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Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC).
PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.
Pharmacodynamics: The steady state AUC, Ctrough, and Cmax in patients administered with 1500 mg every 4 weeks are 6% higher, 19% lower, and 55% higher than those administered with 10 mg/kg every 2 weeks, respectively. Based on the modeling of pharmacokinetic data and exposure relationships for safety, there are no anticipated clinically meaningful differences in efficacy and safety for the doses of 1500 mg every 4 weeks compared to 10 mg/kg every 2 weeks in patients weighing >30 kg with NSCLC.
Clinical Studies: Non-Small Cell Lung Cancer (NSCLC): The efficacy of IMFINZI was evaluated in the PACIFIC Study, a randomised, double-blind, placebo-controlled, multicentre study in 713 patients with locally advanced, unresectable NSCLC. Patients had completed at least 2 cycles of definitive platinum-based chemotherapy with radiation therapy within 1 to 42 days prior to initiation of the study and had a ECOG performance status of 0 or 1. Ninety-two percent of patients had received a total dose of 54 to 66 Gy of radiation. The study excluded patients who had progressed following chemoradiation therapy, patients with prior exposure to any anti-PD-1 or anti-PD-L1 antibody, patients with active or prior documented autoimmune disease within 2 years of initiation of the study; a history of immunodeficiency; a history of severe immune-mediated adverse reactions; medical conditions that required systemic immunosuppression, except physiological dose of systemic corticosteroids; active tuberculosis or hepatitis B or C or HIV infection or patients receiving live attenuated vaccine within 30 days before or after the start of IMFINZI. Patients were randomised 2:1 to receive 10 mg/kg IMFINZI (n=476) or 10 mg/kg placebo (n=237) via intravenous infusion every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed disease progression. Randomisation was stratified by gender, age (<65 years vs. ≥65 years) and smoking status (smoker vs. non-smoker). Patients with disease control at 12 months were given the option to be re-treated upon disease progression. Tumour assessments were conducted every 8 weeks for the first 12 months and then every 12 weeks thereafter.
Patients were enrolled regardless of their tumour PD-L1 expression level. Where available, archival tumour tissue specimens taken prior to chemoradiation therapy were retrospectively tested for PD-L1 expression on tumour cells (TC) using the VENTANA PD-L1 (SP263) IHC assay. Of the 713 patients randomised, 63% of patients provided a tissue sample of sufficient quality and quantity to determine PD-L1 expression and 37% were unknown.
The demographics and baseline disease characteristics were well balanced between study arms. Baseline demographics of the overall study population were as follows: male (70%), age ≥65 years (45%), age ≥75 years (8%), White (69%), Asian (27%), other (4%), current smoker (16%), past-smoker (75%), never smoker (9%), ECOG Performance Status 0 (49%), ECOG Performance Status 1 (51%). Disease characteristics were as follows: Stage IIIA (53%), Stage IIIB (45%), histological sub-groups of squamous (46%), non-squamous (54%). Of 451 patients with PD L1 expression available, 67% were TC ≥1% [PD-L1 TC 1-24% (32%), PD L1 TC ≥25% (35%)] and 33% were TC <1%.
The two primary endpoints of the study were progression-free survival (PFS) and overall survival (OS) of IMFINZI vs. placebo. Secondary efficacy endpoints included PFS at 12 months (PFS 12) and 18 months (PFS 18) from randomisation and Time from Randomisation to Second Progression (PFS2). PFS was assessed by Blinded Independent Central Review (BICR) according to RECIST v1.1.
The study demonstrated a statistically significant improvement in PFS in the IMFINZI-treated group compared with the placebo group [hazard ratio (HR)=0.52 (95% CI: 0.42, 0.65), p <0.0001]. The study demonstrated a statistically significant improvement in OS in the IMFINZI-treated group compared with the placebo group [HR=0.68 (95% CI: 0.53, 0.87), p=0.00251].
In the 5 year follow-up analysis, with a median follow-up of 34.2 months, IMFINZI continued to demonstrate improved OS and PFS compared to placebo. The OS and PFS results from the primary analysis and the follow-up analysis are summarized in Table 1. (See Table 1.)
Click on icon to see table/diagram/imageKaplan-Meier curves for OS and PFS from the 5 year follow-up analysis are presented in Figures 1 and 2. (See Figures 1 and 2.)
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Click on icon to see table/diagram/imageThe improvements in PFS and OS in favour of patients receiving IMFINZI compared to those receiving placebo were consistently observed in all predefined subgroups analysed, including ethnicity, age, gender, smoking history, EGFR mutation status and histology.
Post-hoc subgroup analysis by PD-L1 expression: Additional subgroup analyses were conducted to evaluate the efficacy by tumour PD-L1 expression (≥25%, 1-24%, ≥1%, <1%) and for patients whose PD-L1 status cannot be established (PD-L1 unknown). PFS and OS results from the 5 year follow-up analysis are summarised in Figures 3, 4, 5 and 6. (See Figures 3, 4, 5 and 6.)
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Click on icon to see table/diagram/imageOverall the safety profile of durvalumab in PD-L1 TC ≥1% subgroup was consistent with the intent to treat population, as was the PD-L1 TC <1% subgroup.
Patient-reported outcomes: Patient-reported symptoms, function and health-related quality of life (HRQoL) were collected using the EORTC QLQ-C30 and its lung cancer module (EORTC QLQ-LC13). The LC13 and C30 were assessed at baseline, every 4 weeks for the first 8 weeks, followed by every 8 weeks until completion of the treatment period or discontinuation of IMFINZI due to toxicity or disease progression. Compliance was similar between the IMFINZI and placebo treatment groups (83% vs. 85.1% overall of evaluable forms completed).
At baseline, no differences in patient-reported symptoms, function and HRQoL were observed between IMFINZI and placebo groups. Throughout the duration of the study to Week 48, there was no clinically meaningful difference between IMFINZI and placebo groups in symptoms, functioning and HRQoL (as assessed by a difference of greater than or equal to 10 points).
Small Cell Lung Cancer (SCLC) - CASPIAN Study: CASPIAN was a study designed to evaluate the efficacy of IMFINZI in combination with etoposide and either carboplatin or cisplatin. CASPIAN was a randomized, open-label, multicentre study in 805 treatment naïve ES-SCLC patients with WHO/ECOG Performance status of 0 or 1, body weight >30 kg, suitable to receive a platinum-based chemotherapy regimen as first-line treatment for SCLC, with life expectancy ≥12 weeks, at least one target lesion by RECIST 1.1 and adequate organ and bone marrow function. Patients with asymptomatic or treated brain metastases were eligible. The study excluded patients with a history of chest radiation therapy; a history of active primary immunodeficiency; autoimmune disorders including paraneoplastic syndrome (PNS); active or prior documented autoimmune or inflammatory disorders; use of systemic immunosuppressants within 14 days before the first dose of the treatment except physiological dose of systemic corticosteroids; active tuberculosis or hepatitis B or C or HIV infection; or patients receiving live attenuated vaccine within 30 days before or after the start of IMFINZI.
Randomization was stratified by the planned platinum-based (carboplatin or cisplatin) therapy in cycle 1.
Patients were randomised 1:1:1 to receive: Arm 1: IMFINZI 1500 mg + tremelimumab 75 mg + etoposide and either carboplatin or cisplatin.
Arm 2: IMFINZI 1500 mg + etoposide and either carboplatin or cisplatin.
Arm 3: Either carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75-80 mg/m2) on Day 1 and etoposide (80-100 mg/m2) intravenously on Days 1, 2, and 3 of each 21-day cycle for between 4-6 cycles.
For patients randomised to Arm 1 and 2, etoposide and either carboplatin or cisplatin was limited to 4 cycles on an every 3 week schedule subsequent to randomisation. IMFINZI monotherapy continued every 4 weeks until disease progression or unacceptable toxicity. Administration of IMFINZI monotherapy was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.
Patients randomised to Arm 3 were permitted to receive a total of up to 6 cycles of etoposide and either carboplatin or cisplatin. After completion of etoposide + platinum, PCI was permitted only in Arm 3 per investigator discretion.
Tumour assessments were conducted at Week 6 and Week 12 from the date of randomization, and then every 8 weeks until confirmed objective disease progression. Survival assessments were conducted every 2 months following treatment discontinuation.
The primary endpoints of the study were Overall Survival (OS) of IMFINZI + etoposide + platinum (Arm 2) vs. etoposide + platinum alone (Arm 3) and IMFINZI + tremelimumab + etoposide + platinum (Arm 1) vs. etoposide + platinum alone (Arm 3). The key secondary endpoint was progression-free survival (PFS). Other secondary endpoints were Objective Response Rate (ORR), OS and PFS landmarks and Patient-Reported Outcomes (PRO). PFS and ORR were assessed using Investigator assessments according to RECIST v1.1.
The demographics and baseline disease characteristics were well balanced between the two study arms (268 patients in Arm 2 and 269 patients in Arm 3). Baseline demographics of the overall study population were as follows: male (69.6%), age ≥65 years (39.6%), median age 63 years (range: 28 to 82 years), white (83.8%), Asian (14.5%), black or African American (0.9%), other (0.6%), non-Hispanic or Latino (96.1%), current or past-smoker (93.1%), never smoker (6.9%), WHO/ECOG PS 0 (35.2%), WHO/ECOG PS 1 (64.8%), Stage IV 90.3%, 24.6% of the patients received cisplatin and 74.1% of the patients received carboplatin. In Arm 3, 56.8% of the patients received 6 cycles of etoposide + platinum and 7.8% of the patients received PCI.
At a planned interim (primary) analysis the study demonstrated a statistically significant improvement in OS with IMFINZI + etoposide + platinum (Arm 2) vs. etoposide + platinum alone (Arm 3) [HR=0.73 (95% CI: 0.591, 0.909), p=0.0047]. Although not formally tested for significance, IMFINZI + etoposide + platinum demonstrated an improvement in PFS vs. etoposide + platinum alone [HR=0.78 (95% CI: 0.645, 0.936)].
The PFS, ORR and DoR results from the planned final analysis (DCO: 27 Jan 2020) are summarized in Table 2. Kaplan-Meier curve for PFS is presented in Figure 8.
The OS results with the planned long-term OS follow-up analysis (DCO: 22 March 2021) (median follow-up: 39.3 months) are presented in Table 2. IMFINZI + etoposide + platinum (Arm 2) vs. etoposide + platinum (Arm 3) continued to demonstrate sustained improvement in OS. Kaplan-Meier curve for OS is presented in Figure 7. (See Table 2, Figures 7 and 8.)
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Click on icon to see table/diagram/imageSubgroup analysis: The improvements in OS in favour of patients receiving IMFINZI + etoposide + platinum compared to those receiving etoposide + platinum alone, were consistently observed across the prespecified subgroups based on demographics, geographical region, carboplatin or cisplatin use and disease characteristics.
BTC - TOPAZ-1 Study: TOPAZ-1 was a study designed to evaluate the efficacy of IMFINZI in combination with gemcitabine and cisplatin. TOPAZ-1 was a randomised, double-blind, placebo-controlled, multicentre study in 685 patients with unresectable or metastatic BTC (including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder carcinoma) and ECOG Performance status of 0 or 1. Patients had not received previous therapy in the advanced/unresectable setting. Patients who developed recurrent disease >6 months after surgery and/or completion of adjuvant therapy were included. Patients must have had an adequate organ and bone marrow function, and have had acceptable serum bilirubin levels (≤2.0 x the upper limit of normal (ULN)), and any clinically significant biliary obstruction had to be resolved before randomisation.
The study excluded patients with ampullary carcinoma, with brain metastases, active or prior documented autoimmune or inflammatory disorders, HIV infection or active infections, including tuberculosis or hepatitis C or patients with current or prior use of immunosuppressive medication within 14 days before the first dose of IMFINZI. Patients with active HBV were allowed to participate if they were on antiviral therapy.
Randomisation was stratified by disease status (initially unresectable vs. recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder carcinoma).
Patients were randomised 1:1 to receive: Arm 1: IMFINZI 1500 mg administered on Day 1 + gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 (each administered on Days 1 and 8) every 3 weeks (21 days) for up to 8 cycles, followed by IMFINZI 1500 mg every 4 weeks until disease progression or unacceptable toxicity, or Arm 2: Placebo administered on Day 1 + gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 (each administered on Days 1 and 8) every 3 weeks (21 days) for up to 8 cycles, followed by placebo every 4 weeks until disease progression or unacceptable toxicity.
Tumour assessments were conducted every 6 weeks for the first 24 weeks after the date of randomisation, and then every 8 weeks until confirmed objective disease progression.
The primary endpoint of the study was OS, the key secondary endpoint was PFS. Other secondary endpoints were ORR, DoR and PRO. PFS, ORR and DoR were investigator-assessed according to RECIST v1.1.
The demographics and baseline disease characteristics were well balanced between the two study arms (341 patients in Arm 1 and 344 patients in Arm 2). Baseline demographics of the overall study population were as follows: male (50.4%), age <65 years (53.3%), white (37.2%), Asian (56.4%), Black or African American (2.0%), other (4.2%), non-Hispanic or Latino (93.1%), ECOG PS 0 (49.1%), vs. PS 1 (50.9%), primary tumour location (intrahepatic bile duct 55.9%, extrahepatic bile duct 19.1% and gallbladder 25.0%), disease status [recurrent (19.1%) vs. unresectable (80.7%), metastatic (86.0%) vs. locally advanced (13.9%)]. PD-L1 expression was evaluated on tumour and immune cells using the Ventana PD-L1 (SP263) assay and the TAP (tumour area positivity) algorithm, 58.7% patients had TAP ≥1% and 30.1% TAP <1%.
OS and PFS were formally tested at a pre-planned interim analysis (data cut-off 11 Aug 2021) after a median follow-up of 9.8 months. Efficacy results are shown in Table 3 and Figure 9. The maturity for OS was 62% and the maturity for PFS was 84%. IMFINZI + chemotherapy (Arm 1) showed statistically significant improvement vs. placebo + chemotherapy (Arm 2) in OS and in PFS. (See Table 3.)
Click on icon to see table/diagram/imageAn additional planned follow-up analysis of OS (data cut-off 25 Feb 2022) was performed 6.5 months after the interim analysis with an OS maturity of 77%. IMFINZI + chemotherapy continued to demonstrate improved OS vs. chemotherapy alone [HR=0.76, (95% CI: 0.64, 0.91)] and the median follow-up increased to 12 months. (See Figures 9 and 10.)
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Click on icon to see table/diagram/imagePharmacokinetics: The pharmacokinetics of durvalumab as a single agent was studied in patients with doses ranging from 0.1 mg/kg (0.01 times the approved recommended dosage) to 20 mg/kg (2 times the approved recommended dosage) administered once every two, three or four weeks.
PK exposure increased more than dose-proportionally at doses <3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses ≥to 3 mg/kg every 2 weeks. Steady state was achieved at approximately 16 weeks.
The pharmacokinetics of durvalumab is similar when assessed as a single agent and when in combination with chemotherapy.
Distribution: The geometric mean (% coefficient of variation [CV%]) steady state volume of distribution (Vss) was 5.6 (18%) L.
Elimination: Durvalumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of approximately 23% (57%) resulting in a geometric mean (CV%) steady state clearance (CLss) of 8.2 mL/h (39%) at day 365; the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life, based on baseline CL was approximately 18 (24%) days.
Specific Populations: There were no clinically significant differences in pharmacokinetics of durvalumab based on body weight (31-175 kg), age (18-96 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or Native American), albumin levels (4-57 g/L), lactate dehydrogenase (LDH) levels (18-15,800 U/L), creatinine levels, soluble PD-L1 (67-3,470 pg/mL), tumor type (NSCLC, SCLC and BTC), mild or moderate renal impairment (CLcr 30 to 89 mL/min), mild or moderate hepatic impairment (bilirubin ≤3x ULN and any AST). The effect of severe renal impairment (CLcr 15 to 29 mL/min) or severe hepatic impairment (bilirubin >3x ULN and any AST) on the pharmacokinetics of durvalumab is unknown.
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to durvalumab to the incidence of antibodies to other products may be misleading.
Of 2280 patients who received IMFINZI 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks as a single-agent, 69 patients (3%) tested positive for treatment-emergent anti-drug antibodies (ADA) and 12 (0.5%) tested positive for neutralizing antibodies. The development of ADA against durvalumab appears to have no clinically relevant effect on its pharmacokinetics or safety profile.
Of 201 patients in the CASPIAN study who received IMFINZI 1500 mg every 3 weeks in combination with chemotherapy for four doses followed by IMFINZI 1500 mg every 4 weeks no patients tested positive for treatment-emergent ADA.
Of the 240 patients in the TOPAZ-1 study who received IMFINZI 1500 mg every 3 weeks in combination with chemotherapy up to 8 cycles followed by IMFINZI 1500 mg every 4 weeks, 2 (0.8%) patients tested positive for treatment emergent ADAs and neutralizing antibodies, respectively. There were insufficient numbers of patients with treatment-emergent ADAs or neutralizing antibodies (2 patients each) to determine whether ADAs have an impact on pharmacokinetics, pharmacodynamics, safety and/or effectiveness of IMFINZI.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic and genotoxic potential of durvalumab have not been evaluated.
Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to 3 months duration, there were no notable effects on the male and female reproductive organs.
Animal Toxicology and/or Pharmacology: In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.
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