Sign Out
Durvalumab is a fully human, high affinity, immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that selectively blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1) while leaving PD-1/PD-L2 interaction intact. Durvalumab does not induce antibody dependent cell-mediated cytotoxicity (ADCC). Selective blockade of PD-L1/PD-1 and PD-L1/CD80 interactions enhances antitumour immune responses. These antitumour responses may result in tumour elimination.
In preclinical studies, PD-L1 blockade led to increased T-cell activation and decreased tumour size.
The combination of durvalumab, a PD-L1 inhibitor, and tremelimumab, a CTLA-4 inhibitor functions to enhance anti-tumour T-cell activation and function at multiple stages of the immune response, enhancing anti-tumour immunity.
Clinical efficacy and safety: Durvalumab doses of 10 mg/kg every 2 weeks or 1500 mg every 4 weeks were evaluated in NSCLC and ES-SCLC clinical studies. Based on the modelling and simulation of exposure, exposure-safety relationships and exposure-efficacy data comparisons, there are no anticipated clinically significant differences in efficacy and safety between durvalumab doses of 10 mg/kg every 2 weeks or 1500 mg every 4 weeks.
Locally advanced NSCLC - PACIFIC study: The efficacy of IMFINZI was evaluated in the PACIFIC Study, a randomised, double-blind, placebo-controlled, multicentre study in 713 patients with histologically or cytologically confirmed locally advanced, unresectable NSCLC. Patients had completed at least 2 cycles of definitive platinum-based chemoradiation 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 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%), white (69%), Asian (27%), other (4%), current smoker (16%), past-smoker (75%), and never smoker (9%), WHO/ECOG PS 0 (49%), WHO/ECOG PS 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 overall survival (OS) and progression-free survival (PFS) of IMFINZI vs. placebo. Secondary efficacy endpoints included Objective Response Rate (ORR), Duration of Response (DoR) and Time to Death or Distant Metastasis (TTDM). PFS, ORR, DoR and TTDM were assessed by Blinded Independent Central Review (BICR) according to RECIST v1.1.
The study demonstrated a statistically significant and clinically meaningful 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]. Median OS was not reached in the IMFINZI-treated group and was 28.7 months in the placebo group. The study demonstrated a statistically significant and clinically meaningful 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]. Median PFS was 16.8 months in the IMFINZI-treated group and 5.6 months in the placebo group. See Table 1 and Figures 1 and 2.
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageThe improvements in OS and PFS in favour of patients receiving IMFINZI compared to those receiving placebo were consistently observed across predefined subgroups analysed. Sensitivity analyses of OS and PFS demonstrated a consistent treatment effect with that observed in the primary analysis.
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 are summarised in Figures 3 and 4.
Overall 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. (See Figures 3 and 4.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imagePatient-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 study drug due to toxicity or disease progression. Compliance was high and very similar between the IMFINZI and placebo treatment groups.
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).
SCLC - CASPIAN Study: CASPIAN was a study designed to evaluate the efficacy of IMFINZI with or without tremelimumab in combination with etoposide and either carboplatin or cisplatin. CASPIAN was a randomised, open-label, multicentre study in 805 treatment naïve ES-SCLC patients with WHO/ECOG Performance status of 0 or 1, 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.
Randomisation was stratified by the planned platinum-based therapy in cycle 1 (carboplatin or cisplatin).
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 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 chemotherapy, prophylactic cranial irradiation (PCI) was permitted only in Arm 3 per investigator discretion.
Tumour assessments were conducted at Week 6 and Week 12 from the date of randomisation, 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 OS of IMFINZI + chemotherapy (Arm 2) vs. chemotherapy alone (Arm 3) and IMFINZI + tremelimumab + chemotherapy (Arm 1) vs. chemotherapy alone (Arm 3). The key secondary endpoint was PFS. Other secondary endpoints were ORR, OS and PFS landmarks and Patient-Reported Outcomes (PRO). PFS and ORR were assessed using Investigator assessments according to RECIST v1.1.
At a planned interim analysis, IMFINZI + chemotherapy (Arm 2) vs. chemotherapy (Arm 3) met the efficacy boundary of the primary endpoint of OS. The results are summarised as follows.
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 chemotherapy and 7.8% of the patients received PCI.
The study demonstrated a statistically significant and clinically meaningful improvement in OS with IMFINZI + chemotherapy (Arm 2) vs. chemotherapy alone (Arm 3) [HR=0.73 (95% CI: 0.591, 0.909), p=0.0047]. IMFINZI + chemotherapy demonstrated an improvement in PFS vs. chemotherapy alone [HR=0.78 (95% CI: 0.645, 0.936) nominal p-value=0.0078]. See Table 2 and Figures 5 and 6.
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageSubgroup analysis: The improvements in OS in favour of patients receiving IMFINZI + chemotherapy compared to those receiving chemotherapy alone, were consistently observed across the prespecified subgroups based on demographics, geographical region, carboplatin or cisplatin use and disease characteristics.
Patient-Reported Outcomes: Patient-reported symptoms, function and HRQoL were collected using the EORTC QLQ-C30 and its lung cancer module (EORTC QLQ-LC13). Both questionnaires were administered up to second disease progression (PFS2) or death (whichever came first). At baseline, patient-reported symptoms, functioning or HRQoL scores were comparable between the study arms. Compliance was 60% or higher over 84 weeks in IMFINZI + chemotherapy and 20 weeks in the chemotherapy only arm.
Delay in time to deterioration of symptoms, functioning, and global health status/QoL: IMFINZI + chemotherapy demonstrated improvement by delaying time to deterioration in a broad range of patient-reported symptoms, function, and global health status/QoL compared to chemotherapy alone (see Tables 3 and 4).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageChange from baseline in lung cancer symptoms over 12 months (mixed model for repeated measures): IMFINZI + chemotherapy improved appetite loss by demonstrating a statistically significant difference in mean change from baseline versus chemotherapy alone during the overall time period from randomisation until 12 months (Estimated mean difference -4.5; 99% CI -9.04, -0.04; p=0.009). Both treatment arms demonstrated numerical symptom reduction in cough, chest pain, dyspnoea and fatigue over the same time period.
Patient-reported outcome results should be interpreted in the context of the open-label study design.
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 histologically confirmed locally advanced or metastatic BTC and ECOG performance status of 0 or 1. Patients who developed recurrent disease more than 6 months after surgery and/or completion of adjuvant therapy were included. Patients must have had at least one target lesion by RECIST v1.1 and adequate organ and bone marrow function.
The study excluded patients with ampullary carcinoma, 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.
Randomisation was stratified by disease status and primary tumour location.
Patients were randomised 1:1 to receive: Arm 1: IMFINZI 1500 mg administered intravenously 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 as long as clinical benefit is observed or until unacceptable toxicity, or; Arm 2: Placebo administered intravenously 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 as long as clinical benefit is observed or until 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 and 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 (49.6%), 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 cholangiocarcinoma (55.9%), extrahepatic cholangiocarcinoma (19.1%) and gallbladder cancer (25.0%), disease status recurrent (19.1%) vs. initially unresectable (80.7%), metastatic (86.0%) vs. locally advanced (13.9%).
The study demonstrated a statistically significant improvement in OS and PFS at a pre-planned interim analysis based on a Lan-DeMets alpha spending function with O'Brien Fleming type boundary and the actual number of events observed (Lan and DeMets 1983). The results in OS were [HR=0.80, (95% CI: 0.66, 0.97), p=0.021] and in PFS [HR=0.75, (95% CI: 0.63, 0.89), p=0.001]. The maturity for OS was 61.9% and the maturity for PFS was 83.6%. The boundary for declaring statistical significance for OS was 0.03 for an 4.9% overall alpha. Results from this analysis are presented in Table 5. PFS is also presented in Figure 8.
An additional OS analysis was performed 6.5 months after the interim analysis with an OS maturity of 76.9%. The observed treatment effect was consistent with the interim analysis. The OS HR was 0.76 (95% CI: 0.64, 0.91) and median survival was 12.9 months (95% CI: 11.6, 14.1). (See Table 5 and Figures 7 and 8.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageSubgroup analysis: The improvements in OS and PFS in favour of patients receiving IMFINZI + chemotherapy compared to those receiving placebo + chemotherapy, were consistently observed across the prespecified subgroups based on demographics, geographical region, primary tumour location, disease status, ECOG PS, and PD-L1 expression levels.
Patient-Reported Outcomes: Patient-reported symptoms, function and global health status/QoL (GHS/QoL) were collected using the EORTC QLQ-C30 and its biliary tract cancer module (EORTC QLQ-BIL21). At baseline, patient-reported symptoms, functioning and GHS/QoL scores were comparable between the study arms. Time to deterioration and change from baseline analyses were consistent with no detriment in symptoms, function and GHS/QoL per EORTC QLQ-C30 and EORTC QLQ-BIL21 in the IMFINZI + chemotherapy group compared to the placebo + chemotherapy group (see Tables 6 and 7).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageHCC - HIMALAYA Study: The efficacy of STRIDE was evaluated in the HIMALAYA study, a randomised, open-label, multicentre study in patients with confirmed uHCC who did not receive prior systemic treatment for HCC. The study included patients with BCLC Stage C or B (not eligible for locoregional therapy) and Child-Pugh Score Class A.
The study excluded patients with brain metastases or a history of brain metastases, co-infection of viral hepatitis B and hepatitis C; active or prior documented GI bleeding within 12 months; ascites requiring non-pharmacologic intervention within 6 months; hepatic encephalopathy within 12 months before the start of treatment; active or prior documented autoimmune or inflammatory disorders.
Patients with esophageal varices were included except those with active or prior documented GI bleeding within 12 months prior to study entry.
Randomisation was stratified by macrovascular invasion (MVI) (yes vs. no), etiology of liver disease (confirmed hepatitis B virus vs. confirmed hepatitis C virus vs. others) and ECOG performance status (0 vs. 1).
The HIMALAYA study randomised 1171 patients 1:1:1 to receive: IMFINZI: durvalumab 1500 mg every 4 weeks; STRIDE: tremelimumab 300 mg as a single priming dose + IMFINZI 1500 mg; followed by IMFINZI 1500 mg every 4 weeks; S: Sorafenib 400 mg twice daily.
Tumour assessments were conducted every 8 weeks for the first 12 months and then every 12 weeks thereafter. Survival assessments were conducted every month for the first 3 months following treatment discontinuation and then every 2 months.
The primary endpoint was OS. Key secondary endpoints were PFS, Investigator assessed ORR and DoR according to RECIST v1.1. PROs were also assessed.
The demographics and baseline disease characteristics were generally representative for patients with uHCC. The baseline demographics of the overall study population were as follows: male (83.7%), age <65 years (50.4%), white (44.6%), Asian (50.7%), black or African American (1.7%), other (2.3%), ECOG PS 0 (62.6%); Child-Pugh Class score A (99.5%), macrovascular invasion (25.2%), extrahepatic spread (53.4%), viral etiology; hepatitis B (30.6%), hepatitis C (27.2%), uninfected (42.2%), baseline AFP < 400 ng/ml (63.7%), baseline AFP ≥ 400 ng/ml (34.5%), viral aetiology; hepatitis B (30.6%), hepatitis C (27.2%), uninfected (42.2%), evaluable PD-L1 data (86.3%), PD-L1 Tumour area positivity (TAP) ≥ 1% (38.9%), PD-L1 TAP < 1% (48.3%) [Ventana PD-L1 (SP263) assay].
The study demonstrated a statistically significant and clinically meaningful improvement in OS with STRIDE vs. S [HR=0.78 [95% CI 0.66, 0.92]; p=0.0035]. See Table 8 and Figure 9.
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imagePharmacokinetics: The pharmacokinetics (PK) of durvalumab was assessed for IMFINZI as a single agent, in combination with chemotherapy, and in combination with tremelimumab.
The pharmacokinetics of durvalumab was studied in patients with solid tumours with doses ranging from 0.1 to 20 mg/kg administered once every two, three or four weeks. PK 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 population PK analysis that included patients in the dose range of 10 mg/kg Q2W, 15 mg/kg Q3W and 20 mg/kg Q4W, the geometric mean, steady state volume of distribution (Vss) was 5.64 L. Durvalumab clearance (CL) decreased over time resulting in a geometric mean steady state clearance (CLss) of 8.16 mL/h at Day 365; the decrease in CLss was not considered clinically relevant. The terminal half-life (t½), based on baseline CL, was approximately 18 days. There was no clinically meaningful difference between the PK of durvalumab as a single agent, in combination with chemotherapy or in combination with tremelimumab.
Special populations: Age (19-96 years), body weight (31-149 kg), gender, positive anti-drug antibody (ADA) status, albumin levels, LDH levels, creatinine levels, soluble PD-L1, tumour type, race, mild renal impairment (creatinine clearance (CrCL) 60 to 89 mL/min), moderate renal impairment (creatinine clearance (CrCL) 30 to 59 mL/min), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1.0 to 1.5 × ULN and any AST), moderate hepatic impairment (bilirubin > 1.5 to 3 x ULN and any AST) or ECOG/WHO status had no clinically significant effect on the pharmacokinetics of durvalumab.
The effect of severe renal impairment (CrCL 15 to 29 mL/min) or severe hepatic impairment (bilirubin > 3.0 x ULN and any AST) on the pharmacokinetics of durvalumab is unknown.
Elderly: No dose adjustment is required for elderly patients (≥ 65 years of age).
Of the 476 patients with locally advanced, unresectable NSCLC (primary efficacy population) treated with IMFINZI, 215 patients were 65 years or older. No overall clinically meaningful differences in safety were reported between patients ≥ 65 years of age and younger patients.
Of the 265 patients with ES-SCLC treated with IMFINZI in combination with chemotherapy, 101 (38%) patients were 65 years or older. There were no overall clinically meaningful differences in safety or effectiveness between patients ≥ 65 years of age and younger patients.
Of the 338 patients with BTC treated with IMFINZI in combination with chemotherapy, 158 (46.7%) patients were 65 years or older. There were no overall clinically meaningful differences in safety or effectiveness between patients ≥65 years of age and younger patients.
Of the 462 patients with uHCC treated with STRIDE, 173 (37.4%) patients were 65 years or older and 63 (13.6%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.
Drug interaction studies: PK drug-drug interaction between durvalumab and chemotherapy was assessed in the CASPIAN study and no clinically meaningful PK drug-drug interaction was identified.
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. Immunogenicity of IMFINZI as monotherapy is based on pooled data in 2280 patients who were treated with IMFINZI 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks as a single-agent and evaluable for the presence of anti-drug antibodies (ADA). Sixty-nine patients (3.0%) tested positive for treatment emergent ADA. Neutralizing antibodies against durvalumab were detected in 0.5% (12/2280) patients. The presence of ADAs did not have a clinically relevant effect on pharmacokinetics, pharmacodynamics or safety.
In the CASPIAN study, of the 201 patients who were treated with IMFINZI 1500 mg every 3 weeks in combination with chemotherapy and evaluable for the presence of ADAs, 0 (0%) patients tested positive for treatment-emergent ADAs. The impact of treatment-emergent ADA on pharmacokinetics and clinical safety of durvalumab was not evaluable as no patient samples tested positive for treatment-emergent durvalumab ADA.
In the TOPAZ-1 study, of the 240 patients who were treated with IMFINZI 1500 mg every 3 weeks in combination with chemotherapy, followed by IMFINZI 1500 mg every 4 weeks and evaluable for the presence of ADAs, 2 (0.8%) patients tested positive for treatment-emergent ADAs. 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 and clinical safety of durvalumab.
In the HIMALAYA study, of the 294 patients who were treated with STRIDE and evaluable for the presence of ADAs, 9 (3.1%) patients tested positive for treatment-emergent ADAs. Neutralizing antibodies against durvalumab were detected in 1.7% (5/294) patients. The presence of ADAs did not have an apparent effect on pharmacokinetics or safety.
Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease.
For these reasons, comparison of incidence of antibodies to IMFINZI with the incidence of antibodies to other products may be misleading.
Toxicology: Preclinical safety data: Carcinogenicity and mutagenicity: The carcinogenic and genotoxic potential of durvalumab has not been evaluated.
Reproductive toxicology: As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the foetus, and in mouse allogeneic pregnancy models disruption of PD-L1 signalling was shown to result in an increase in foetal loss. In reproduction studies in cynomolgus monkeys, administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 22 times higher than those observed at the clinical dose of 10 mg/kg of durvalumab (based on AUC) was not associated with maternal toxicity or effects on embryofoetal development, pregnancy outcome or postnatal development.
Animal toxicology and/or pharmacology: Repeat dose toxicity studies in sexually mature cynomolgus monkeys with durvalumab of up to 3 months duration were not associated with any adverse effects that were considered of relevance to humans.
