea (difficulty breathing; 4%), acute kidney injury, abdominal pain (pain in stomach area; 4%), venous thromboembolism (blood clots in the vein), sepsis (blood infection) and pneumonia (lung infection). Three people (0.9%) experienced either sepsis, pneumonitis (lung problems) or intestinal obstruction, which led to death. Tecentriq was discontinued for adverse reactions in 3.2% (10) of the 310 patients.

Background: The ORR and survival of mUC patients (pts) who progress after platinum-based chemotherapy (pctx) are poor. Atezolizumab (atezo) reinvigorates antitumor immunity by targeting PD-L1 and has shown promising Ph 1 activity in mUC.
Methods: IMvigor 210 cohort 2 (NCT02108652) enrolled 316 mUC pts who progressed during or following pctx. Pts received atezo at 1200 mg IV q3w until loss of clinical benefit. The SP142 IHC assay centrally assessed PD-L1 expression. Pts/investigators were blinded to PD-L1 status. Co-primary endpoints were confirmed ORR by RECIST v1.1 per central review (IRF) and modified (m) RECIST per investigator, which were met if null hypothesis (ORR = 10%) was rejected (α = 5%). ORR endpoints were stratified by PD-L1 tumor-infiltrating immune cell (IC) status: IC2/3, IC1/2/3, all comers.
Results: Efficacy/safety-evaluable pts (N = 311) had a median age of 66 y, CrCl < 60 mL/min (35%) and ≥ 2 prior regimens for mUC (40%). Many had poor prognostic factors (Table). At 5/5/15 data cutoff (follow up ≥ 24 w), 43/47 responding pts had ongoing responses. Both IRF (Table) and mRECIST ORR correlated with IC status. Durable responses were seen including poor prognostic subgroups (Table). mDOR was not reached in any PD-L1 or prognostic subgroup. mPFS was 2.1 mo in all PD-L1 subgroups. Median treatment duration was 12 w (range 0-46). Treatment-related AEs (most commonly fatigue) occurred in 66% of pts (all Grade); 15% had G3-4 related AE and 4% had G3-4 immune-mediated AE. 27% of AEs led to dose interruption and 3% led to withdrawal. No renal toxicity was seen.
Conclusions: IMvigor 210, the first Ph 2 study targeting PD-L1/PD-1 in mUC, demonstrated significantly improved ORR vs historic controls. Responses were durable and associated with higher PD-L1 IC expression; poor prognostic factors did not preclude response. Atezo was well tolerated, and a randomized Ph 3 study vs ctx is ongoing (IMvigor 211; NCT02302807).

Jean H. Hoffman-Censits, Petros Grivas, Michiel Simon Van Der Heijden, Robert Dreicer, Yohann Loriot, Margitta Retz, Nicholas J. Vogelzang, Jose Luis Perez-Gracia, Arash Rezazadeh, Sergio Bracarda, Evan Y. Yu, Christopher J. Hoimes, Joaquim Bellmunt, David I. Quinn, Daniel Peter Petrylak, Syed A. Hussain, Na Cui, Sanjeev Mariathasan, Oyewale O. Abidoye, Jonathan E. Rosenberg; The Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; University of Virginia School of Medicine, Charlottesville, VA; Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, Villejuif, France; Department of Urology, Klinikum rechts der Isar, TU München, Munich, Germany; US Oncology Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain; Norton Cancer Inst, Louisville, KY; Medical Oncology, Ospedale San Donato USL8, Istituto Toscano Tumori, Arezzo, Italy; University of Washington, Seattle Cancer Care Alliance, Seattle, WA; Case – Seidman Cancer Ctr, Cleveland, OH; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; USC Norris Comprehensive Cancer Center, Los Angeles, CA; Yale Cancer Center, New Haven, CT; University of Liverpool, Clatterbridge Cancer Centre, Liverpool, United Kingdom; Genentech, Inc., South San Francisco, CA; Genentech, San Francisco, CA; Memorial Sloan Kettering Cancer Center, New York, NY

Roche material
Phase II IMvigor 210 study abstract

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