Pharmacology: Pharmacodynamics: Mechanism of action: Expression of programmed cell death ligand-1 (PD-L1) protein is an adaptive immune response that helps tumors evade detection and elimination by the immune system. PD-L1 can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production.
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 tumor 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, maximizing anti-tumour immunity.
Clinical efficacy and safety: Durvalumab doses of 10 mg/kg every 2 weeks, 1120 mg every 3 weeks or 1500 mg every 4 weeks were evaluated in UC, NSCLC, ES-SCLC and endometrial cancer 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, 1120 mg every 3 weeks or 1500 mg every 4 weeks.
Urothelial Carcinoma-Study 1108: The efficacy of IMFINZI was evaluated in a multicentre, multi-cohort, open-label clinical trial, Study 1108. In the urothelial carcinoma cohort, 191 patients received IMFINZI 10 mg/kg every 2 weeks (Q2W) and had an opportunity to be followed for at least 16 weeks as of DCO (had tumour assessments at Weeks 6, 12, and 16). One hundred and eighty-two (182) of 191 patients with locally advanced or metastatic urothelial carcinoma had progressed while on or after a platinum-based therapy, including those patients who progressed within 12 months of receiving therapy in a neoadjuvant or adjuvant setting. Of the remaining 9 patients, 7 patients were cisplatin-ineligible at the time of study entry and 2 patients were cisplatin eligible and did not receive prior systemic therapy.
Sixty nine percent (69%) of patients received prior cisplatin, 29% had prior carboplatin and 33% received 2 or more prior lines of systemic therapy. The trial excluded patients with a history of immunodeficiency, medical conditions that required systemic immunosuppression; history of severe immune-mediated adverse reactions; untreated CNS metastases; HIV; active tuberculosis, or hepatitis B or C infection.
In this cohort, the median age was 67 years (range: 34 to 88), 71% were male, 71% were Caucasian. Ninety-three percent (93%) had visceral metastasis, including 43% with liver metastasis. Lymph-node only metastasis was present in 7% of patients. ECOG performance status 0 (33.5%) or 1 (66.5%). Forty-three percent (43%) had a baseline creatinine clearance of <60 mL/min. The median duration of follow-up for this cohort was 5.78 months (range: 0.24 to 25.9).
All patients received IMFINZI 10 mg/kg via intravenous infusion every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed disease progression. Tumour assessments were performed at Weeks 6, 12 and 16, then every 8 weeks for the first year and every 12 weeks thereafter. The primary efficacy endpoint was Objective Response Rate (ORR) according to RECIST v1.1 as assessed by Blinded Independent Central Review (BICR). Additional efficacy endpoint included Duration of Response (DoR).
Tumour specimens were evaluated for PD-L1 expression on tumour cells (TC) and immune cells (IC) using the Ventana PD-L1 (SP263) Assay. All testing was performed prospectively at a central laboratory. Of the 191 patients, 98 were classified as PD-L1 high (TC ≥25% or IC ≥25%), 79 as PDL1 low/negative (TC <25% and IC <25%) and samples for 14 patients were inadequate for evaluation. Table 1 summarises the efficacy results. PD-L1 high expression in patients with urothelial carcinoma was associated with numerically increased ORR. The median duration of response has not been reached.
Eight patients in the UC cohort did not have ongoing responses at the time of DCO. Seven patients progressed per BICR after an initial response, and 1 patient had PR per BICR based on the last available evaluable disease assessment (Day 168); however, the patient discontinued from treatment due to PD assessed by investigator, did not have any follow-up scans after discontinuation, and died due to disease progression on Day 608.
Among the total 34 responding patients, 76.5% (26/34) had ongoing responses at the time of analysis for ORR, 17 patients had ongoing responses of 6 months or longer, 10 patients had ongoing responses of 9 months or longer and 5 patients had ongoing responses of 12 months or longer. Of the 7 patients who progressed per BICR after an initial response, 3 patients remain on IMFINZI 10 mg/kg Q2W, and 4 patients completed 12 months of treatment with IMFINZI. (See Table 1 and Figure 1.)
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Muscle invasive bladder cancer (MIBC)-NIAGARA Study: NIAGARA was a randomised, open-label, multicentre Phase III study designed to evaluate the efficacy of neoadjuvant IMFINZI in combination with gemcitabine and cisplatin followed by adjuvant IMFINZI monotherapy in patients with MIBC. The study randomised 1063 patients who were candidates for radical cystectomy and had not received prior systemic chemotherapy or immune mediated therapy for the treatment of MIBC. The study excluded patients with pure non-urothelial histology, any small cell histology and primary non-bladder (i.e., ureter, urethral, or renal pelvis) cancer of the urothelium, active or prior documented autoimmune disease, active tuberculosis or hepatitis B or C or HIV infection, or use of immuno-suppressive medication within 14 days of the first dose of durvalumab except systemic corticosteroids when used at physiological doses or as premedication.
Randomisation was stratified by clinical tumour stage T2N0 vs. >T2N0 (including T2N1, T3, and T4a), renal function (adequate renal function: creatinine clearance [CrCl] ≥60 mL/min vs. borderline renal function: CrCl ≥40 mL/min to <60 mL/min), and PD-L1 expression (high vs. low/negative) status.
Patients were randomised 1:1 to receive perioperative IMFINZI with neoadjuvant chemotherapy (Arm 1) or neoadjuvant chemotherapy alone (Arm 2): Arm 1 (IMFINZI + chemotherapy): IMFINZI 1500 mg + gemcitabine 1000 mg/m
2 and cisplatin 70 mg/m
2 every 3 weeks for 4 cycles prior to surgery, followed by IMFINZI 1500 mg every 4 weeks for up to 8 cycles after surgery, or Arm 2 (Chemotherapy): gemcitabine 1000 mg/m
2 and cisplatin 70 mg/m
2 every 3 weeks for 4 cycles prior to surgery, without post-surgery treatment.
Patients with borderline renal function received split dose cisplatin of 35 mg/m
2 on days 1 and 8 of each cycle.
A RECIST 1.1 tumour assessment was performed at baseline and upon completion of neoadjuvant therapy (prior to surgery). After surgery, RECIST 1.1 tumour assessments were performed every 12 weeks for the first 24 months, then every 24 weeks for 36 months, and then every 52 weeks thereafter until progression, the end of study, or death.
The primary endpoints were pathological complete response (pCR) by blinded central pathology review and event-free survival (EFS) which included blinded independent central review (BICR) assessment. The key secondary endpoint was overall survival (OS). Other secondary efficacy endpoints included proportion of patients who achieve <P2 per local pathology review, the proportion of patients who underwent radical cystectomy, metastasis-free survival (MFS), 24-month EFS, disease-free survival (DFS) and time from randomisation to second progression on subsequent therapy (PFS2).
The demographics and baseline disease characteristics were generally well-balanced between the 533 patients in Arm 1 and 530 patients in Arm 2. Baseline demographics were as follows: male (81.8%), age <65 years (46.9%), white (67%), Asian (27.9%), black or African American (0.9%), other (0.8%), Hispanic or Latino (8.0%), and ECOG PS 0 (78.4%) vs. PS 1 (21.6%). Disease characteristics were as follows: Tumour Stage T2N0 (40.3%) and >T2N0a (59.7%), Regional lymph nodes N0 (94.5%) and N1 (5.5%), adequate renal function (81.1%) and borderline renal function (18.9%), and PD-L1 expression status high (73.1%) and low/negative (26.9%). The histologic subtypes included urothelial carcinoma (84.5%), urothelial carcinoma with squamous differentiation (8.2%), urothelial carcinoma with variant histology (5.0%), and urothelial carcinoma with glandular differentiation (2.4%).
At a pre-specified interim analysis, the study demonstrated a statistically significant and clinically meaningful improvement in EFS in the IMFINZI + chemotherapy arm compared to the chemotherapy arm [HR = 0.68 (95% CI: 0.56, 0.82), p = <0.0001]. The study also demonstrated a statistically significant and clinically meaningful improvement in OS in the IMFINZI + chemotherapy arm compared to the chemotherapy arm [HR=0.75 (95% CI: 0.59, 0.93), p=0.0106]. A numerical improvement in pCR rates was observed in the IMFINZI + chemotherapy arm [Response rate = 37.3% (95% CI: 33.2, 41.6)] compared to the chemotherapy arm [Response rate = 27.5% (95% CI: 23.8, 31.6)] See Table 2 and Figures 2 and 3.
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Subgroup analysis: Improvements in EFS favouring patients in Arm 1 compared to patients in Arm 2 were consistent across pre-specified subgroups based on demographic and baseline disease characteristics.
Improvements in OS favouring patients in Arm 1 compared to patients in Arm 2 were generally consistent across pre-specified subgroups based on demographic and baseline disease characteristics.
Patient Reported Outcomes (PRO): Patient-reported symptoms, functioning, and health related quality of life (HRQoL) were collected using the EORTC QLQ-C30. The questionnaire was to be collected on Day 1 of every cycle and administered before discussion of disease progression and dosing. At baseline, patient-reported symptoms, functioning or HRQoL scores were comparable between the study arms. Overall, the PRO/HRQoL data was generally similar between treatment arms throughout the overall study period. Time to deterioration and change from baseline analyses were consistent with no detriment in symptoms, functioning and HRQoL per EORTC QLQC30 in Arm 1 compared to Arm 2.
Locally Advanced NSCLC-PACIFIC Study: The efficacy of IMFINZI was evaluated in the PACIFIC Study, a randomized, double-blind, placebo-controlled, multicenter 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 randomized 2:1 to receive 10 mg/kg IMFINZI (n=476) or placebo (n=237) via intravenous infusion every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed disease progression. Randomization was stratified by gender, age (<65 years vs. ≥65 years) and smoking status (smoker vs. non-smoker). Tumour assessments were conducted every 8 weeks for the first 12 months and then every 12 weeks thereafter.
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%), PD-L1 expression TC≥25% (22%), PD-L1 expression TC<25% (41%). (PD-L1 status was retrospectively analysed in 451 patients with available samples, taken prior to concurrent chemoradiation therapy).
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.
At the primary analysis 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 (95% CI: 13.0, 18.1) in the IMFINZI treated group and 5.6 months (95% CI: 4.6, 7.8) in the placebo group. 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. See Table 3 and Figures 4 and 5.
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The improvements in OS and PFS in favor of patients receiving IMFINZI compared to those receiving placebo were consistently observed across predefined subgroups analyzed. Sensitivity analyses of OS and PFS demonstrated a consistent treatment effect with that observed in the primary analysis.
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 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).
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 randomised, open-label, multicentre 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 a 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 randomisation, patients had tumour PD-L1 status confirmed by using the Ventana PD-L1 (SP263) Assay. Patients had a World Health Organization/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
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. TC<50%), disease stage (Stage IVA vs. Stage IVB), and histology (non-squamous vs. squamous).
Patients were randomised 1:1:1 to receive: Arm 1: IMFINZI 1500 mg with tremelimumab 75 mg and platinum-based chemotherapy every 3 weeks for 4 cycles, followed by, IMFINZI 1500 mg every 4 weeks as monotherapy. A fifth dose of tremelimumab 75 mg was given at Week 16 alongside IMFINZI dose 6.
Arm 2: IMFINZI 1500 mg and platinum-based chemotherapy every 3 weeks for 4 cycles, followed by, IMFINZI 1500 mg every 4 weeks as monotherapy.
Arm 3: Platinum-based chemotherapy every 3 weeks for 4 cycles as monotherapy. Patients could receive additional 2 cycles (a total of 6 cycles post-randomisation), as clinically indicated, at investigator's discretion.
In the 3 treatment arms, patients received one of the following histology-based chemotherapy regimens: Non-squamous NSCLC: Pemetrexed 500 mg/m
2 with carboplatin AUC 5-6 or cisplatin 75 mg/m
2 every 3 weeks, unless contraindicated by the investigator, pemetrexed maintenance could be given.
Squamous NSCLC: Gemcitabine 1000 or 1250 mg/m
2 on Days 1 and 8 with cisplatin 75 mg/m
2 or carboplatin AUC 5-6 on Day 1 every 3 weeks.
Non-squamous and Squamous NSCLC: Nab-paclitaxel 100 mg/m
2 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. 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 with disease progression during IMFINZI monotherapy were given the option to to be retreated with 4 additional cycles of tremelimumab alongside IMFINZI.
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 dual primary endpoints of the study were PFS and OS for IMFINZI + platinum-based chemotherapy (Arm 2) vs. platinum-based chemotherapy alone (Arm 3). The key secondary endpoints of the study were PFS and OS for IMFINZI + tremelimumab + platinum-based chemotherapy (Arm 1) vs. platinum-based chemotherapy alone (Arm 3). The secondary endpoints included ORR and DoR. PFS, ORR, and DoR were assessed using BICR according to RECIST v1.1. At planned analyses for OS and PFS, IMFINZI + tremelimumab + platinum-based chemotherapy (Arm 1) vs. platinum-based chemotherapy (Arm 3) met the efficacy boundaries for the endpoints of OS and PFS. The results are summarised as follows.
The demographics and baseline disease characteristics were generally well-balanced between study arms. Baseline demographics of the overall study population were as follows: male (76.0%), age ≥65 years (47.1%), 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%), and never smoker (21.9%), WHO/ECOG PS 0 (33.4%), WHO/ECOG PS 1 (66.5%). Disease characteristics were as follows: Stage IVA (50.0%), Stage IVB (49.6%), histological sub-groups of squamous (36.9%), non-squamous (62.9%), PD-L1 expression TC≥50% (28.8%), PD-L1 expression TC <50% (71.1%).
The study demonstrated a statistically significant and clinically meaningful improvement in OS in the IMFINZI + tremelimumab + platinum-based chemotherapy (Arm 1) vs. platinum-based chemotherapy alone (Arm 3) [HR=0.77 (95% CI: 0.650, 0.916), p=0.00304]. IMFINZI + tremelimumab + platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in PFS vs. platinum-based chemotherapy alone (Arm 3) [HR=0.72 (95% CI: 0.600, 0.860), p=0.00031]. See Table 4 and Figures 6 and 7.
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Subgroup analysis: The improvements in OS and PFS favour patients receiving IMFINZI + tremelimumab + platinum-based chemotherapy compared to those receiving platinum-based chemotherapy alone and were consistently observed across the prespecified subgroups based on demographic and baseline characteristics, biomarker status, histology, planned chemotherapy, and disease characteristics. An exception was noted in the never smoker subgroup for OS. However, due to the small numbers of patients, no definitive conclusions can be drawn from these data.
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). 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. Overall compliance for EORTC QLQ-C30 and EORTC QLQ-L13 were 73.0% and 72.8% in the T + D + SoC arm and 65.0% and 64.8% in the SoC chemotherapy arm.
Delay in time to deterioration (TTD) of symptoms, functioning, and global health status/QoL: D+T+SoC prolonged the median TTD in patient-reported symptoms, functioning and global health status/QoL compared to SoC alone (see Tables 5 and 6). Nominally significant differences in TTD in favor of T + D + SoC compared to SoC alone were observed for the pre-specified domains of interest of global health status/QoL, physical functioning and dyspnea (EORTC QLQ-LC13) (HRs ranging from 0.75 to 0.78; nominal p-values <0.05). (See Tables 5 and 6.)
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Resectable NSCLC-AEGEAN Study: AEGEAN was a randomized, double-blind, placebo-controlled, multicentre, Phase III study designed to evaluate the efficacy of IMFINZI in combination with chemotherapy as neoadjuvant treatment, then continued as IMFINZI monotherapy after surgery, in patients with resectable NSCLC (Stage IIA to select Stage IIIB [AJCC, 8th edition]). The study enrolled previously untreated patients with documented squamous or non-squamous NSCLC and 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. Prior to randomization, patients had tumour PD-L1 expression status confirmed using the Ventana PD-L1 (SP263) Assay.
The study excluded patients with active or prior documented autoimmune disease, or use of immunosuppressive medication within 14 days of the first dose of durvalumab. The study population for efficacy analysis (modified intent-to-treat [mITT]) excluded patients with known EGFR mutations or ALK rearrangements.
Randomisation was stratified by disease stage (Stage II vs. Stage III) and by PD-L1 expression (TC<1% vs. TC≥1%) status.
The AEGEAN study randomized 802 patients in a 1:1 ratio to receive perioperative IMFINZI (Arm 1) or placebo (Arm 2) in combination with neoadjuvant chemotherapy. Crossover between the study arms was not permitted. Efficacy analysis was conducted based on 740 patients in the mITT population.
Arm 1: IMFINZI 1500 mg + chemotherapy every 3 weeks for up to 4 cycles prior to surgery, followed by IMFINZI 1500 mg every 4 weeks for up to 12 cycles after surgery.
Arm 2: Placebo + chemotherapy every 3 weeks for up to 4 cycles prior to surgery, followed by Placebo every 4 weeks for up to 12 cycles after surgery.
A RECIST 1.1 tumour assessment was performed at baseline, and upon completion of the neoadjuvant period (prior to surgery). The first post-surgical CT/MRI scan of the chest and abdomen (including the entire liver and both adrenals) was acquired 5 weeks ±2 weeks after surgery and prior to, but as close as possible to the start of adjuvant therapy. Tumour assessments were then conducted every 12 weeks (relative to the date of surgery) until week 48, every 24 weeks (relative to the date of surgery) until week 192 (approximately 4 years), and then every 48 weeks (relative to the date of surgery) thereafter until RECIST 1.1 defined radiological PD, consent withdrawal, or death.
Survival assessments were conducted at month 2, 3, and 4 following treatment discontinuation and then every 2 months until month 12 followed by every 3 months.
The primary endpoints 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. The key secondary endpoints were major pathological response (MPR) by blinded central pathology review, DFS by BICR, and OS. Other secondary efficacy objectives included were EFS (PD-L1-TC ≥1% analysis set), pCR (PD-L1-TC ≥1% analysis set), and Patient Reported Outcomes (PRO).
At the planned interim analysis of pCR, the study met its prespecified boundary for declaring statistical significance for pCR and MPR. Subsequently, at the first planned interim analysis of EFS, the study met its prespecified boundary for declaring statistical significance for EFS.
The demographics and baseline disease characteristics were well balanced between the two study arms (366 patients in Arm 1 and 374 patients in Arm 2 of the mITT set). Baseline demographics and disease characteristics of the population for efficacy analysis (mITT) were as follows: male (71.6%), female (28.4%), age ≥65 years (51.6%), median age 65 years (range: 30 to 88), WHO/ECOG PS 0 (68.4%), WHO/ECOG PS 1 (31.6), White (53.6%), Asian (41.5%), Black or African American (0.9%), American Indian or Alaska Native (1.4%), Other Race (2.6%), Hispanic or Latino (16.1%), Not Hispanic or Latino (83.9%), current or past smokers (85.5%), never smoker (14.5%), squamous histology (48.6%) and non-squamous histology (50.7%), Stage II (28.4%), Stage III (71.6%), PD-L1 expression status TC ≥1% (66.6%), PD-L1 expression status TC <1% (33.4%). The demographics and baseline characteristics for the mITT population were similar to the ITT population except for the absence of patients with known EGFR mutations or ALK rearrangements.
In the mITT population there were 295 (80.6%) patients in Arm 1 who underwent curative intent surgery compared to 302 (80.7%) patients in Arm 2. There were 284 (77.6%) patients in Arm 1 who completed curative intent surgery compared to 287 (76.7%) patients in Arm 2. The resection margin status within the mITT population, who completed surgery, was (Arm 1 vs. Arm 2).
R0 (no residual tumour): 94.7% vs. 91.3%; R1 (microscopic residual tumour): 4.2% vs. 7.7%; R2 (macroscopic residual tumour): 0.7% vs. 0.7%.
The study demonstrated a statistically significant and clinically meaningful improvement in EFS [HR=0.68 (95% CI: 0.53, 0.88), p=0.003902] of the IMFINZI arm compared to the placebo arm. The study also demonstrated a statistically significant and meaningful improvement in pCR [Difference in proportions, 12.96% (95% CI: 8.67, 17.57)] of the IMFINZI arm compared to the placebo arm. Overall survival (OS) data were not mature at the time of EFS analysis. See Table 7 and Figure 8.
At the primary (pre-specified) EFS analysis (DCO: 10 November 2022), with a maturity of 31.9% and a median EFS follow-up in censored patients of 11.7 months, the study demonstrated a statistically significant and clinically meaningful improvement in the IMFINZI arm compared to the placebo arm [HR=0.68 (95% CI: 0.53, 0.88), p=0.003902].
At the updated (pre-specified) EFS analysis (DCO: 10 May 2024), the median EFS follow-up in censored patients was 25.9 months. At this analysis, DFS was not statistically significant; however, a trend for improved DFS favouring the IMFINZI arm was observed [HR=0.66 (95% CI: 0.47, 0.92)]. OS was not formally tested for statistical significance; however, a trend for improved OS favouring the IMFINZI arm was observed [HR=0.89 (95% CI: 0.70, 1.14)]. (See Table 7.)
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The boundary for declaring statistical significance for each of the efficacy endpoints were determined by a Lan-DeMets alpha spending function that approximates an O'Brien Fleming approach (EFS=0.9899%, pCR=0.0082%, MPR=0.0082%, 2-sided). (See Figure 8.)
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Subgroup analysis: The improvement in EFS and pCR favouring patients in Arm 1 compared to patients in Arm 2 were consistently observed across prespecified subgroups based on demographic and baseline disease characteristics, histology, and planned chemotherapy.
Patient Reported Outcomes (PRO): Patient-reported symptoms, function, and health related quality of life (HRQoL) were collected using the EORTC QLQ-C30, complementary EORTC QLQ-LC13, and exploratory PGIS, EQ-5D-5L, and PRO-CTCAE. These questionnaires were administered before discussion of disease progression and dosing and collected on month 1, 2, 3, and 6 post last dose. Overall compliance rates were high at neoadjuvant baseline (>90%) in the IMFINZI in combination with chemotherapy arm and the placebo in combination with chemotherapy arm.
Overall, the PRO/HRQoL data was generally similar between treatment arms throughout the neoadjuvant period. The proportion of patients with a clinically meaningful (≥10 point change) improvement in EORTC QLQ-C30 GHS/QoL was similar over the neoadjuvant period (reported for approximately a quarter of patients in both treatment arms). Clinically meaningful changes (≥10 point from baseline) were observed in only two scales: worsening fatigue (EORTC QLQ-C30) in the D + CTx arm (12.57 points [D + CTx] vs 8.50 points [placebo + CTx]) and decreased coughing (EORTC QLQ-LC13) in the placebo + CTx arm (-9.26 points [D + CTx] vs -11.60 points [placebo + CTx).
In the adjuvant period, all PRO instruments (EORTC QLQ-C30, EORTC QLQ-LC13, EQ-5D/EQ-VAS, PGIS, and PRO-CTCAE) were administered at adjuvant baseline, the EORTC QLQ-C30 and PRO-CTCAE were administered every 4 weeks and the PGIS was administered at Weeks 20 and 44 during the adjuvant treatment period. Compliance rates were high (>81%) in both arms at adjuvant baseline for all PRO instruments. For those instruments administered beyond adjuvant baseline, the compliance rates remained high throughout the adjuvant period and were similar in both treatment arms.
Overall, the PRO/HRQoL data was generally similar between treatment arms throughout the adjuvant period. The proportions of patients with a meaningful improvement (defined as a ≥10 point improvement) in EORTC QLQ-C30 GHS/QoL was similar over the adjuvant period. The PRO/HRQoL at adjuvant baseline was either maintained or slightly improved (numerically) throughout the adjuvant period for both treatment arms. The proportion of patients with a clinically meaningful deterioration (defined as a ≥10-point worsening) were small (mostly <20%) across GHS/QoL and functional domains during the adjuvant period and similar in both treatment arms, except for GHS/QoL in which the proportion of patients in the D + CTx arm with a meaningful deterioration were slightly (numerically) greater than those of the placebo + CTx arm.
SCLC-ADRIATIC Study: ADRIATIC was a study designed to evaluate the efficacy of IMFINZI with or without tremelimumab. ADRIATIC was a randomised, double-blind, placebo-controlled multicentre study in 730 patients with histologically or cytologically confirmed LS-SCLC (Stage I to III according to AJCC, 8th edition) who had not progressed following concurrent chemoradiation therapy. Patients who were Stage I or II had to be medically inoperable as determined by the investigator. Patients completed 4 cycles of definitive platinum-based chemoradiation, 60-66 Gy once daily (QD) over 6 weeks or 45 Gy twice daily (BID) over 3 weeks, within 1 to 42 days prior to the first dose of study treatment. Prophylactic cranial irradiation (PCI) could be delivered at the discretion of the investigator after chemoradiation therapy and within 1 to 42 days prior to the first dose of study treatment.
The study excluded patients with active or prior documented autoimmune disease within 5 years of initiation of the study; a history of active primary immunodeficiency; a history of Grade ≥2 pneumonitis or active tuberculosis or hepatitis B or C or HIV infection and patients with active interstitial lung disease. Patients with mixed SCLC and NSCLC histology were also excluded.
Randomisation was stratified by stage (I/II versus III) and receipt of PCI (yes versus no). Patients were randomised 1:1:1 to receive: Arm 1: IMFINZI 1500 mg + placebo every 4 weeks for 4 cycles, followed by IMFINZI 1500 mg every 4 weeks; Arm 2: Placebo + a second placebo every 4 weeks for 4 cycles, followed by a single placebo every 4 weeks; Arm 3: IMFINZI 1500 mg + tremelimumab 75 mg every 4 weeks for 4 cycles, followed by IMFINZI 1500 mg every 4 weeks.
Once 600 patients had been randomised across all three arms, subsequent patients were randomised 1:1 to either arm 1 or 2, and received either IMFINZI 1500 mg every 4 weeks or placebo every 4 weeks.
Treatment continued until disease progression, until unacceptable toxicity, or for a maximum of 24 months. Tumour assessments were conducted every 8 weeks for the first 72 weeks, then every 12 weeks up to 96 weeks, and then every 24 weeks thereafter.
The demographics and baseline disease characteristics were well balanced between study arms. Baseline demographics and disease characteristics of the IMFINZI and placebo arms were as follows: male (69.1%), age ≥65 years (39.2%), White (50.4%), Black or African-American (0.8%), Asian (47.5%), other (1.3%), Hispanic or Latino (4.2%), current smoker (22.3%), past-smoker (68.5%), never smoker (9.2%), WHO/ECOG PS 0 (48.7%), WHO/ECOG PS 1 (51.3%), Stage I (3.6%), Stage II (9.1%), Stage III (87.4%).
Prior to randomisation, all patients received platinum-based chemotherapy (66.2% cisplatin-etoposide, 33.8% carboplatin-etoposide); 72.1% of patients received RT QD (of which 92.4% received ≥60 - ≤66 Gy QD); 27.9% received RT BID (of which 96.6% received 45 Gy BID) and 53.8% patients received PCI. Response to CRT was as follows: complete response (12.3%), partial response (73.8%), stable disease (14.0%).
The dual primary endpoints of the study were OS and PFS of IMFINZI vs. placebo. Secondary efficacy endpoints included ORR of IMFINZI vs. placebo. PFS and ORR were assessed by BICR according to RECIST v1.1.
At a planned interim analysis, the study demonstrated a statistically significant and clinically meaningful improvement in OS for IMFINZI compared with placebo [HR=0.73 (95% CI: 0.569, 0.928), p=0.01042]. The study also demonstrated a statistically significant and clinically meaningful improvement in PFS for IMFINZI compared with placebo [HR=0.76 (95% CI: 0.606, 0.950), p=0.01608]. See Table 8 and Figures 9 and 10.
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The improvements in OS and PFS in favour of patients receiving IMFINZI compared to those receiving placebo were generally consistent across predefined subgroups analysed.
Patient Reported Outcomes: Patient-reported physical functioning and disease-related symptoms 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 scores were assessed at baseline, weekly for the first 8 weeks (LC13 only, C30 was assessed every 4 weeks), followed by every 4 weeks until completion of the treatment period or discontinuation of study drug due to toxicity or disease progression. At baseline, patient-reported physical functioning and symptoms were comparable between IMFINZI and placebo arms.
Throughout the duration of the study to Week 48, there was no clinically meaningful difference between IMFINZI and placebo arms in symptoms, functioning and HRQoL (as assessed by a difference of greater than or equal to 10 points).
SCLC-CASPIAN Study: The efficacy of IMFINZI in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was investigated in CASPIAN, a randomized, multicenter, active-controlled, open-label trial (NCT03043872). Eligible patients had WHO Performance Status of 0 or 1 and were suitable to receive a platinum-based chemotherapy regimen as first-line treatment for SCLC. Patients with asymptomatic or treated brain metastases were eligible. Choice of platinum agent was at the investigator's discretion, taking into consideration the calculated creatinine clearance. Patients with history of chest radiation therapy; a history of active primary immunodeficiency; autoimmune disorders including paraneoplastic syndrome; 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 were ineligible.
Randomization was stratified by the planned platinum-based therapy in cycle 1 (carboplatin or cisplatin).
The evaluation of efficacy for ES-SCLC relied on comparison between: IMFINZI 1500 mg, and investigator's choice of carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75-80 mg/m
2) on Day 1 and etoposide (80-100 mg/m
2) intravenously on Days 1, 2, and 3 of each 21-day cycle for 4 cycles, followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity; or Investigator's choice of carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75-80 mg/m
2) on Day 1 and etoposide (80-100 mg/m
2) intravenously on Days 1, 2, and 3 of each 21-day cycle, up to 6 cycles. After completion of chemotherapy, prophylactic cranial irradiation (PCI) as administered per investigator discretion.
Administration of IMFINZI as a single agent was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.
The major efficacy outcome measure was overall survival (OS) of IMFINZI plus chemotherapy vs. chemotherapy alone. Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR), per RECIST v1.1.
The study population characteristics were: median age of 63 years (range: 28 to 82); 40% age 65 or older; 70% male; 84% White, 15% Asian, and 0.9% Black; 65% WHO/ECOG PS of 1; and 93% were former/current smokers. Ninety percent of patients had Stage IV disease and 10% had brain metastasis at baseline. A total of 25% of the patients received cisplatin and 74% of the patients received carboplatin. In the chemotherapy alone arm, 57% of the patients received 6 cycles of chemotherapy, and 8% of the patients received PCI.
The OS results are summarized in Table 9 and Figure 11. (See Table 9 and Figure 11.)
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Investigator-assessed PFS (96% of total planned events) showed a HR of 0.78 (95% CI: 0.65, 0.94), with median PFS of 5.1 months (95% CI: 4.7, 6.2) in the IMFINZI plus chemotherapy arm and 5.4 months (95% CI: 4.8, 6.2) in the chemotherapy alone arm. The investigator-assessed confirmed ORR was 68% (95% CI: 62%, 73%) in the IMFINZI plus chemotherapy arm and 58% (95% CI: 52%, 63%) in the chemotherapy alone arm.
In the exploratory subgroup analyses of OS based on the planned platinum chemotherapy received at cycle 1, the HR was 0.70 (95% CI 0.55, 0.89) in patients who received carboplatin, and the HR was 0.88 (95% CI 0.55, 1.41) in patients who received cisplatin.
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/m
2 and cisplatin 25 mg/m
2 (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/m
2 and cisplatin 25 mg/m
2 (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 (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 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 and clinically meaningful improvement in OS and PFS at a pre-planned interim (primary) analysis. 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%. Results from this analysis are presented in Table 10 and Figure 12.
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 for the IMFINZI + gemcitabine and cisplatin arm). Results from this analysis for OS are presented in the Table 10 and Figure 12. (See Table 10 and Figures 12 and 13.)
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Subgroup 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.
HCC-HIMALAYA Study: The efficacy of STRIDE was evaluated in the HIMALAYA study, a randomised, open-label, multicenter 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 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 randomized 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.
Treatment continued as long as clinical benefit was observed or until unacceptable toxicity. Patients in all arms could continue to receive treatment after evidence of disease progression if, in the Investigator's opinion, they were benefiting from study drug and met all inclusion and exclusion criteria for treatment beyond progression. In addition, patients in the STRIDE arm who continued treatment beyond progression were allowed to be rechallenged once with an additional single dose of tremelimumab 300 mg after cycle five of IMFINZI. Of the 182 patients enrolled to the STRIDE arm who received IMFINZI beyond progression, the median OS was 19.5 months (95% CI: 15.4, 23.4). Of the 30 patients who were enrolled to the STRIDE arm who were rechallenged with tremelimumab, the median OS was 30.4 months (95% CI: 23.4, NR).
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 for STRIDE vs. S. The key secondary objective was OS for non-inferiority based on the comparison of IMFINZI vs. S. Key secondary endpoints were Investigator assessed PFS, 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%).
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]. The study also met the key secondary objective of OS non-inferiority of IMFINZI to S with the upper limit of the 95.67% CI being below the pre-specified non-inferiority margin of 1.08. (See Table 11 and Figures 14 and 15.)
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Patient reported outcomes: Patient-reported symptoms, function and health-related quality of life (HRQoL) were collected using the EORTC QLQ-C30 and its hepatocellular carcinoma module (EORTC QLQ-HCC18). At baseline, patient-reported symptoms, functioning or HRQoL scores were comparable between the study arms.
STRIDE vs. S: Delay in time to deterioration of symptoms, functioning, and global health status/QoL: STRIDE vs. S demonstrated a clinically meaningful improvement by delaying time to deterioration in a broad range of patient-reported symptoms, function, and global health status/QoL compared to S. Longer time to deterioration (median in months) was observed in the STRIDE arm compared to S for the following symptoms: Global Health Status (7.5 vs. 5.7 months, HR 0.76, p=0.0306); physical functioning (12.9 vs. 7.4 months, HR 0.68; p=0.0020), fatigue (7.4 vs. 5.4 months, HR 0.71; p=0.0026), nausea (25.0 vs. 11.0 months, HR 0.65; p=0.0033), appetite loss (12.6 vs. 6.9 months, HR 0.59; p <0.0001), abdominal pain (16.8 vs. 8.9 months, HR 0.61; p=0.0008) and abdominal swelling (20.9 vs. 11.1 months, HR 0.74; p=0.0431).
Change from baseline in patient-reported symptoms (mixed model for repeated measures): STRIDE improved patient-reported HRQoL functioning and diarrhoea by demonstrating a nominal difference and clinically meaningful mean change from baseline vs. S from randomisation until 8 months (Estimated mean difference at 8 months: -18.5 95% CI: -23.24, -13.84 and p-value: <0.0001).
Patient-reported outcome results should be interpreted in the context of the open-label study design.
IMFINZI vs. S: Delay in time to deterioration of symptoms, functioning and GHS/QoL: Treatment with IMFINZI demonstrated a clinically meaningful delay in time to deterioration in a broad range of patient-reported symptoms, function and GHS/QoL compared with S. Longer median time to deterioration was observed in the IMFINZI arm compared to S for the following: EORTC QLQ-C30 appetite loss (11.1 vs. 6.9 months, HR=0.60; p<0.0001), fatigue (6.9 vs. 5.4 months, HR=0.75; p=0.0162), physical functioning (14.1 vs. 7.4 months, HR=0.66; p=0.0008) and GHS/QoL domain (7.4 vs. 5.7 months, HR=0.77; p=0.0300); and EORTC QLQ-HCC18 abdominal pain (14.1 vs. 8.9 months, HR=0.67; p=0.0022).
Change from baseline in patient-reported symptoms (mixed model for repeated measures): Treatment with IMFINZI also demonstrated fewer patient-reported symptoms, better function and improved GHS/QoL burden over time as evidenced by the change from baseline scores compared with S.
Patient-reported outcome results should be interpreted in the context of the open-label study design.
HCC-Study 22: The safety and efficacy of STRIDE was evaluated in Study 22, an open-label, multi-part, multicenter study in 75 immunotherapy naïve patients with uHCC who had progressed on, are intolerant to, or have refused sorafenib. The study included patients with BCLC Stage C or B (not eligible for locoregional therapy), ECOG performance status of 0 or 1 and Child-Pugh Score Class A.
The study excluded patients with 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.
Treatment continued as long as clinical benefit was observed or until unacceptable toxicity. Patients who completed the assigned dosing cycles and were benefiting from study drug in the investigator's opinion and subsequently had evidence of disease progression during the IMFINZI monotherapy phase could be rechallenged with tremelimumab 300 mg.
Tumour assessments were conducted every 8 weeks.
The primary objective was safety and tolerability. Key secondary endpoints included OS, ORR and DoR. ORR, DoR and PFS were based on Investigator assessments and BICR according to RECIST 1.1.
The baseline demographics of the study population (STRIDE) were as follows: male (86.7%); age <65 years (45.3%), white (36.0%); Asian (58.7%); black or African American (5.3%); other (0%), ECOG PS 0 (61.3%), Child-Pugh Class/Score A/5 (68.0%), Child-Pugh Class/Score A/6 (30.7%), macrovascular invasion (21.3%); extrahepatic spread (70.7%), viral etiology; hepatitis B (36.0%), hepatitis C (28.0%), uninfected (36.0%); prior systemic therapy (73.3%).
Efficacy results are shown in Table 12. (See Table 12.)
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Endometrial 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 maintenance IMFINZI with or without olaparib in patients with advanced or recurrent endometrial cancer. 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 1120 mg IMFINZI every 3 weeks. Following completion of chemotherapy treatment, patients without objective disease progression received 1500 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 1120 mg IMFINZI every 3 weeks. Following completion of chemotherapy treatment, patients without objective disease progression received 1500 mg durvalumab every 4 weeks with 300 mg olaparib tablets twice daily as maintenance treatment until disease progression.
Patients who discontinued either product (durvalumab/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 demographics and baseline disease characteristics were generally well balanced between the three study arms (241 patients in Arm 1, 238 patients in Arm 2 and 239 patients in Arm 3). Baseline demographics were as follows: age ≥65 years (47%), median age of 64 years (range: 22 to 86 years), White (57%), Asian (30%), Black (5%) and other (4%). Disease characteristics were as follows: WHO/ECOG PS 0 (67%) vs. PS 1 (33%), 47% newly diagnosed and 53% recurrent disease, 80% with pMMR tumour status and 20% with dMMR tumour status. The histologic subtypes were endometrioid (60%), serous (21%), carcinosarcoma (7%), mixed epithelial (4%), clear cell (3%), undifferentiated (2%), mucinous (<1%) and other (3%).
The primary endpoint was PFS, determined by investigator assessment using RECIST 1.1. Secondary efficacy endpoints included OS, PFS2, TFST, TDT, TSST, ORR and DoR.
The study demonstrated a statistically significant improvement in PFS for patients treated with platinum-based chemotherapy + IMFINZI + olaparib, and for patients treated with platinum-based chemotherapy + IMFINZI compared to platinum-based chemotherapy alone (see Table 13 and Figures 16 and 17). PFS results according to BICR assessment were consistent. The median follow-up time in censored patients was 15.4 months in the platinum-based chemotherapy + IMFINZI + olaparib arm, 15.4 months in the platinum-based chemotherapy + IMFINZI arm, and 12.6 months in the platinumbased chemotherapy arm. At the time of PFS analysis, interim OS data were 28% mature with events in 199 of 718 patients. (See Table 13 and Figures 16 and 17.)
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Efficacy analyses by MMR status are presented in Table 14. (See Table 14.)
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Patient-Reported Outcomes: IMFINZI in combination with platinum-based chemotherapy followed by maintenance treatment with IMFINZI as monotherapy or in combination with olaparib when compared with platinum-based chemotherapy, had no detrimental effect on endometrial cancer/disease symptoms. Changes from baseline in a range of patient-reported symptoms, functions, and global health status/QoL were similar across the arms.
Paediatric and adolescents: Study D419EC00001 was a multi-centre, open-label dose finding and dose expansion study to evaluate the safety, preliminary efficacy and pharmacokinetics of IMFINZI in combination with tremelimumab followed by IMFINZI monotherapy, in paediatric patients with advanced malignant solid tumours (except primary central nervous system tumours) who had disease progression and for whom no standard of care treatment exists. The study enrolled 50 paediatric patients with an age range from 1 to 17 years with primary tumour categories: neuroblastoma, solid tumour and sarcoma. Patients received either IMFINZI 20 mg/kg in combination with tremelimumab 1 mg/kg or IMFINZI 30 mg/kg in combination with tremelimumab 1 mg/kg intravenously every 4 weeks for 4 cycles, followed by IMFINZI as monotherapy every 4 weeks. In the dose finding phase, IMFINZI and tremelimumab combination therapy was preceded by a single cycle of IMFINZI monotherapy; 8 patients in this phase however discontinued treatment prior to receiving tremelimumab.
Pharmacokinetics: The pharmacokinetics (PK) of durvalumab was assessed for IMFINZI as a single agent, in combination with chemotherapy, in combination with tremelimumab and platinum-based chemotherapy, in combination with tremelimumab and in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib.
The PK of durvalumab was studied in patients with solid tumors 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 (t
½), 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, in combination with tremelimumab and platinum-based chemotherapy, in combination with tremelimumab or in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib.
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, tumor 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.
Paediatric and adolescents: The PK of durvalumab in combination with tremelimumab was evaluated in a study of 50 paediatric patients with an age range from 1 to 17 years, in study D419EC00001. Patients received either durvalumab 20 mg/kg in combination with tremelimumab 1 mg/kg or durvalumab 30 mg/kg in combination with tremelimumab 1 mg/kg intravenously every 4 weeks for 4 cycles, followed by durvalumab as monotherapy every 4 weeks. Based on population PK analysis, durvalumab systemic exposure in paediatric patients ≥35 kg receiving durvalumab 20 mg/kg every 4 weeks was similar to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks, whereas in paediatric patients (≥35 kg) receiving durvalumab 30 mg/kg every 4 weeks, exposure was approximately 1.5 fold higher compared to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks. In paediatric patients <35 kg receiving durvalumab 30 mg/kg every 4 weeks, the systemic exposure was similar to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks.
Elderly: No dose adjustment is required for elderly patients (≥65 years of age). Of the 191 patients with urothelial carcinoma (primary efficacy population) treated with IMFINZI, 118 patients were 65 years or older. No overall clinically meaningful differences in safety or efficacy were reported between patients ≥65 years of age and younger patients.
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 401 patients with resectable NSCLC treated with IMFINZI in combination with chemotherapy in the AEGEAN study, 209 (52%) patients were 65 years or older and 49 (12%) patients were 75 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 262 patients with LS-SCLC treated with IMFINZI, 103 (39.3%) 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 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 metastatic NSCLC treated with IMFINZI in combination with tremelimumab and platinum-based chemotherapy, 147 (43%) 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.
Of the 389 patients with uHCC treated with IMFINZI, 130 (33.4%) patients were 65 years or older and 56 (14.4%) 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.
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 238 patients with endometrial cancer randomised to receive platinum-based chemotherapy + IMFINZI, 116 (48.7%) patients were 65 years or older and 29 (12.2%) patients were 75 years or older. Of the 239 patients with endometrial cancer randomised to receive platinum-based chemotherapy + IMFINZI + olaparib, 104 (43.5%) patients were 65 years or older and 19 (7.9%) 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.
Of the 533 patients with MIBC treated with IMFINZI in combination with chemotherapy, 275 (51.6%) 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.
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.
PK drug-drug interaction between durvalumab and tremelimumab and platinum-based chemotherapy was assessed in the POSEIDON 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. Neutralising antibodies against durvalumab were detected in 0.5% (12/2280) of patients. The presence of ADAs did not have a clinically relevant effect on pharmacokinetics, pharmacodynamics or safety.
In the ADRIATIC study, of the 206 patients who were treated with IMFINZI monotherapy and evaluable for the presence of ADAs, 7 (3.4%) patients tested positive for treatment-emergent ADAs. Neutralising antibodies against durvalumab were detected in 1% (2/206) patients. The presence of ADAs did not have an apparent effect on the pharmacokinetics or safety.
In the AEGEAN study, of the 375 patients who were treated with IMFINZI 1500 mg in combination with chemotherapy every 3 weeks prior to surgery, followed by IMFINZI 1500 mg every 4 weeks following surgery, and were evaluable for the presence of ADAs, 25 (6.7%) patients tested positive for treatment emergent ADAs. Neutralizing antibodies against durvalumab were detected in 2 patients (0.5%). The presence of ADAs did not have an apparent effect on the pharmacokinetics or safety of IMFINZI.
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 types of AEs reported in patients positive for durvalumab ADA were similar to those reported in patients who were negative for durvalumab ADA. 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 POSEIDON study, of the 286 patients who were treated with IMFINZI 1500 mg in combination with tremelimumab every 3 weeks and platinum-based chemotherapy and evaluable for the presence of ADAs, 29 (10.1%) patients tested positive for treatment emergent ADAs. Neutralizing antibodies against durvalumab were detected in 1% (3/286) patients. The presence of ADAs did not have an apparent effect on pharmacokinetics or safety.
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.
In the HIMALAYA study, of the 282 patients who were treated with IMFINZI monotherapy and evaluable for the presence of ADAs, 8 (2.8%) patients tested positive for treatment-emergent ADAs. Neutralising antibodies against durvalumab were detected in 0.7% (2/282) patients. The presence of ADAs did not have an apparent effect on the pharmacokinetics or safety.
In the DUO-E study, the number of the 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. Neutralising 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 neutralising antibodies to determine whether ADAs have an impact on pharmacokinetics or safety of durvalumab.
In the NIAGARA study, of the 453 patients who were treated with IMFINZI 1500 mg in combination with chemotherapy every 3 weeks prior to surgery followed by IMFINZI 1500 mg every 4 weeks following surgery and were evaluable for the presence of ADAs, 8 (1.8%) patients tested positive for treatment-emergent ADAs. Neutralising antibodies against durvalumab were detected in 6 (1.3%) patients. The presence of ADAs did not have an apparent effect on the 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 fetus, 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 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.
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