Summary Basis of Decision for Imfinzi

Clinical Pharmacology

Durvalumab (the medicinal ingredient in Imfinzi) is a recombinant human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody produced in Chinese hamster ovary (CHO) cells. Durvalumab binds to human programmed cell death ligand 1 (PD-L1) residing on tumour-infiltrating immune cells and tumour cells, thereby inhibiting interactions between PD-L1 and programmed cell death protein 1 (PD-1) and PD-L1 and CD80 (B7.1). Both of these interactions can provide inhibitory signals to T cells resulting in T-cell anergy and an attenuated anti-tumour response. By removing these inhibitory signals, the T-cell response against malignant cells can be enhanced, resulting in immune-mediated tumour cell death.

The pharmacokinetics (PK) of Imfinzi was studied in 1,324 patients with solid tumours with doses ranging from 0.1 to 20 mg/kg administered once every two, three or four weeks. Pharmacokinetic exposure increased more than dose-proportionally (non-linear PK) at doses <3 mg/kg and dose proportionally (linear PK) at doses ≥3 mg/kg. Steady state was achieved at approximately 16 weeks.

Based on the population pharmacokinetics analysis that included 1, 310 patients (dose ≥10 mg/kg), the covariate of age (19-96 years), body weight (34-149 Kg), gender, positive anti-drug antibody (ADA) status, albumin levels, lactate dehydrogenase (LDH) levels, creatinine levels, soluble PD-L1, tumour type, race, mild renal impairment (creatinine clearance [CrCL] 60 to 89 mL/min), moderate renal impairment (CrCL 30 to 59 mL/min), mild hepatic impairment (bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or bilirubin >1.0 to 1.5 × ULN and any AST), or Eastern Cooperative Oncology Group (ECOG) status were shown to have no clinically significant effect on the pharmacokinetics parameters.

The effect of moderate hepatic impairment (bilirubin >1.5 to 3 times ULN and any AST) or severe hepatic impairment (bilirubin >3.0 x ULN and any AST) on the pharmacokinetics of durvalumab is unknown.

The effect of severe renal impairment (CrCL 15 to 29 mL/min) on the pharmacokinetics of durvalumab is unknown.

Overall, the clinical pharmacological data submitted by the sponsor supports the use of Imfinzi for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Imfinzi (durvalumab), in terms of tumour response rate, was evaluated primarily in one Phase I/II, global, multicenter, multi-cohort, open-label, single-arm clinical trial, CD-ON-MEDI4736-1108. The main objective of this trial was to determine the safety profile and the anti-tumour activity of Imfinzi monotherapy in a variety of advanced and malignant solid tumour types. For the purposes of this submission, the population of interest with respect to anti-tumour activity was the cohort of patients with locally advanced and metastatic urothelial carcinoma who had previously received platinum-based chemotherapy. A total of 191 patients were enrolled in this cohort. The evaluation of efficacy was based on 182 patients with locally advanced or metastatic urothelial carcinoma whose disease had progressed during or after a platinum-based therapy, including those patients whose disease had progressed within 12 months of receiving therapy in a neo-adjuvant or adjuvant setting (second line or greater urothelial carcinoma cohort). The remaining 9 patients were treatment naïve (or first line patients) and thereby excluded from the efficacy analysis.

Trial CD-ON-MEDI4736-1108

Clinical trial CD-ON-MEDI4736-1108 (hereafter referred to as trial 1108) was a Phase I/II, global, multicentre, multi-cohort, open-label, single-arm clinical trial which enrolled, in the urothelial carcinoma cohort, a total of 191 patients with locally advanced or metastatic urothelial carcinoma whose disease recurred or progressed after receiving platinum based chemotherapy.

Patients were administered Imfinzi 10 mg/kg intravenously over 60 minutes once every two weeks. Patients were followed for at least 16 weeks as of the data cut-off date and had tumour assessments at Weeks 6, 12, and 16 followed by every 8 weeks thereafter. Patients continued to receive Imfinzi for up to 12 months or until unacceptable toxicity or confirmed disease progression. In the absence of clinical deterioration, patients were permitted to continue to receive Imfinzi after confirmed progression of disease if investigators considered that they continued to derive a clinical benefit.

The median duration of follow-up for the 182 patients who had received prior platinum based chemotherapy was 5.57 months (range: 0.4 to 25.9 months). Overall, the enrolled patients represented a typical advanced urothelial carcinoma population that was predominantly male (72%) and of advanced age (median = 67 years). The majority of patients were considered to have advanced disease with poor prognoses (visceral and/or liver metastases present).

The primary efficacy endpoint was objective response rate based on Response Evaluation Criteria In Solid Tumours (RECIST v1.1) as assessed by a blinded independent central review group. The trial excluded patients with a history of immunodeficiency; medical conditions that required systemic immunosuppression; history of severe immune-mediated adverse reactions; untreated central nervous system metastases; human immunodeficiency virus; active tuberculosis, or hepatitis B or C infection. Additional efficacy endpoints included Duration of Response, Disease-Control Rate and Overall Survival.

In trial 1108, tumour specimens were evaluated for PD-L1 expression using the VENTANA PD-L1 (SP263 clone) immunohistochemical assay. Testing was performed prospectively at a central laboratory by pathologists trained in the use of the SP263 assay for the evaluation of PD-L1 expression. The test detects membrane and cytoplasmic PD-L1 expression by tumour cells and tumour associated immune cells (IC). Programmed cell death ligand 1 (PD-L1) status was determined by the percentage of tumour cells with any membrane PD-L1 staining above background or by the percentage of immune cells with PD-L1 staining (IC+) at any intensity above background. The percent of tumour area occupied by any tumour-associated immune cells (Immune Cells Present, ICP) was used to determine IC+, which is the percent area of ICP exhibiting PD-L1 positive immune cell staining. PD-L1 status is considered high if any of the following are met:

• ≥25% of tumour cells exhibit membrane staining; or,
• ICP >1% and IC+ ≥25%; or,
• ICP ≤1% and IC+ = 100%

If none of these criteria were met, PD-L1 status was considered low or negative.

Of the 182 patients that had received prior platinum based chemotherapy, 95 patients were classified as PD-L1 high, 73 patients as PD-L1 low or negative and 14 patients were not evaluable for PD-L1 status.

Efficacy results

Trial 1108 reported an objective response rate, for the previously treated (with platinum) urothelial carcinoma cohort of 17.6% (32/182; 95% confidence interval [CI]: 12.3%, 23.9%). The lower-bound of the 95% CI exceeded the pre-defined benchmark of 10%, which was based on a random effect meta-analysis of a variety of studies in which urothelial carcinoma patients, previously treated with platinum-based chemotherapy, were treated with single-agent salvage therapy. Thus, based on this endpoint, the study succeeded in meeting its primary efficacy endpoint. In exploratory assessments of objective response rate among patients with high or low/negative (low/neg) levels of PD-L1 expression, the objective response rates by the blinded independent central review group were 27.4% (95% CI : 18.7%, 37.5%) and 4.1% (0.9%, 11.5%), respectively. While not statistically significant, the data suggest there is a clinically meaningful difference in the rate of response between PD-L1 high and low/neg expressers. These data have been fully described in the Clinical Trials section of the Imfinzi Product Monograph in order to inform health care providers that certain PD-L1 expression subgroups may be more likely to respond to treatment than others.

The key secondary outcome was duration of response. Duration of response is a key secondary endpoint in trials of response rates for checkpoint inhibitors, mainly due to observations that responses achieved on checkpoint therapy are generally more durable than those observed with traditional chemotherapy regimens. The duration of response results are not mature; however, the results suggest that responses to durvalumab are prolonged. The median duration of response was reached only among the group of 4 responders classified as PD-L1 low/neg (12.25 months). Median duration of response was not reached among responders having high PD-L1 expression or in the overall group of responders. The lower bounds of the 95% CI for both the overall and PD-L1 high groups were estimated to be 6.1 months. The overall range of duration of response was 0.9+ to 19.9+ months (+ denotes ongoing response).

Time-to-event endpoints including progression free survival and overall survival were included in the submission; however, given the trial design (single-arm study), these endpoints were not considered in the assessment of benefit-risk profile. The sponsor has committed to characterize these endpoints further in at least one randomized controlled clinical study in patients with locally advanced or metastatic urothelial carcinoma.

In summary, Imfinzi, an immunotherapy designed to enhance the immune system's ability to mount an anti-tumour response, was studied as monotherapy in a single-arm study designed to evaluate the safety and anti-tumour effect. Imfinzi was associated with a modest overall response rate in a difficult-to-treat patient population. The observed responses were durable compared to previously reported responses obtained using cytotoxic salvage chemotherapies.

Given the lack of therapeutic options available to patients within the approved indication, the evidence provided in support of the efficacy of Imfinzi is considered promising such that the preliminary assessment of benefit-risk can be considered favourable. Confirmation of efficacy in a well-controlled, randomized clinical study is necessary to confirm the benefit-risk balance for Imfinzi and is a condition of authorization. Imfinzi has been granted -marketing authorization with conditions, pending further results 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 Imfinzi was filed by the sponsor with the following indication:

• Imfinzi (durvalumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed during or after platinum-based chemotherapy.

To ensure safe and effective use of the product, Health Canada approved the following indication:

• Imfinzi 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 neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

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

Clinical Safety

The clinical safety of Imfinzi (durvalumab) was primarily evaluated in the urothelial carcinoma cohort of trial 1108 described in the Clinical Efficacy section. This cohort enrolled 191 patients with locally advanced or metastatic urothelial carcinoma. Of the 191 patients enrolled, 182 patients had urothelial carcinoma that had progressed during or after platinum-based chemotherapy or had progressed within 12 months of platinum-based neoadjuvant or adjuvant chemotherapy.

In general, Imfinzi monotherapy 10 mg/kg administered intravenously every two weeks was well-tolerated. Adverse reactions were generally manageable and reversible with interruption of dosing and treatment with immunosuppressants, such as corticosteroids.

Overall, and regardless of relationship to treatment, an adverse event was experienced by 99.0% (189/191) of treated patients. At least one serious adverse event (SAE) was reported in 54.5% (104/191) of patients (for 12 of these patients, disease progression was reported as an SAE) and 9 (4.7%) patients had treatment-related SAE. The most common SAEs (occurring in ≥2% of patients) were back pain (4.7%), urinary tract infection (4.2%), acute kidney injury (4.2%), general physical health deterioration (3.7%), sepsis (3.1%), abdominal pain (2.6%), vomiting (2.6%), hypercalcemia (2.6%), and pyrexia (2.1%). Of the 191 enrolled urothelial carcinoma patients, 15 (7.9%) had adverse events that resulted in death, including cardio respiratory arrest, subileus, general physical deterioration, immune-mediated hepatitis, chronic hepatic failure, sepsis, cerebrovascular accident, acute kidney injury and pneumonitis. Of these, investigators considered one Grade 5 event each of pneumonitis and immune-mediated hepatitis to be related to treatment with durvalumab.

The most common adverse events observed regardless of relationship to treatment (any Grade; occurring in ≥10% of patients) were fatigue (35.6%), constipation (25.7%), decreased appetite (22.5%), nausea (22.0%), anemia (18.3%), diarrhea (16.8%), back pain (16.8%), urinary tract infection (16.2%), fever (15.7%), peripheral edema (14.1%), vomiting (13.1%), cough (11.5%), dyspnea (11.5%), increased blood creatinine (11.0%), arthralgia (10.5%) and asthenia (10.5%). The majority of adverse events were Grade 1 or 2 (mild to moderate) in severity; Grade 3 or 4 adverse events were reported in 52 (27.2%) patients. The most common Grade 3 or 4 adverse events (>3% of patients) were anemia (9.9%), hyponatremia (5.8%), acute kidney injury (4.7%), urinary tract infection (4.2%), back pain (4.2%), fatigue, sepsis, hypercalcemia and asthenia (3.1% each). Treatment-related Grade 3 or 4 adverse events were reported in 6.8% of patients; the most common (≥1%) were increased aspartate aminotransferase (1.6%), increased alanine aminotransferase (1.0%), and increased gamma-glutamyl transferase (1.0%), all of which were generally manageable and reversible.

Adverse events (excluding disease progression) leading to the delay, interruption or discontinuation of Imfinzi occurred in 68 (35.6%), 3 (1.6%), and 9 (4.7%) patients, respectively. The most common reasons for dose delay (occurring in >1% of patients) were back pain (3.7%), urinary tract infection (2.6%), acute kidney injury (1.6%), aspartate aminotransferase increased (1.6%), gamma-glutamyl transferase increased (1.6%), and pneumonia (1.6%). The most common reason for dose discontinuation (occurring in ≥1% of patients) was general physical health deterioration in 2 (1.0%) patients.

In the urothelial carcinoma cohort (number of patients = 191) of trial 1108, a range of immune-mediated adverse events occurred. Immune mediated adverse events were defined as requiring the use of systemic corticosteroids/hormone replacement therapy with no clear alternate etiology. The types of immune-mediated adverse events observed were consistent with those observed in other clinical trials with products targeting programmed cell death protein 1 (PD-1) or PD-L1 and include: pneumonitis, hepatitis, colitis and diarrhea, renal and urinary disorders, and skin and subcutaneous tissue disorders.

For further information on immune-mediated adverse reactions (e.g., pneumonitis, hepatitis, colitis, endocrinopathies, nephritis, and rash/dermatitis) and frequency observed in the urothelial carcinoma cohort and overall trial population, refer to the Imfinzi Product Monograph.

Overall, the safety profile of Imfinzi was well characterized in the clinical setting and is considered consistent with other authorized products which target PD-1 and PD-L1 signaling pathway. Appropriate warnings and precautions are in place in the approved Imfinzi Product Monograph to address the identified safety concerns. In addition, a Risk Management Plan for Imfinzi has also been put in place to minimize risks associated with the product. As such, in view of the intended use of Imfinzi, currently there are no foreseen issues within this submission which preclude authorization of the product.

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