TECENTRIQ Concentrate for solution for infusion Ref.[6321] Active ingredients: Atezolizumab

Source: European Medicines Agency (EU)  Revision Year: 2019  Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies
ATC code: L01XC32

Mechanism of action

Programmed death-ligand 1 (PD-L1) may be expressed on tumour cells and/or tumour-infiltrating immune cells, and can contribute to the inhibition of the antitumour immune response in the tumour microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T-cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production.

Atezolizumab is an Fc-engineered, humanised immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to PD-L1 and provides a dual blockade of the PD-1 and B7.1 receptors, releasing PD-L1/PD-1 mediated inhibition of the immune response, including reactivating the antitumour immune response without inducing antibody-dependent cellular cytotoxicity. Atezolizumab spares the PD-L2/PD-1 interaction allowing PD-L2/PD-1 mediated inhibitory signals to persist.

Clinical efficacy and safety

Duration of treatment

Treatment with atezolizumab until loss of clinical benefit was permitted as defined by the following criteria:

  • Absence of symptoms and signs (including worsening of laboratory values [e.g. new or worsening hypercalcaemia]) indicating unequivocal progression of disease.
  • No decline in ECOG performance status.
  • Absence of tumour progression at critical anatomical sites (e.g. leptomeningeal disease) that cannot be readily managed and stabilised by protocol-allowed medical interventions prior to repeat dosing.
  • Evidence of clinical benefit as assessed by the investigator.

Patients with ES-SCLC were treated with atezolizumab until disease progression. Treatment beyond disease progression was permitted at the discretion of the physician.

Patients with locally advanced or metastatic UC who are ineligible for cisplatin therapy were treated with atezolizumab until disease progression.

Urothelial carcinoma

IMvigor211 (GO29294): Randomised trial in locally advanced or metastatic UC patients previously treated with chemotherapy

A phase III, open-label, multi-center, international, randomised study, (IMvigor211), was conducted to evaluate the efficacy and safety of atezolizumab compared with chemotherapy (investigator’s choice of vinflunine, docetaxel, or paclitaxel) in patients with locally advanced or metastatic UC who progressed during or following a platinum-containing regimen. This study excluded patients who had a history of autoimmune disease; active or corticosteroid-dependent brain metastases; administration of a live, attenuated vaccine within 28 days prior to enrolment; and administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal product within 2 weeks prior to enrolment. Tumour assessments were conducted every 9 weeks for the first 54 weeks, and every 12 weeks thereafter. Tumour specimens were evaluated prospectively for PD-L1 expression on tumour-infiltrating immune cells (IC) and the results were used to define the PD-L1 expression subgroups for the analyses described below.

A total of 931 patients were enrolled. Patients were randomised (1:1) to receive either atezolizumab or chemotherapy. Randomisation was stratified by chemotherapy (vinflunine vs. taxane), PD-L1 expression status on IC (<5% vs. ≥5%), number of prognostic risk factors (0 vs. 1-3), and liver metastases (yes vs. no). Prognostic risk factors included time from prior chemotherapy of <3 months, ECOG performance status >0 and haemoglobin <10 g/dL.

Atezolizumab was administered as a fixed dose of 1,200 mg by intravenous infusion every 3 weeks. No dose reduction of atezolizumab was allowed. Patients were treated until loss of clinical benefit as assessed by the investigator or unacceptable toxicity. Vinflunine was administered 320 mg/m² by intravenous infusion on day 1 of each 3-week cycle until disease progression or unacceptable toxicity. Paclitaxel was administered 175 mg/m² by intravenous infusion over 3 hours on day 1 of each 3-week cycle until disease progression or unacceptable toxicity. Docetaxel was administered 75 mg/m² by intravenous infusion on day 1 of each 3-week cycle until disease progression or unacceptable toxicity. For all treated patients, the median duration of treatment was 2.8 months for the atezolizumab arm, 2.1 months for the vinflunine and paclitaxel arms and 1.6 months for the docetaxel arm.

The demographic and baseline disease characteristics of the primary analysis population were well balanced between the treatment arms. The median age was 67 years (range: 31 to 88), and 77.1% of patients were male. The majority of patients were white (72.1%), 53.9% of patients within the chemotherapy arm received vinflunine, 71.4% of patients had at least one poor prognostic risk factor and 28.8% had liver metastases at baseline. Baseline ECOG performance status was 0 (45.6%) or 1 (54.4%). Bladder was the primary tumour site for 71.1% of patients and 25.4% of patients had upper tract urothelial carcinoma. There were 24.2% of patients who received only prior platinum-containing adjuvant or neoadjuvant therapy and progressed within 12 months.

The primary efficacy endpoint for IMvigor211 is overall survival (OS). Secondary efficacy endpoints evaluated per investigator-assessed Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 are objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR). Comparisons with respect to OS between the treatment arm and control arm within the IC2/3, IC1/2/3, and ITT (Intention-to-treat, i.e. all comers) populations were tested using a hierarchical fixed-sequence procedure based on a stratified log-rank test at two-sided level of 5% as follows: step 1) IC2/3 population; step 2) IC1/2/3 population; step 3) all comers population. OS results for each of steps 2 and 3 could be formally tested for statistical significance only if the result in the preceding step was statistically significant.

The median survival follow-up is 17 months. The primary analysis of study IMvigor211 did not meet its primary endpoint of OS. Atezolizumab did not demonstrate a statistically significant survival benefit compared to chemotherapy in patients with previously treated, locally advanced or metastatic urothelial carcinoma. Per the pre-specified hierarchical testing order, the IC2/3 population was tested first, with an OS HR of 0.87 (95% CI: 0.63, 1.21; median OS of 11.1 vs. 10.6 months for atezolizumab and chemotherapy respectively). The stratified log-rank p-value was 0.41 and therefore the results are considered not statistically significant in this population. As a consequence, no formal tests of statistical significance could be performed for OS in the IC1/2/3 or all comer populations, and results of those analyses would be considered exploratory. The key results in the all comer population are summarised in Table 3. The Kaplan-Meier curve for OS in the all comer population is presented in Figure 1.

Table 3. Summary of efficacy in all comers (IMvigor211):

Figure 1. Kaplan-Meier curve for overall survival (IMvigor211):

IMvigor210 (GO29293): Single-arm trial in previously untreated urothelial carcinoma patients who are ineligible for cisplatin therapy and in urothelial carcinoma patients previously treated with chemotherapy

A phase II, multi-centre, international, two-cohort, single-arm clinical trial, IMvigor210, was conducted in patients with locally advanced or metastatic UC (also known as urothelial bladder cancer).

The study enrolled a total of 438 patients and had two patient cohorts. Cohort 1 included previously untreated patients with locally advanced or metastatic UC who were ineligible or unfit for cisplatin-based chemotherapy or had disease progression at least 12 months after treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Cohort 2 included patients who received at least one platinum-based chemotherapy regimen for locally advanced or metastatic UC or had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen.

In Cohort 1, 119 patients were treated with atezolizumab 1,200 mg by intravenous infusion every 3 weeks until disease progression. The median age was 73 years. Most patients were male (81%), and the majority of patients were White (91%).

Cohort 1 included 45 patients (38%) with ECOG performance status of 0, 50 patients (42%) with ECOG performance status of 1 and 24 patients (20%) with ECOG performance status of 2, 35 patients (29%) with no Bajorin risk factors (ECOG performance status ≥2 and visceral metastasis), 66 patients (56%) with one Bajorin risk factor and 18 patients (15%) with two Bajorin risk factors, 84 patients (71%) with impaired renal function (glomerular filtration rate [GFR] <60 mL/min), and 25 patients (21%) with liver metastasis.

The primary efficacy endpoint for Cohort 1 was confirmed objective response rate (ORR) as assessed by an independent review facility (IRF) using RECIST v1.1.

The primary analysis was performed when all patients had at least 24 weeks of follow-up. Median duration of treatment was 15.0 weeks and median duration of survival follow-up was 8.5 months in all comers. Clinically relevant IRF-assessed ORRs per RECIST v1.1 were shown; however, when compared to a pre-specified historical control response rate of 10%, statistical significance was not reached for the primary endpoint. The confirmed ORRs per IRF-RECIST v1.1 were 21.9% (95% CI: 9.3, 40.0) in patients with PD-L1 expression ≥5%, 18.8% (95% CI: 10.9, 29.0) in patients with PD-L1 expression ≥1%, and 19.3% (95% CI: 12.7, 27.6) in all comers. The median duration of response (DOR) was not reached in any PD-L1 expression subgroup or in all comers. OS was not mature with an event patient ratio of approximately 40%. Median OS for all patient subgroups (PD-L1 expression ≥5% and ≥1%) and in all comers was 10.6 months.

An updated analysis was performed with a median duration of survival follow-up of 17.2 months for Cohort 1 and is summarised in Table 4. The median DOR was not reached in any PD-L1 expression subgroup or in all comers.

Table 4. Summary of updated efficacy (IMvigor210 Cohort 1):

In Cohort 2, the co-primary efficacy endpoints were confirmed ORR as assessed by an IRF using RECIST v1.1 and investigator-assessed ORR according to Modified RECIST (mRECIST) criteria. There were 310 patients treated with atezolizumab 1,200 mg by intravenous infusion every 3 weeks until loss of clinical benefit. The primary analysis of Cohort 2 was performed when all patients had at least 24 weeks of follow-up. The study met its co-primary endpoints in Cohort 2, demonstrating statistically significant ORRs per IRF-assessed RECIST v1.1 and investigator-assessed mRECIST compared to a pre-specified historical control response rate of 10%.

An analysis was also performed with a median duration of survival follow-up of 21.1 months for Cohort 2. The confirmed ORRs per IRF-RECIST v1.1 were 28.0% (95% CI: 19.5, 37.9) in patients with PD-L1 expression ≥5%, 19.3% (95% CI: 14.2, 25.4) in patients with PD-L1 expression ≥1%, and 15.8% (95% CI: 11.9, 20.4) in all comers. The confirmed ORR per investigator-assessed mRECIST was 29.0% (95% CI: 20.4, 38.9) in patients with PD-L1 expression ≥5%, 23.7% (95% CI: 18.1, 30.1) in patients with PD-L1 expression ≥1%, and 19.7% (95% CI: 15.4, 24.6) in all comers.

The rate of complete response per IRF-RECIST v1.1 in the all comer population was 6.1% (95% CI: 3.7, 9.4). For Cohort 2, median DOR was not reached in any PD-L1 expression subgroup or in all comers, however was reached in patients with PD-L1 expression <1% (13.3 months; 95% CI 4.2, NE). The OS rate at 12 month was 37% in all comers.

IMvigor130 (WO30070): Phase III multi-center, randomized, placebo-controlled study of atezolizumab as monotherapy and in combination with platinum-based chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma

Based on an independent Data Monitoring Committee (iDMC) recommendation following an early review of survival data, accrual of patients on the atezolizumab monotherapy treatment arm whose tumours have a low PD-L1 expression (less than 5% of immune cells staining positive for PD-L1 by immunohistochemistry) was stopped after observing decreased overall survival for this subgroup. The iDMC did not recommend any change of therapy for patients who had already been randomized to and were receiving treatment in the monotherapy arm. No other changes were recommended.

Non-small cell lung cancer

First-line treatment of non-small cell lung cancer

IMpower150 (GO29436): Randomised phase III trial in chemotherapy-naïve patients with metastatic non-squamous NSCLC, in combination with paclitaxel and carboplatin with or without bevacizumab:

A phase III, open-label, multicenter, international, randomised study, IMpower150, was conducted to evaluate the efficacy and safety of atezolizumab in combination with paclitaxel and carboplatin, with or without bevacizumab, in chemotherapy-naïve patients with metastatic non-squamous NSCLC.

Patients were excluded if they had history of autoimmune disease, administration of a live, attenuated vaccine within 28 days prior to randomisation, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal product within 2 weeks prior to randomisation, active or untreated CNS metastases, clear tumour infiltration into the thoracic great vessels or clear cavitation of pulmonary lesions, as seen on imaging. Tumour assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter. Tumour specimens were evaluated for PD-L1 expression on tumour cells (TC) and tumour-infiltrating immune cells (IC) and the results were used to define the PD-L1 expression subgroups for the analyses described below.

A total of 1,202 patients were enrolled and were randomised (1:1:1) to receive one of the treatment regimens described in Table 5. Randomization was stratified by sex, presence of liver metastases and PD-L1 tumour expression on TC and IC.

Table 5. Intravenous treatment regimens (IMpower150):

Treatment regimenInduction (Four or Six 21-day cycles)Maintenance (21-day cycles)
AAtezolizumaba (1,200 mg) + paclitaxel (200 mg/m²)b,c + carboplatinc (AUC 6)Atezolizumaba (1,200 mg)
BAtezolizumaba (1,200 mg) + bevacizumabd (15 mg/kg) + paclitaxel (200 mg/m²)b,c + carboplatinc (AUC 6)Atezolizumaba (1,200 mg) + bevacizumabd (15 mg/kg)
CBevacizumabd (15 mg/kg) + paclitaxel (200 mg/m²)b,c + carboplatinc (AUC 6)Bevacizumabd (15 mg/kg)

a Atezolizumab is administered until loss of clinical benefit as assessed by the investigator
b The paclitaxel starting dose for patients of Asian race/ethnicity was 175 mg/m² due to higher overall level of haematologic toxicities in patients from Asian countries compared with those from non-Asian countries
c Paclitaxel and carboplatin are administered until completion of 4 or 6 cycles, or progressive disease, or unacceptable toxicity whichever occurs first
d Bevacizumab is administered until progressive disease or unacceptable toxicity

The demographics and baseline disease characteristics of the study population were well balanced between the treatment arms. The median age was 63 years (range: 31 to 90), and 60% of patients were male. The majority of patients were white (82%). Approximately 10% of patients had known EGFR mutation, 4% had known ALK rearrangements, 14% had liver metastasis at baseline, and most patients were current or previous smokers (80%). Baseline ECOG performance status was 0 (43%) or 1 (57%). 51% of patients' tumours had PD-L1 expression of ≥1% TC or ≥1% IC and 49% of patients' tumours had PD-L1 expression of <1% TC and <1% IC.

At the time of the final analysis for PFS, patients had a median follow up time of 15.3 months. The ITT population, including patients with EGFR mutations or ALK rearrangements who should have been previously treated with tyrosine kinase inhibitors, demonstrated clinically meaningful PFS improvement in Arm B as compared to Arm C (HR of 0.61, 95% CI: 0.52, 0.72; median PFS 8.3 vs. 6.8 months).

At the time of the interim OS analysis, patients had a median follow-up of 19.7 months. The key results from this analysis as well as from the updated PFS analysis in the ITT population are summarised in Tables 6 and 7. The Kaplan-Meier curve for OS in the ITT population is presented in Figure 2. Figure 3 summarises the results of OS in the ITT and PD-L1 subgroups. Updated PFS results are also presented in Figures 4 and 5.

Table 6. Summary of updated efficacy in the ITT population (IMpower150):

Table 7. Summary of updated efficacy for Arm A vs. Arm B in the ITT population (IMpower150):

Figure 2. Kaplan-Meier curve for overall survival in the ITT population (IMpower150):

Figure 3. Forest plot of overall survival by PD-L1 expression in the ITT population, Arm B vs. C (IMpower150):

Figure 4. Kaplan-Meier curve for PFS in the ITT population (IMpower150):

Figure 5. Forest plot of progression free survival by PD-L1 expression in the ITT population, Arm B vs. C (IMpower150):

In Arm B as compared to Arm C, pre-specified subgroup analyses from the interim OS analysis showed an OS improvement for patients with EGFR mutations or ALK rearrangements (hazard ratio [HR] of 0.54, 95% CI: 0.29, 1.03; median OS not reached vs. 17.5 months), and liver metastases (HR of 0.52, 95% CI: 0.33, 0.82; median OS 13.3 vs. 9.4 months). PFS improvements were also shown in patients with EGFR mutations or ALK rearrangements (HR of 0.55, 95% CI: 0.35, 0.87; median PFS 10.0 vs. 6.1 months) and liver metastases (HR of 0.41, 95% CI: 0.26, 0.62; median PFS 8.2 vs. 5.4 months). OS results were similar for patients aged <65 and ≥65 subgroups, respectively. Data for patients ≥75 years of age are too limited to draw conclusions on this population. For all subgroup analyses, formal statistical testing was not planned.

IMpower130 (GO29537): Randomised phase III trial in chemotherapy-naïve patients with metastatic non-squamous NSCLC, in combination with nab-paclitaxel and carboplatin:

A phase III, open-label, randomised study, GO29537 (IMpower130), was conducted to evaluate the efficacy and safety of atezolizumab in combination with nab-paclitaxel and carboplatin, in chemotherapy-naïve patients with metastatic non-squamous NSCLC. Patients with EGFR mutations or ALK rearrangements should have been previously treated with tyrosine kinase inhibitors.

Patients were staged according to the American Joint Committee on Cancer (AJCC) 7th edition. Patients were excluded if they had a history of autoimmune disease, administration of live, attenuated vaccine within 28 days prior to randomisation, administration of immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomisation, and active or untreated CNS metastases. Patients who had prior treatment with CD137 agonists or immune checkpoint blockade therapies (anti-PD-1, and anti-PD-L1 therapeutic antibodies) were not eligible. However, patients who had prior anti-CTLA-4 treatment could be enrolled, as long as the last dose was received at least 6 weeks prior to randomization, and there was no history of severe immune-related adverse effects from anti-CTLA-4 (NCI CTCAE Grades 3 and 4). Tumour assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, then every 9 weeks thereafter. Tumour specimens were evaluated for PD-L1 expression on tumour cells (TC) and tumour infiltrating immune cells (IC) and the results were used to define the PD-L1 expression subgroups for the analyses described below.

Patients, including those with EGFR mutations or ALK rearrangements, were enrolled and were randomised in a 2:1 ratio to receive one of the treatment regimens described in Table 8. Randomisation was stratified by sex, presence of liver metastases and PD-L1 expression on TC and IC. Patients receiving treatment regimen B were able to crossover and receive atezolizumab monotherapy following disease progression.

Table 8. Intravenous treatment regimens (IMpower130):

Treatment RegimenInduction (Four or six 21-day cycles)Maintenance (21-day cycles)
AAtezolizumab (1,200 mg)a + nab-paclitaxel (100 mg/m²)b,c + carboplatin (AUC 6)cAtezolizumab (1,200 mg)a
BNab-paclitaxel (100 mg/m²)b,c + carboplatin (AUC 6)cBest supportive care or pemetrexed

a Atezolizumab is administered until loss of clinical benefit as assessed by investigator.
b Nab-paclitaxel is administered on days 1, 8, and 15 of each cycle c Nab-paclitaxel and carboplatin are administered until completion of 4-6 cycles, or progressive disease or unacceptable toxicity whichever occurs first.

The demographics and baseline disease characteristics of the study population defined as ITT-WT (n=679) were well balanced between the treatment arms. The median age was 64 years (range 18 to 86 years). The majority of the patients were male (59%) and white (90%). Fourteen point seven percent of patients had liver metastases at baseline, and most patients were current or previous smokers (90%). The majority of patients had a baseline ECOG performance status of 1 (59%) and PD-L1 expression <1% (approximately 52%). Among 107 Arm B patients who had a response status of stable disease, partial response, or complete response after induction therapy, 40 received pemetrexed switch maintenance therapy.

The primary analysis was conducted in all patients, excluding those with EGFR mutations or ALK rearrangements, defined as ITT-WT population (n=679). Patients had a median survival follow up time of 18.6 months and showed improved OS and PFS with atezolizumab, nab-paclitaxel and carboplatin as compared to the control. The key results are summarised in Table 9 and Kaplan-Meier curves for OS and PFS are presented in Figures 6 and 8, respectively. The exploratory results of OS and PFS by PD-L1 expression are summarised in Figures 7 and 9, respectively. Patients with liver metastases did not show improved PFS or OS with atezolizumab, nab-paclitaxel and carboplatin, compared to nab-paclitaxel and carboplatin (HR of 0.93, 95% CI: 0.59, 1.47 for PFS and HR of 1.04, 95% CI: 0.63, 1.72 for OS, respectively).

Fifty-nine percent of patients in the nab-paclitaxel and carboplatin arm received any cancer immunotherapy after disease progression, which includes atezolizumab as crossover treatment (41% of all patients), compared to 7.3% of patients in the atezolizumab, nab paclitaxel and carboplatin arm.

In an exploratory analysis with longer follow up (median: 24.1 months), the median OS for both arms was unchanged relative to the primary analysis, with HR=0.82 (95% CI: 0.67, 1.01).

Table 9. Summary of efficacy from IMpower130 in the primary analysis (ITT-WT population):

Figure 6. Kaplan-Meier curves for overall survival (IMpower130):

Figure 7. Forest plot of overall survival by PD-L1 expression (IMpower130):

Figure 8. Kaplan-Meier curves for progression free survival (IMpower130):

Figure 9. Forest plot of progression free survival by PD-L1 expression (IMpower130):

Second-line treatment of non-small cell lung cancer

OAK (GO28915): Randomised phase III trial in locally advanced or metastatic NSCLC patients previously treated with chemotherapy:

A phase III, open-label, multi-center, international, randomised study, OAK, was conducted to evaluate the efficacy and safety of atezolizumab compared with docetaxel in patients with locally advanced or metastatic NSCLC who progressed during or following a platinum-containing regimen. This study excluded patients who had a history of autoimmune disease, active or corticosteroid-dependent brain metastases, administration of a live, attenuated vaccine within 28 days prior to enrolment, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal product within 2 weeks prior to enrolment. Tumour assessments were conducted every 6 weeks for the first 36 weeks, and every 9 weeks thereafter. Tumour specimens were evaluated prospectively for PD-L1 expression on tumour cells (TC) and tumour-infiltrating immune cells (IC).

A total of 1,225 patients were enrolled and per the analysis plan the first 850 randomised patients were included in the primary efficacy analysis. Randomisation was stratified by PD-L1 expression status on IC, by the number of prior chemotherapy regimens, and by histology. Patients were randomised (1:1) to receive either atezolizumab or docetaxel.

Atezolizumab was administered as a fixed dose of 1,200 mg by intravenous infusion every 3 weeks. No dose reduction was allowed. Patients were treated until loss of clinical benefit as assessed by the investigator. Docetaxel was administered 75 mg/m 2 by intravenous infusion on day 1 of each 3-week cycle until disease progression. For all treated patients, the median duration of treatment was 2.1 months for the docetaxel arm and 3.4 months for the atezolizumab arm.

The demographic and baseline disease characteristics of the primary analysis population were well balanced between the treatment arms. The median age was 64 years (range: 33 to 85), and 61% of patients were male. The majority of patients were white (70%). Approximately three-quarters of patients had non-squamous histology (74%), 10% had known EGFR mutation, 0.2% had known ALK rearrangements, 10% had CNS metastases at baseline, and most patients were current or previous smokers (82%). Baseline ECOG performance status was 0 (37%) or 1 (63%). Seventy-five percent of patients received only one prior platinum-based therapeutic regimen.

The primary efficacy endpoint was OS. The key results of this study with a median survival follow-up of 21 months are summarised in Table 10. Kaplan-Meier curves for OS in the ITT population are presented in Figure 10. Figure 11 summarises the results of OS in the ITT and PD-L1 subgroups, demonstrating OS benefit with atezolizumab in all subgroups, including those with PD-L1 expression <1% in TC and IC.

Table 10. Summary of efficacy in the primary analysis population (all comers) (OAK):*

Figure 10. Kaplan-Meier curve for overall survival in the primary analysis population (all comers) (OAK):*

Figure 11. Forest plot of overall survival by PD-L1 expression in the primary analysis population (OAK):

An improvement in OS was observed with atezolizumab compared to docetaxel in both non-squamous NSCLC patients (hazard ratio [HR] of 0.73, 95% CI: 0.60, 0.89; median OS of 15.6 vs. 11.2 months for atezolizumab and docetaxel, respectively) and squamous NSCLC patients (HR of 0.73, 95% CI: 0.54, 0.98; median OS of 8.9 vs. 7.7 months for atezolizumab and docetaxel, respectively). The observed OS improvement was consistently demonstrated across subgroups of patients including those with brain metastases at baseline (HR of 0.54, 95% CI: 0.31, 0.94; median OS of 20.1 vs. 11.9 months for atezolizumab and docetaxel respectively) and patients who were never smokers (HR of 0.71, 95% CI: 0.47, 1.08; median OS of 16.3 vs. 12.6 months for atezolizumab and docetaxel, respectively). However, patients with EGFR mutations did not show improved OS with atezolizumab compared to docetaxel (HR of 1.24, 95% CI: 0.71, 2.18; median OS of 10.5 vs. 16.2 months for atezolizumab and docetaxel, respectively).

Prolonged time to deterioration of patient-reported pain in chest as measured by the EORTC QLQ-LC13 was observed with atezolizumab compared to docetaxel (HR of 0.71, 95% CI: 0.49, 1.05; median not reached in either arm). The time to deterioration in other lung cancer symptoms (i.e. cough, dyspnoea, and arm/shoulder pain) as measured by the EORTC QLQ-LC13 was similar between atezolizumab and docetaxel. These results should be interpreted with caution due to the open-label design of the study.

POPLAR (GO28753): Randomised phase II trial in locally advanced or metastatic NSCLC patients previously treated with chemotherapy:

A phase II, multi-centre, international, randomised, open-label, controlled study, POPLAR, was conducted in patients with locally advanced or metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression. The primary efficacy outcome was overall survival. A total of 287 patients were randomised 1:1 to receive either atezolizumab (1,200 mg by intravenous infusion every 3 weeks until loss of clinical benefit) or docetaxel (75 mg/m² by intravenous infusion on day 1 of each 3-week cycle until disease progression). Randomisation was stratified by PD-L1 expression status on IC, by the number of prior chemotherapy regimens and by histology. An updated analysis with a total of 200 deaths observed and a median survival follow-up of 22 months showed a median OS of 12.6 months in patients treated with atezolizumab, vs. 9.7 months in patients treated with docetaxel (HR of 0.69, 95% CI: 0.52, 0.92). ORR was 15.3% vs. 14.7% and median DOR was 18.6 months vs. 7.2 months for atezolizumab vs. docetaxel, respectively.

Small cell lung cancer

IMpower133 (GO30081): Randomised phase I/III trial in patients with chemotherapy-naïve extensive-stage SCLC, in combination with carboplatin and etoposide

A Phase I/III, randomised, multicentre, double-blind, placebo-controlled study, IMpower133, was conducted to evaluate the efficacy and safety of atezolizumab in combination with carboplatin and etoposide in patients with chemotherapy-naïve extensive-stage small cell lung cancer (ES-SCLC).

Patients were excluded if they had active or untreated CNS metastases; history of autoimmune disease; administration of live, attenuated vaccine within 4 weeks prior to randomisation; administration of systemic immunosuppressive medications within 1 week prior to randomisation. Tumour assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter. Patients who met established criteria and who agreed to be treated beyond disease progression had tumour assessments conducted every 6 weeks until treatment discontinuation.

A total of 403 patients were enrolled and randomised (1:1) to receive one of the treatment regimens described in Table 11. Randomisation was stratified by sex, ECOG performance status, and presence of brain metastases.

Table 11. Intravenous treatment regimens (IMpower133):

Treatment regimenInduction (Four 21-Day Cycles)Maintenance (21-Day Cycles)
Aatezolizumab (1,200 mg)a + carboplatin (AUC 5)b + etoposide (100 mg/m²)b,catezolizumab (1,200 mg)a
Bplacebo + carboplatin (AUC 5)b + etoposide (100 mg/m²)b,cplacebo

a Atezolizumab was administered until loss of clinical benefit as assessed by investigator.
b Carboplatin and etoposide were administered until completion of 4 cycles, or progressive disease or unacceptable toxicity, whichever occurs first.
c Etoposide was administered on day 1, 2 and 3 of each cycle.

The demographic and baseline disease characteristics of the study population were well balanced between the treatment arms. The median age was 64 years (range: 26 to 90 years) with 10% of patients ≥75 years of age. The majority of patients were male (65%), white (80%), and 9% had brain metastases and most patients were current or previous smokers (97%). Baseline ECOG performance status was 0 (35%) or 1 (65%).

At the time of the primary analysis, patients had a median survival follow up time of 13.9 months. A statistically significant improvement in OS was observed with atezolizumab in combination with carboplatin and etoposide compared to the control arm (HR of 0.70, 95% CI: 0.54, 0.91; median OS of 12.3 months vs. 10.3 months). In the exploratory OS final analysis with longer follow up (median: 22.9 months), the median OS for both arms was unchanged relative to the primary OS interim analysis. The PFS, ORR and DOR results from the primary analysis as well as the exploratory OS final analysis results are summarized in Table 12. Kaplan-Meier curves for OS and PFS are presented in Figures 12 and 13. Data for patients with brain metastases are too limited to draw conclusions on this population.

Table 12. Summary of efficacy (IMpower133):

Figure 12. Kaplan-Meier curve for overall survival (IMpower133):

Figure 13. Kaplan-Meier curve for progression-free survival (IMpower133):

Efficacy in elderly patients

No overall differences in efficacy were observed between patients ≥65 years of age and younger patients receiving atezolizumab monotherapy. In study IMpower150, age ≥65 was associated with a diminished effect of atezolizumab in patients receiving atezolizumab in combination with carboplatin and paclitaxel.

In studies IMpower150 and IMpower133, data for patients ≥75 years of age are too limited to draw conclusions on this population.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with atezolizumab in all subsets of the paediatric population in the treatment of malignant neoplasms (except central nervous system tumours, haematopoietic and lymphoid tissue neoplasms) (see section 4.2 for information on paediatric use).

Pharmacokinetic properties

Exposure to atezolizumab increased dose proportionally over the dose range 1 mg/kg to 20 mg/kg including the fixed dose 1,200 mg administered every 3 weeks. A population analysis that included 472 patients described atezolizumab pharmacokinetics for the dose range: 1 to 20 mg/kg with a linear two-compartment disposition model with first-order elimination. A population pharmacokinetic analysis suggests that steady-state is obtained after 6 to 9 weeks (2 to 3 cycles) of repeated dosing. The systemic accumulation in area under the curve, maximum concentration and trough concentration was 1.91, 1.46 and 2.75-fold, respectively.

Absorption

Atezolizumab is administered as an intravenous infusion. There have been no studies performed with other routes of administration.

Distribution

A population pharmacokinetic analysis indicates that central compartment volume of distribution is 3.28 L and volume at steady-state is 6.91 L in the typical patient.

Biotransformation

The metabolism of atezolizumab has not been directly studied. Antibodies are cleared principally by catabolism.

Elimination

A population pharmacokinetic analysis indicates that the clearance of atezolizumab is 0.200 L/day and the typical terminal elimination half-life is 27 days.

Special populations

Based on population PK and exposure-response analyses age (21-89 years), region, ethnicity, renal impairment, mild hepatic impairment, level of PD-L1 expression, or ECOG performance status have no effect on atezolizumab pharmacokinetics. Body weight, gender, positive ADA status, albumin levels and tumour burden have a statistically significant, but not clinically relevant effect on atezolizumab pharmacokinetics. No dose adjustments are recommended.

Elderly

No dedicated studies of atezolizumab have been conducted in elderly patients. The effect of age on the pharmacokinetics of atezolizumab was assessed in a population pharmacokinetic analysis. Age was not identified as a significant covariate influencing atezolizumab pharmacokinetics based on patients of age range of 21-89 years (n=472), and median of 62 years of age. No clinically important difference was observed in the pharmacokinetics of atezolizumab among patients <65 years (n=274), patients between 65−75 years (n=152) and patients >75 years (n=46) (see section 4.2).

Paediatric population

No studies have been conducted to investigate the pharmacokinetics of atezolizumab in children or adolescents.

Renal impairment

No dedicated studies of atezolizumab have been conducted in patients with renal impairment. In the population pharmacokinetic analysis, no clinically important differences in the clearance of atezolizumab were found in patients with mild (estimated glomerular filtration rate [eGFR] 60 to 89 mL/min/1.73 m²; n=208) or, moderate (eGFR 30 to 59 mL/min/1.73 m²; n=116) renal impairment compared to patients with normal (eGFR greater than or equal to 90 mL/min/1.73 m²; n=140) renal function. Only a few patients had severe renal impairment (eGFR 15 to 29 mL/min/1.73 m²; n=8) (see section 4.2). The effect of severe renal impairment on the pharmacokinetics of atezolizumab is unknown.

Hepatic impairment

No dedicated studies of atezolizumab have been conducted in patients with hepatic impairment. In the population pharmacokinetic analysis, there were no clinically important differences in the clearance of atezolizumab between patients with mild hepatic impairment (bilirubin ≤ULN and AST >ULN or bilirubin >1.0 × to 1.5 × ULN and any AST, n=71) and normal hepatic function (bilirubin and AST ≤ULN, n=401). No data are available in patients with either moderate or severe hepatic impairment. Hepatic impairment was defined by the National Cancer Institute (NCI) criteria of hepatic dysfunction (see section 4.2). The effect of moderate or severe hepatic impairment (bilirubin >1.5 × to 3 × ULN and any AST or bilirubin >3 × ULN and any AST) on the pharmacokinetics of atezolizumab is unknown.

Preclinical safety data

Carcinogenicity

Carcinogenicity studies have not been performed to establish the carcinogenic potential of atezolizumab.

Mutagenicity

Mutagenicity studies have not been performed to establish the mutagenic potential of atezolizumab. However, monoclonal antibodies are not expected to alter DNA or chromosomes.

Fertility

No fertility studies have been conducted with atezolizumab; however assessment of the cynomolgus monkey male and female reproductive organs was included in the chronic toxicity study. Weekly administration of atezolizumab to female monkeys at an estimated AUC approximately 6 times the AUC in patients receiving the recommended dose caused an irregular menstrual cycle pattern and a lack of newly formed corpora lutea in the ovaries which were reversible. There was no effect on the male reproductive organs.

Teratogenicity

No reproductive or teratogenicity studies in animals have been conducted with atezolizumab. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to immune-related rejection of the developing foetus resulting in foetal death. Administration of atezolizumab could cause foetal harm, including embryo-foetal lethality.

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