Summary Basis of Decision for Tecentriq

Clinical Pharmacology

Atezolizumab, the medicinal ingredient in Tecentriq, is an Fc-engineered humanized immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to PD-L1 protein and blocks interactions with the PD-1 and B7.1 receptors, releasing PD-L1/PD-1 pathway-mediated inhibition of the immune response, resulting in reactivation of the anti-tumour immune response.

The clinical pharmacology was characterized in one study in patients with urothelial carcinoma. The study was a Phase I dose-escalation study of the safety and pharmacokinetics (PK) of atezolizumab administered via intravenous infusion. The study also enrolled patients with various tumour types including ovarian, gastric, colorectal, head and neck, melanoma, triple-negative breast cancer, clear cell renal cell cancer, and non-small cell lung cancer. Based on these data, two population PK reports were generated to further characterize the clinical pharmacology of atezolizumab in urothelial carcinoma patients.

The reported PK parameters were generated based on the data from all patients enrolled as of the clinical data cut-off. The non-compartmental analysis of serum concentrations from 473 PK-evaluable patients, across a variety of tumour types, suggested that atezolizumab PK is linear in the dose range of 1-20 mg/kg. The observed increases in systemic exposure were dose-proportional and there were no significant changes in clearance or elimination half-life with increasing dose.

Population PK analyses based on 423/429 (98.6%) urothelial carcinoma patients enrolled in the pivotal efficacy study IMvigor210, and treated with 1,200 mg atezolizumab every 3 weeks, suggested that none of gender, body weight, serum albumin, tumour burden, nor the presence of anti-therapeutic antibodies, affected individual PK parameters in a clinically meaningful way.

Exposure-response analyses indicated that steady-state exposure of atezolizumab administered as 1,200 mg every 3 weeks is not a significant predictor of either the probability of response or the probability of suffering an adverse event.

Overall, the clinical pharmacology of Tecentriq has been sufficiently characterized in patients with locally advanced or metastatic urothelial carcinoma.

For further details, please refer to the Tecentriq Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Tecentriq (atezolizumab) was evaluated in one Phase II, single-arm, multicentre, international study (IMvigor210) that enrolled patients with locally advanced or metastatic urothelial carcinoma. All patients were prospectively evaluated for PD-L1expression on both tumour cells and immune cells using a validated immunohistochemistry assay (Ventana SP142). The study was composed of two cohorts where patients were enrolled based on prior treatment status. Cohort 1 patients were treatment-naïve for advanced urothelial carcinoma and considered cisplatin ineligible (number of patients [n] = 119). Cohort 2 patients received at least 1 prior platinum-based treatment regimen in the neo-adjuvant, adjuvant or metastatic setting (n = 310). Of the 310 patients treated with Tecentriq in Cohort 2, 210 patients had <5% immune cell PD-L1 expression and 100 patients had immune cell PD-L1 expression ≥5%. The majority of patients in Cohort 2 had received two or more prior systemic chemotherapy regimens (61.9%). All patients had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. Cohort 2 was considered pivotal for this drug submission as it represented the population targeted with the proposed indication.

The sponsor pre-defined a sequential testing design based on PD-L1 expression level to maintain the type-I error at 5%. The independent review facility (IRF) used Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria and the investigator used modified RECIST immune response criteria to determine the overall response rates against a historically-derived response rate of 10%. However, the historically-derived response rate of 10% was questioned given that it was based on a systematic review of responses observed in a true second-line metastatic urothelial carcinoma population, whereas the population enrolled in the IMvigor210 study was more heavily pre-treated. Also, although a focus was maintained on randomized studies, the response rates were derived from studies of a wide variety of single-agent regimens to which the rates of response were highly variable. However, it was recognised that salvage therapies are often not used in this setting, and that treatment options are limited. Therefore, the response results were considered in light of the fact that there are few options for the majority of patients at this stage of their disease.

Based on the most up-to-date results (November 27, 2015), the IRF assessment confirmed the overall response rate as per RECIST version 1.1 to be 14.8% (95% confidence interval [CI]: 11.1, 19.3) for the all-comers (number [n] = 310) population. The complete response rate in the all-comers population was 5.5%. In patients with PD-L1 immune cell expression <5% (n = 210), the confirmed overall response rate was lower than observed overall (9.5% [95% CI: 5.9, 14.3]); however, low PD-L1 expression was not sufficient to exclude the possibility of response or complete response (CR = 5 [2.4%]). Patients with immune cell PD-L1 expression ≥5% (n = 100) had a confirmed overall response rate of 26.0% (95% CI: 17.7, 35.7) and a complete response rate of 12.0% suggesting that the probability of response increases with higher immune cell PD-L1 expression. However, the predictive value of immune cell PD-L1 expression in urothelial carcinoma needs further exploration in the setting of a randomised, well-controlled clinical study.

Duration of response was not estimable (NE) (95% CI: 12.7, NE) for the all-comers population with 81.7% of responders still in response at 1 year. For the <5% immune cell PD-L1 group of patients, the median duration of response was 12.7 months (95% CI: NE). For the ≥5% immune cell PD-L1 group, the median duration of response was NE (95% CI: NE). At the 12-month landmark analysis, 84.6% of responding immune cell PD-L1 ≥5% patients had not progressed.

In summary, Tecentriq was associated with a modest overall response rate in a heavily pre-treated, difficult to treat population. The observed responses were durable compared to previously reported responses obtained with salvage chemotherapy. Given the lack of therapeutic options available for this set of patients, the evidence provided in support of the efficacy of Tecentriq is considered promising. Confirmation of efficacy in a well-controlled, randomized clinical study is necessary to confirm the benefit/risk balance for Tecentriq and is a condition of authorization. Tecentriq has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. See question 4 What follow-up measures will the company take? Patients should be advised of the nature of the authorization.

Indication

The New Drug Submission for Tecentriq was filed with the following indication.

• Tecentriq (atezolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma after prior chemotherapy.

Health Canada recommended that the sponsor revise the indication to adequately reflect the characteristics of the patients enrolled in the pivotal study for this submission. Health Canada authorized the following indication:

• Tecentriq (atezolizumab) is 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 neo-adjuvant or adjuvant treatment with platinum-containing chemotherapy

For more information, refer to the Tecentriq Product Monograph approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Tecentriq (atezolizumab) was primarily based on use in 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following prior platinum-based chemotherapy or who had disease progression within 12 months of platinum-based neoadjuvant or adjuvant chemotherapy. These patients were enrolled in Cohort 2 of the Phase II single-arm multicentre, international clinical study, IMvigor210, in which patients received Tecentriq 1,200 mg every 3 weeks by intravenous infusion until there was no longer a clinical benefit as assessed by investigators or until unacceptable toxicity. The Cohort 2 population was pivotal for this drug submission as it represented the population targeted with the proposed indication. Cohort 1 patients were treatment naïve and considered cisplatin ineligible (n = 119). Cohort 1 was reviewed, along with the results of Cohort 2 and a Phase I dose-escalation study (n = 92 patients with metastatic urothelial carcinoma) in the evaluation of safety. Additional safety information was available based on studies carried out across a variety of tumour types, but predominantly in patients with non-small cell lung cancer (NSCLC, n = 1,026).

Overall, 303/310 (97.7%) patients enrolled in Cohort 2 had at least one adverse event and grade 3-4 events were experienced by 186 (60.0%) patients. Serious adverse events occurred in 144 (46.5%) patients. Adverse events leading to death occurred in 3 (1.0%) patients. Adverse events leading to dose interruption occurred in 100 (32.3%) patients and withdrawal from Tecentriq due to adverse events occurred in 12 (3.9%) patients.

In Cohort 2, the most common adverse events (reported by ≥10% patients) were fatigue (51.0%), decreased appetite (27.1%), nausea (26.5%), constipation (26.1%), urinary tract infection (23.2%), pyrexia (22.3%), peripheral edema (14.2%), diarrhea (21.6%), vomiting (19.4%), back pain (18.1%), dyspnea (17.4%), chills (10.6%), arthralgia (17.7%), anemia (17.1%), cough (16.5%), hematuria (16.1%), pruritus (14.8%), abdominal pain (13.9%), rash (11.6%), pain in extremities (10.3%), headache (10.0%), and pain (10.0%). The majority of adverse reactions were mild to moderate (Grade 1 or 2) in severity. The most common adverse events leading to dose interruption were urinary tract infection (2.6%), diarrhea, pyrexia (2.3% each), fatigue (1.9%), increased blood bilirubin, dyspnea and pneumonitis (1.6% each), increased aspartate aminotransferase, increased blood creatinine, confusional state, hypotension, sepsis and increased transaminases (1.3% each). Two patients were withdrawn from Tecentriq due to sepsis.

Immune-related adverse events (AEs) are well known to occur in patients receiving checkpoint inhibitors, including atezolizumab. Immune-related adverse events were identified through ongoing analysis of IMvigor210 Cohort 2 as well as other studies across a variety of tumour types in which atezolizumab had been tested. Identified immune-related AEs included pneumonitis, colitis, hepatitis, endocrinopathies (hypophysitis, diabetes mellitus, hyperthyroidism, hypothyroidism), and others (uveitis and skin reactions). In clinical studies, most immune-related AEs were reversible and managed with dose interruption, administration of corticosteroids and/or supportive care. Immune-related adverse events are adequately described in the Tecentriq Product Monograph and measures for the management of immune related AEs have been included in the Warnings and Precautions and the Dosage and Administrations sections.

Post-marketing safety data is not available for Tecentriq.

Appropriate warnings and precautions are in place in the approved Tecentriq Product Monograph to address the identified safety concerns.

For more information, refer to the Tecentriq Product Monograph, approved by Health Canada and available through the Drug Product Database.