FDA approves new, targeted treatment for bladder cancer.

May 18, 2016

tecentiqThe U.S. Food and Drug Administration approved Tecentriq (atezolizumab) to treat the most common type of bladder cancer, called urothelial carcinoma.

This is the first product in its class (PD-1/PD-L1 inhibitors) approved to treat this type of cancer.

CLINICAL PHARMACOLOGY

MECHANISM OF ACTION

  • Programmed death-ligand 1 (PD-L1; also B7-H1, CD274) is expressed on both tumor cells (TCs) and tumor-infiltrating immune cells (ICs) in the tumor microenvironment.
  • PD-L1 negatively regulates T-cell proliferation and function by binding to its receptors, programmed death-1 (PD-1) and B7. on activated T lymphocytes and other immune cells, which allows tumors to evade immune surveillance and eradication.
  • PD-L1 expression is associated with a worse prognosis in RCC.
  • Atezolizumab (also known as MPDL3280A; anti-PDL1) is an investigational monoclonal antibody designed to bind with a protein called programmed death ligand-1 (PD-L1).
  • Atezolizumab is designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with PD-1 and B7.1 receptors.
  • By inhibiting PD-L1, atezolizumab may enable the activation of T cells. Atezolizumab may also affect normal cells.
  • While patients who received Tecentriq experienced a tumor response across the study, the greater effect in those who were classified as “positive” for PD-L1 expression suggests that the level of PD-L1 expression in tumor-infiltrating immune cells may help identify patients who are more likely to respond to treatment with Tecentriq.

Therefore, the FDA also approved the Ventana PD-L1 (SP142) assay to detect PD-L1 protein expression levels on patients’ tumor-infiltrating immune cells and help physicians determine which patients may benefit most from treatment with Tecentriq.

INDICATIONS AND USAGE

TECENTRIQ is a programmed death-ligand 1 (PD-L1) blocking antibody indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:
•Have disease progression during or following platinum-containing chemotherapy
•Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

WARNINGS AND PRECAUTIONS

  • Immune-Related Pneumonitis: Withhold for moderate and permanently discontinue for severe or life-threatening pneumonitis.
  • Immune-Related Hepatitis: Monitor for changes in liver function. Withhold for moderate and permanently discontinue for severe or lifethreatening transaminase or total bilirubin elevation.
  • Immune-Related Colitis: Withhold for moderate or severe, and permanently discontinue for life-threatening colitis.
  • Immune-Related Endocrinopathies 
    • Hypophysitis: Withhold for moderate or severe and permanently discontinue for life-threatening hypophysitis.
    • Thyroid Disorders: Monitor for changes in thyroid function. Withhold for symptomatic thyroid disease.
    • Adrenal Insufficiency: Withhold for symptomatic adrenal insufficiency.
    • Type 1 Diabetes Mellitus: Withhold for ≥ Grade 3 hyperglycemia.
  • Immune-Related Myasthenic Syndrome/Myasthenia Gravis, GuillainBarré or Meningoencephalitis: Permanently discontinue for any grade.
  • Ocular Inflammatory Toxicity: Withhold for moderate and permanently discontinue for severe ocular inflammatory toxicity
  • Immune-Related Pancreatitis: Withhold for moderate or severe, and permanently discontinue for life-threatening pancreatitis, or any grade of recurring pancreatitis.
  • Infection: Withhold for severe or life-threatening infection.
  • Infusion Reaction: Interrupt or slow the rate of infusion for mild or moderate infusion reactions and discontinue for severe or lifethreatening infusion reactions.
  • Embryo-Fetal Toxicity: TECENTRIQ can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception.

SAFETY & EFFICACY

Clinical Data From the Mvigor 210 Trial

  • The FDA approval was based on the results of the Mvigor 210 trial, an open-label, multicenter, phase 2 study that evaluated the safety and efficacy of atezolizumab in 310 patients with locally advanced or metastatic urothelial carcinoma, regardless of PD-L1 expression.
  • All patients received a 1200-mg intravenous dose of the agent on day 1 of 21-day cycles until unacceptable toxicity or either radiographic or clinical progression occurred.
  • The primary endpoint of the study was objective response rate (ORR); the median follow-up period for this cohort was 14.4 months.
  • The ORR was 26% for the subgroup with the highest positivity for PD-L1, 18% for the subgroup with lower positivity, and 15% for all patients.
  •  Complete responses were seen in up to 11% of patients in the highest-positivity subgroup and in 5% of all patients. Responses were durable. The median duration of response (range, 2.1, 13.8+ months) was not reached in the cohort as a whole or in the high-positivity group (4.2, 13.8+).
  • For those in the lower-positivity group, the median duration of response of 12.7 months.
  • Median progression-free survival was 2.1 months for all patients. At 6 months, it was 30% in the highest-positivity subgroup, 17% in the lower-positivity subgroup, and 21% in the subgroup with no/minimal PD-L1 expression.
  •  Median overall survival was 7.9 months for all patients, 11.4 months for the highest-positivity subgroup, and 6.7 months for the lowest-positivity subgroup. Twelve-month overall survival was 36% for all patients, 48% for the high group, and 30% for the low group.

Adverse Effects

  • The most common side effects of treatment with Tencentriq were fatigue, decreased appetite, nausea, urinary tract infection, fever (pyrexia) and constipation.
  • Tencentriq also has the potential to cause infection and serious side effects that result from the immune system effect of Tencentriq (known as “immune-mediated side effects”).
  • These severe immune-mediated side effects involve healthy organs, including the lung, colon and endocrine system.

The FDA granted the Tecentriq application breakthrough therapy designation,priority review status and accelerated approval for this indication. 

Tecentriq is marketed by Genentech based in San Francisco, California. The Ventana PD-L1 (SP142) assay complementary diagnostic for Tecentriq is marketed by Ventana Medical Systems, based in Tucson, Arizona.

Reference:

FDA News