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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 1,500 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 1,500 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): Neoadjuvant and Adjuvant Treatment of Resectable NSCLC-AEGEAN Study: The efficacy of IMFINZI in combination with neoadjuvant chemotherapy, followed by surgery and continued adjuvant treatment with IMFINZI as a single agent was investigated in AEGEAN (NCT03800134), a randomized, double-blind, placebo-controlled, multicenter trial conducted in 802 patients with previously untreated and resectable squamous or non-squamous NSCLC (Stage IIA to select Stage IIIB [AJCC, 8th edition]). Patients were enrolled regardless of tumor PD-L1 expression. Eligible patients had no prior exposure to immune-mediated therapy, a WHO/ECOG Performance status of 0 or 1, and at least one RECIST 1.1 target lesion.
Patients with active or prior documented autoimmune disease, or use of any immunosuppressive medication within 14 days of the first dose of IMFINZI were ineligible. The population for efficacy analyses was a modified intent-to-treat [mITT] which excluded patients with known EGFR mutations or ALK rearrangements.
Crossover between the study arms was not permitted. Randomization was stratified by disease stage (Stage II vs. Stage III) and by PD-L1 expression (TC <1% vs. TC ≥1%) status. Patients were randomized 1:1 to one of the following treatment arms: Arm 1: Neoadjuvant IMFINZI 1,500 mg once every 3 weeks for up to 4 cycles in combination with: Squamous tumor histology: carboplatin AUC 6 and paclitaxel 200 mg/m2 on Day1 of each 3-week cycle, OR cisplatin 75 mg/m2 on Day 1 and gemcitabine 1250 mg/m2 on Day 1 and Day 8 of each 3-week cycle, for 4 cycles.
Non-squamous tumor histology: pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on Day 1 of each 3-week cycle, for 4 cycles OR pemetrexed 500 mg/m2 and carboplatin AUC 5 on Day 1 of each 3-week cycle, for 4 cycles.
Followed by adjuvant IMFINZI 1,500 mg as a single agent for up to 12 cycles post-surgery.
Arm 2: Neoadjuvant placebo in combination with 4 cycles of chemotherapy (see previously mentioned) prior to surgery.
Followed by placebo for up to 12 cycles post-surgery.
All study medications were administered via intravenous infusion. In the event of unfavorable tolerability, patients who met the eligibility criteria were switched from cisplatin to carboplatin therapy at any point during the study. In patients with comorbidities or unable to tolerate cisplatin as per Investigators judgment, carboplatin AUC 5 could be administered from cycle 1. Treatment with IMFINZI or placebo continued until completion of the treatment, disease progression that precluded definitive surgery, inability to complete definitive surgery, disease recurrence in the adjuvant phase, or unacceptable toxicity. A RECIST 1.1 tumor assessment was performed at baseline, and upon completion of the neoadjuvant period (prior to surgery). Tumor assessments were conducted at 5 weeks postoperatively, prior to the start of adjuvant therapy and every 12 weeks until week 48, every 24 weeks for approximately 4 years, and then every 48 weeks thereafter until disease progression, consent withdrawal, or death.
The trial was not designed to isolate the effect of IMFINZI in each phase (neoadjuvant or adjuvant) of treatment.
The major efficacy outcome measures of the study were pathological complete response (pCR) by blinded central pathology review and event-free survival (EFS) by blinded independent central review (BICR) assessment. Additional efficacy outcome measures were major pathological response (MPR) by blinded central pathology review, DFS by BICR, and OS.
The demographics and baseline disease characteristics were as follows: male (72%); median age 65 years (range: 30 to 88); age ≥65 years (52%); WHO/ECOG PS 0 (68%), WHO/ECOG PS 1 (32); White (54%), Asian (41%), Black or African American (0.9%), American Indian or Alaska Native (1.4%), Other Race (2.6%); Not Hispanic or Latino (84%); current or past smokers (86%); squamous histology (49%) and non-squamous histology (51%); Stage II (28%), Stage III (71%); PD-L1 expression status TC ≥1% (67%), PD-L1 expression status TC <1% (33%).
In the mITT population, 78% of patients in Arm 1 completed definitive surgery compared to 77% of patients in Arm 2.
The trial demonstrated statistically significant improvements in EFS and pCR rate (see Table 1 and Figure 1) in the IMFINZI in combination with chemotherapy arm compared to the placebo in combination with chemotherapy arm. (See Table 1 and Figure 1.)
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Click on icon to see table/diagram/imageAt the interim analysis, the trial demonstrated a statistically significant difference in MPR rate (34% vs. 14%; p <0.0001). At the time of the prespecified interim analyses, overall survival (OS) was not formally tested for statistical significance.
PACIFIC Study: 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 2. (See Table 2.)
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 2 and 3. (See Figures 2 and 3.)
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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 4, 5, 6, and 7. (See Figures 4, 5, 6, and 7.)
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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 1,500 mg + tremelimumab 75 mg + etoposide and either carboplatin or cisplatin.
Arm 2: IMFINZI 1,500 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 3. Kaplan-Meier curve for PFS is presented in Figure 9.
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 3. 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 8. (See Table 3, Figures 8 and 9.)
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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.
Metastatic NSCLC-POSEIDON Study: POSEIDON was a study designed to evaluate the efficacy of IMFINZI with or without tremelimumab in combination with platinum-based chemotherapy. POSEIDON was a randomized, open-label, multicenter study in 1013 metastatic NSCLC patients with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumour aberrations. Patients with histologically or cytologically documented metastatic NSCLC were eligible for enrolment. Patients had no prior chemotherapy or any other systemic therapy for metastatic NSCLC. Prior to randomization, patients had tumour PD-L1 status confirmed by using the Ventana PD-L1 (SP263) assay. Patients had a World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrolment.
The study excluded patients with active or prior documented autoimmune disease; active and/or untreated brain metastases; a history of immunodeficiency; administration of systemic immunosuppression within 14 days before the start of IMFINZI or tremelimumab, 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 and/or tremelimumab.
Randomisation was stratified by tumour cells (TC) PD-L1 expression (TC ≥50% vs. TS <8th 50%), disease stage (Stage IVA vs. Stage IVB, per the 8th edition of American Joint Committeeon Cancer), and histology (non-squamous and squamous).
Patients were randomized 1:1:1 to receive: Arm1: IMFINZI 1,500 mg with tremelimumab 75 mg and platinum-based chemotherapy every 3 weeks for 4 cycles followed by, IMFINZI 1,500 mg every 4weeks as monotherapy. A fifth dose of tremelimumab 75 mg was given at Week 16 alongside IMFINZI dose 6.
Arm 2: IMFINZI 1,500 mg and platinum-based chemotherapy every 3 weeks for 4 cycles, followed by IMFINZI 1,500 mg every 4 weeks as monotherapy.
Arm 3: Platinum-based chemotherapy every 3 weeks for 4 cycles. Patient could receive 2 additional cycles (a total of 6 cycles post-randomisation), as clinically indicated, atthe Investigator's discretion.
In the 3 treatment arms, patients received one of the following histology-based chemotherapy regimens: Non-squamous NSCLC: Pemetrexed 500 mg/m2 with carboplatin AUC 5-6 or cisplatin 75 mg/m2 every 3 weeks. Unless contraindicated by the investigator, pemetrexed maintenance could be given.
Squamous NSCLC: Gemcitabine 1000 or 1,250 mg/m2 on Days 1 and 8 with cisplatin 75 mg/m2 or carboplatin AUC 5-6 on Day 1 every 3 weeks.
Non-squamous or squamous NSCLC: Nab-paclitaxel 100 mg/m2 on Days 1, 8, and 15 with carboplatin AUC 5-6 on Day 1 every 3 weeks.
Tremelimumab was given up to a maximum of 5 doses unless there was disease progression or unacceptable toxicity, IMFINZI and histology-based pemetrexed maintenance therapy (when applicable) was continued until disease progression or unacceptable toxicity.
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 dual primary endpoints of the study were progression-free survival (PFS) and overall survival (OS) for IMFINZI + platinum-based chemotherapy vs. platinum-based chemotherapy alone. The key secondary endpoints of the study were PFS and OS for IMFINZI + tremelimumab + platinum-based chemotherapy and platinum-based chemotherapy alone. The secondary endpoints included objection response rate (ORR) and Duration of Response (DoR). PFS, ORR, and DoR, were assessed using Blinded Independent Central Review (BICR)according to RECIST v1.1.
The demographic and baseline disease characteristics were well-balanced between study arms. Baseline demographic of the overall study population were as follows: male (76.0%), age ≥65 years (47.1%), age ≥75 years (11.3%) median age 64 years (range: 27 to 87 years), White (55.9%), Asian (34.6%), Black or African American (2.0%), Other (7.6%), non-Hispanic or Latino (84.2%), current smoker or past-smoker (78.0%), WHO/ECOG PS 0 (33.4%), WHO/ECOG PS 1 (66.5%). Disease characteristics as follows: Stage IVA (50.0%), Stage IVB (49.6%), histological sub-groups of squamous (36.9%), non-squamous (62.9%), brain metastases (10.5%), PD-L1 expression TC ≥50% (28.8), PD-L1 expression TC <50% (71.1%).
The study showed a statistically significant improved in OS with IMFINZI + tremelimumab + platinum-based chemotherapy vs. platinum-based chemotherapy. IMFINZI + tremelimumab + platinum-based chemotherapy showed a statistically significant improvement in PFS vs. platinum-based chemotherapy alone. The results are summarized as follows: (See Table 4, Figures 10 and 11.)
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Click on icon to see table/diagram/imageFigure 12 summarises efficacy results of OS by tumour PD-L1 expression in prespecified subgroup analyses. (See Figure 12.)
Click on icon to see table/diagram/imageElderly population: A total of 75 patients aged ≥75 years were enrolled in the IMFINZI in combination with tremelimumab and chemotherapy (n=35) and platinum-based chemotherapy only (n=40) arms of the POSEIDON study. An exploratory HR of 1.05 (95% CI: 0.64, 1.71) for OS was observed for the IMFINZI in combination with tremelimumab and platinum-based chemotherapy vs. platinum-based chemotherapy within this study subgroup. Due to the exploratory nature of this subgroup analysis no definitive conclusions can be drawn, but caution is suggested when considering this regimen for elderly patients.
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 1,500 mg administered on Day 1 + gemcitabine 1,000 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 1,500 mg every 4 weeks until disease progression or unacceptable toxicity, or Arm 2: Placebo administered on Day 1 + gemcitabine 1,000 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 5 and Figure 13. 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 5.)
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 13 and 14.)
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Click on icon to see table/diagram/imageHCC: HIMALAYA Study: The efficacy of IMFINZI given in combination with a single dose of tremelimumab 300 mg was evaluated in the HIMALAYA Study, a randomized, open-label, multicentre study in patients with confirmed uHCC who did not receive prior systemic treatment for HCC. The study included patients with Barcelona Clinic Liver Cancer (BLCC) 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 gastrointestinal (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 disease.
Patients with oesophageal 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), aetiology of liver disease (confirmed hepatitis B virus vs. confirmed hepatitis C virus vs. others) and ECOG performance status (0 vs. 1). The HIMALAYA study randomized 1171 patients 1:1:1 to receive: IMFINZI: durvalumab 1,500 mg every 4 weeks; Tremelimumab 300 mg as a single dose + IMFINZI 1,500 mg; followed by IMFINZI 1,500 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. Secondary endpoints included PFS, Investigator-assessed ORR and DoR according to RECIST v1.1.The demographics and baseline disease characteristics were well balanced between study arms. 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 race (2.3%), ECOG PS 0 (62.6%); Child-Pugh Class score A (99.5%), macrovascular invasion (25.2%), extrahepatic spread (53.4%), 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].
Results are presented in Table 6 and Figure 15. (See Table 6 and Figure 15.)
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Click on icon to see table/diagram/imageEndometrial Cancer: DUO-E Study: DUO-E was a randomised, multicentre, double-blind, placebo-controlled Phase III study of first-line platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI with or without olaparib in patients with advanced or recurrent endometrial cancer. Patients had to have endometrial cancer in one of the following categories: newly diagnosed Stage III disease (measurable disease per RECIST v1.1 following surgery or diagnostic biopsy), newly diagnosed Stage IV disease (with or without disease following surgery or diagnostic biopsy), or recurrence of disease (measurable or nonmeasurable disease per RECIST v1.1) where the potential for cure by surgery alone or in combination is poor. For patients with recurrent disease, prior chemotherapy was allowed only if it was administered in the adjuvant setting and there was at least 12 months from the date of last dose of chemotherapy administered to the date of subsequent relapse. The study included patients with epithelial endometrial carcinomas of all histologies, including carcinosarcomas. Patients with endometrial sarcoma were excluded.
Randomisation was stratified by tumour tissue's mismatch repair (MMR) status (proficient versus deficient), disease status (recurrent versus newly diagnosed), and geographic region (Asia versus rest of the world). Patients were randomised 1:1:1 to one of the following arms: Arm 1 (Platinum-based chemotherapy): Platinum-based chemotherapy (paclitaxel and carboplatin) every 3 weeks for a maximum of 6 cycles with durvalumab placebo every 3 weeks. Following completion of chemotherapy treatment, patients without objective disease progression received durvalumab placebo every 4 weeks and olaparib placebo tablets twice daily as maintenance treatment until disease progression.
Arm 2 (Platinum-based chemotherapy + IMFINZI): Platinum-based chemotherapy (paclitaxel and carboplatin) every 3 weeks for a maximum of 6 cycles with 1,120 mg durvalumab every 3 weeks. Following completion of chemotherapy treatment, patients without objective disease progression received 1,500 mg durvalumab every 4 weeks with olaparib placebo tablets twice daily as maintenance treatment until disease progression.
Arm 3 (Platinum-based chemotherapy + IMFINZI + olaparib): Platinum-based chemotherapy (paclitaxel and carboplatin) every 3 weeks for a maximum of 6 cycles with 1,120 mg durvalumab every 3 weeks. Following completion of chemotherapy treatment, patients without objective disease progression received 1,500 mg durvalumab every 4 weeks with 300 mg olaparib tablets twice daily as maintenance treatment until disease progression.
Patients who discontinued either product (IMFINZI/placebo or olaparib/placebo) for reasons other than disease progression could continue treatment with the other product if appropriate based on toxicity considerations and investigator discretion.
Treatment was continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Assessment of tumour status was performed every 9 weeks for the first 18 weeks relative to randomisation and every 12 weeks thereafter.
The primary endpoint was PFS, determined by investigator assessment using RECIST v1.1. Secondary efficacy endpoints included OS, ORR and DoR.
The study demonstrated a statistically significant improvement in PFS in the ITT population, for patients treated with platinum-based chemotherapy + IMFINZI + olaparib compared to platinum-based chemotherapy [HR=0.55 (95% CI: 0.43, 0.69), p=<0.0001], and for patients treated with platinum-based chemotherapy + IMFINZI compared to platinum-based chemotherapy [HR=0.71 (95% CI: 0.57, 0.89), p=0.003]. At the time of PFS analysis, interim OS data were 28% mature with events in 199 of 718 patients.
Mismatch repair (MMR) status was determined centrally using an MMR immunohistochemistry panel assay. Of a total of 718 patients randomized in the study, 575 (80%) patients had MMR-proficient (pMMR) tumour status and 143 (20%) patients had MMR-deficient (dMMR) tumour status.
Patients with MMR-deficient (dMMR) endometrial cancer: Among patients with dMMR tumour status, demographic and baseline characteristics were generally well balanced between the treatment arms. Baseline demographics across all three arms were as follows: median age of 62 years (range: 34 to 85), 41% age 65 or older, 1.5% age 75 or older, 62% White, 29% Asian, and 2% Black or African American. Disease characteristics were as follows: ECOG PS of 0 (58%) or 1 (42%), 46% newly diagnosed and 54% recurrent disease. The histologic subtypes were endometrioid (83%), mixed epithelial (5%), serous (3%), carcinosarcoma (3%), undifferentiated (2%), and other (3%).
In patients with dMMR tumour status, the results are summarised in Table 7 and Figure 16. The median follow-up time for PFS in censored patients with dMMR tumour status was 15.5 months in the platinum-based chemotherapy + IMFINZI arm and 10.2 months in the platinum-based chemotherapy arm. At the time of PFS analysis, interim OS data were 26% mature with events in 25 of 95 patients treated with platinum-based chemotherapy + IMFINZI and platinum-based chemotherapy. (See Table 7 and Figure 16.)
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Click on icon to see table/diagram/imagePatients with MMR-proficient (pMMR) endometrial cancer: Among patients with pMMR tumour status, demographic and baseline characteristics were generally well balanced between the treatment arms. Baseline demographics across all three arms were as follows: median age of 64 years (range: 22 to 86), 48% age 65 or older, 8.1% age 75 or older, 56% White, 30% Asian, and 6% Black or African American. Disease characteristics were as follows: ECOG PS of 0 (69%) or 1 (31%), 47% newly diagnosed and 53% recurrent disease. The histologic subtypes were endometrioid (54%), serous (26%), carcinosarcoma (8%), mixed epithelial (4%), clear cell (3%), undifferentiated (2%), mucinous (<1%), and other (3%).
Results in patients with pMMR tumour status are summarised in Table 8 and Figure 17. The median follow-up time in censored patients with pMMR tumour status was 15.2 months in the platinum-based chemotherapy + IMFINZI + olaparib arm, and 12.8 months in the platinum-based chemotherapy arm. At the time of PFS analysis, interim OS data were 29% mature with events in 110 of 383 patients treated with platinum-based chemotherapy + IMFINZI + olaparib and platinum-based chemotherapy. (See Table 8 and Figure 17.)
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Click on icon to see table/diagram/imageAmong patients with pMMR tumour status, the PFS HRs were 0.44 (95% CI: 0.31, 0.61) in patients with PD-L1 expression positive status (236/383; 62%) and 0.87 (95% CI: 0.59, 1.28) in patients with PD-L1 expression negative status (140/383; 37%), for the platinum-based chemotherapy + IMFINZI + olaparib arm compared to the platinum-based chemotherapy arm. PD-L1 expression positive was defined as tumour area positive (TAP) ≥1%.
Pharmacokinetics: 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 and in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib.
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: The observed incidence of anti-drug antibodies (ADA) highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparison of the incidence of ADAs in the studies described as follows with the incidence of ADAs in other studies including those of IMFINZI.
During the 10 to 48 week treatment period across PACIFIC, CASPIAN, TOPAZ-1, HIMALAYA, POSEIDON, DUO-E, AEGEAN and other clinical trials, in patients who received IMFINZI at dosages of 1,500 mg every 4 hours, 10 mg/kg every 2 weeks, 20 mg/kg every 4 weeks as a single agent or 1,120 mg every 3 weeks, or 1,500 mg every 3 weeks in the combination therapies, 3.2% (151/4668) of evaluable patients tested positive for anti-durvalumab antibodies, and 19.2% (29/151) of ADA positive patients had neutralizing antibodies against durvalumab. There were no identified clinically significant effects of ADAs on durvalumab pharmacokinetics or safety; however, the effect of these ADAs on the effectiveness of IMFINZI is unknown.
In the DUO-E study, the number of patients who were treated with platinum-based chemotherapy + IMFINZI (n=198) or platinum-based chemotherapy + IMFINZI + Olaparib (n=207) and evaluable for the presence of ADAs, 2 (1.0%) patients tested positive for treatment-emergent ADAs in the platinum-based chemotherapy + IMFINZI arm and no patients tested positive for treatment-emergent ADAs in the platinum-based chemotherapy + IMFINZI + olaparib arm. Neutralizing antibodies against durvalumab were detected in 1 (0.5%) patient in the platinum-based chemotherapy + IMFINZI arm and 0 patients in the platinum-based chemotherapy + IMFINZI + olaparib arm. There were insufficient number of patients with treatment-emergent ADAs or neutralizing antibodies to determine whether ADAs have an impact on pharmacokinetics or safety of durvalumab.
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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