Phase III Study Evaluating Efficacy and Safety of Canakinumab in Combination With Docetaxel in Adult Subjects With Non-small Cell Lung Cancers as a Second or Third Line Therapy

OS is defined as the time from randomization to date of death due to any cause. The OS distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated for each treatment group. If a subject was not known to have died, then OS was censored at the latest date the subject was known to be alive (on or before the cut-off date).

Time frame: From randomization until death or final analysis data cutoff date (08-Jan-2021) whichever comes first (up to approximately (approx.) 18 months)

Population: Full Analysis Set (FAS) in randomized part: All participants to whom study treatment was assigned by randomization.

Percentage of participants with DLTs. A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 42 days of docetaxel and canakinumab treatment.

Time frame: During the first 42 days of dosing

Population: Participants in the safety run-in part to whom study treatment was assigned, who received at least one dose of any study treatment (including incomplete infusion) and met the minimum exposure criterion and have sufficient safety evaluations, or experienced a DLT during the first 42 days of dosing

DCR is defined as the percentage of participants with CR or PR or with stable disease (SD) as per investigator assessment according to RECIST 1.1 criteria. The 95% CIs were computed using Clopper and Pearson method. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.

Time frame: Through final analysis data cutoff date of 08-Jan-2021 (assessed up to approx. 10 months for the safety run-in part and 18 months for the randomized part)

Population: FAS in Safety run-in part: all participants to whom study treatment was assigned and who received at least one dose of any study treatment (including incomplete infusion) FAS in Randomized part: all participants to whom study treatment was assigned by randomization

DOR is defined as the time from first documented response of CR or PR to date of first documented progression or death, by investigator's assessment according to RECIST 1.1 criteria. The DOR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated for each treatment group. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

Time frame: From first documented response of CR or PR to date of first documented progression, death or final analysis data cutoff date (08-Jan-2021) whichever comes first (up to approx. 10 months for the safety run-in and 18 months for the randomized)

Population: FAS in Safety run-in part: all participants to whom study treatment was assigned and who received at least one dose of any study treatment (including incomplete infusion) for whom best overall response is CR or PR FAS in Randomized part: all participants to whom study treatment was assigned by randomization for whom best overall response is CR or PR

ORR is defined as the percentage of participants with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1. The 95% confidence intervals (CIs) were computed using Clopper and Pearson method. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

Time frame: Through final analysis data cutoff date of 08-Jan-2021 (assessed up to approx. 10 months for the safety run-in part and 18 months for the randomized part)

Population: FAS in Safety run-in part: all participants to whom study treatment was assigned and who received at least one dose of any study treatment (including incomplete infusion) FAS in Randomized part: all participants to whom study treatment was assigned by randomization

Venous whole blood samples were collected for pharmacokinetics characterization. AUClast of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.

Time frame: Cycle 1 Day 1 and Cycle 4 Day 1 at pre-infusion, end of infusion, and 2, 4 and 6 hours post-dose. Each cycle is 21 days

Population: Docetaxel PAS in randomized part: all subjects who received at least one dose of canakinumab in the randomized part and have at least one evaluable docetaxel PK concentration. Number analyzed represents participants evaluable at specified time points

ADA incidence on-treatment was calculated as the percentage of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)

Time frame: Pre-dose at Cycle 1 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, Cycle 12 Day 1 , end of treatment, and 130 days after end of treatment through final analysis data cutoff date of 08-Jan-2021 (assessed up to 18 months). Each cycle is 21 days

Population: All participants randomized to canakinumab+docetaxel arm

ADA prevalence at baseline was calculated as the percentage of participants who had an ADA positive result at baseline

Time frame: Baseline

Population: All participants randomized to canakinumab+docetaxel arm

The EORTC QLQ-LC13 is a 13-item questionnaire. It comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, dyspnea, and chest pain) and treatment-related symptoms from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, and dysphagia). Scores for each scale and single-item range from 0 to 100, with higher scores indicating higher (worse) level of symptoms. Changes from baseline in chest pain, cough and dyspnea scores are presented. A positive change from baseline indicates improvement. For subjects who discontinued treatment without disease progression, post-treatment efficacy visits 1, 2, 3 and 5 were conducted every 6 weeks (for the first 12 months since start of treatment) and every 12 weeks (after 12 months since start of treatment) until disease progression

Time frame: Baseline, every 3 weeks from Week 3 until end of treatment, every 6 or 12 weeks post-treatment until progression (post-treatment efficacy visits), 7 and 28 days post progression through final analysis cutoff date of 08Jan2021 (up to approx. 18 months)

Population: FAS in Randomized part: All participants to whom study treatment was assigned by randomization. Number analyzed represents participants with data available at the specified data points

The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each of these dimensions, the participant self-assigned a score: from 1 (no problems) to 5 (extreme problems). The 5 digit health states obtained for each dimension was converted into a single mean index value based on the EQ-5D crosswalk value set for the UK using the time trade-off method. This index ranges from -0.594 (worst health) to 1.0 (best health). A positive change from baseline indicates improvement. For subjects who discontinued treatment without disease progression, post-treatment efficacy visits 1, 2, 3 and 5 were conducted every 6 weeks (for the first 12 months since start of treatment) and every 12 weeks (after 12 months since start of treatment) until disease progression

Time frame: Baseline, every 3 weeks from Week 3 until end of treatment, every 6 or 12 weeks post-treatment until progression (post-treatment efficacy visits), 7 and 28 days post progression through final analysis cutoff date of 08Jan2021 (up to approx. 18 months)

Population: FAS in Randomized part: All participants to whom study treatment was assigned by randomization. Number analyzed represents participants with data available at the specified data points

The EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional and social), 3 symptom scales (fatigue, pain and nausea/vomiting), a GHS/QoL scale, and 6 single items (constipation, diarrhea, insomnia, dyspnoea, appetite loss and financial difficulties). For each scale and item, scores range 0-100. A high score for functional scales/QoL represents better functioning/QoL; a high score for symptom scales and items represents significant symptomatology. Changes from baseline in QoL, shortness of breath and pain scores are presented. For QoL, a negative change from baseline indicates improvement; for shortness of breath and pain a positive change from baseline indicates improvement. For subjects who discontinued treatment without disease progression, post-treatment efficacy visits 1, 2, 3 and 5 were conducted every 6 weeks (for the first 12 months since start of treatment) and every 12 weeks (after 12 months since start of treatment) until disease progression

Time frame: Baseline, every 3 weeks from Week 3 until end of treatment, every 6 or 12 weeks post-treatment until progression (post-treatment efficacy visits), 7 and 28 days post progression through final analysis cutoff date of 08Jan2021 (up to approx. 18 months)

Population: FAS in Randomized part: All participants to whom study treatment was assigned by randomization. Number analyzed represents participants with data available at the specified data points

Venous whole blood samples were collected for pharmacokinetics characterization. Cmax of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.

Time frame: Cycle 1 Day 1 and Cycle 4 Day 1 at pre-infusion, end of infusion, and 2, 4 and 6 hours post-dose. Each cycle is 21 days

Population: Docetaxel PAS in randomized part: all subjects who received at least one dose of canakinumab in the randomized part and have at least one evaluable docetaxel PK concentration. Number analyzed represents participants evaluable at specified time points

Venous whole blood samples were collected for pharmacokinetics characterization. CTrough of canakinumab was calculated from canakinumab plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.

Time frame: Pre-dose on Cycle 1 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, Cycle 12 Day 1 and Cycle 18 Day 1. Each cycle is 21 days.

Population: Canakinumab PAS in randomized part: all subjects who received at least one dose of canakinumab in the randomized part and have at least one evaluable canakinumab pharmacokinetic (PK) concentration. Number analyzed represents participants evaluable at specified time points.

PFS is defined as the time from randomization to the date of the first documented radiological progression by investigator assessment according to RECIST 1.1 response criteria or death due to any cause. The PFS distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated for each treatment group. If a participant did not have disease progression or die at the analysis cut-off date, PFS was censored at the date of last adequate tumor assessment.

Time frame: From randomization until disease progression, death or final analysis data cutoff date (08-Jan-2021) whichever comes first (assessed up to approx. 18 months)

Population: FAS in Randomized part: All participants to whom study treatment was assigned by randomization

The EORTC QLQ-C30 includes 5 functional scales (physical,role,cognitive,emotional and social), 3 symptom scales (fatigue,pain and nausea/vomiting), a GHS/QoL scale, and 6 single items (constipation,diarrhea,insomnia,shortness of breath,appetite loss and financial difficulties). For each scale and single-item, scores range between 0 and 100. A high score for functional scales/ GHS/QoL represents better functioning or QoL, a high score for symptom scales/single items represents significant symptomatology. TTD in GHS/QoL, shortness of breath and pain is defined as the time from randomization to the date of event, defined as at least 10 points absolute worsening from baseline of the corresponding scale score, with no later change below this threshold i.e.\<10 points was observed or if this worsening was observed at the last assessment for the subject, or death due to any cause (whichever occurs earlier). If a subject did not have an event, TTD was censored at the last adequate assessment.

Time frame: From baseline through final analysis data cutoff date of 08-Jan-2021 (assessed up to approx. 18 months)

Population: FAS in Randomized part: All participants to whom study treatment was assigned by randomization

The EORTC QLQ-LC13 comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, dyspnea, and chest pain) and treatment-related symptoms from conventional chemotherapy and radiotherapy (ie. hair loss, neuropathy, sore mouth, and dysphagia). Scores for each scale and single-item range from 0 to 100, with higher scores indicating higher level of symptoms. TTD for chest pain, cough and dyspnea is defined as the time from randomization to the date of event, which is defined as at least 10 points absolute worsening from baseline of the corresponding scale score, with no later change below this threshold ie.\<10 points was observed or if this worsening was observed at the last assessment for the subject, or death due to any cause (whichever occurs earlier). If a subject did not have an event, TTD was censored at the last adequate assessment.

Time frame: From baseline through final analysis data cutoff date of 08-Jan-2021 (assessed up to approx. 18 months)

Population: FAS in Randomized part: All participants to whom study treatment was assigned by randomization

TTR is defined as the time from the date of randomization to the date of first documented response of either CR or PR, by investigator's assessment according to RECIST 1.1 criteria. The TTR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated for each treatment group. Subjects without a confirmed CR or PR at the time of the analysis cut-off date were censored at the study-maximum follow-up time for subjects with a PFS event (i.e., disease progression or death due to any cause), or at the date of the last adequate tumor assessment for subjects without a PFS event. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

Time frame: From randomization until first documented response or final analysis data cutoff date (08-Jan-2021) whichever comes first (up to approx. 18 months)

Population: FAS in Randomized part: All participants to whom study treatment was assigned by randomization

Venous whole blood samples were collected for pharmacokinetics characterization. Tmax of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. Actual recorded sampling times were considered for the calculations.

Time frame: Cycle 1 Day 1 and Cycle 4 Day 1 at pre-infusion, end of infusion, and 2, 4 and 6 hours post-dose. Each cycle is 21 days

Population: Docetaxel PAS in randomized part: all subjects who received at least one dose of canakinumab in the randomized part and have at least one evaluable docetaxel PK concentration. Number analyzed represents participants evaluable at specified time points

Venous whole blood samples were collected for pharmacokinetics characterization. AUClast of canakinumab was calculated from canakinumab plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.

Time frame: Cycle 1 Day 1 at pre-dose and end of infusion and 24, 48, 168 and 336 hours (h) post-infusion. Each cycle is 21 days

Population: Canakinumab PAS in safety run-in part: all subjects who received at least one dose of canakinumab in the safety run-in part and have at least one evaluable canakinumab PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in this analysis

Venous whole blood samples were collected for pharmacokinetics characterization. AUClast of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.

Time frame: Cycle 1 Day 1 and Cycle 2 Day 1 at pre-infusion, end of infusion, and 2, 4, 6 and 8 hours post-dose. Each cycle is 21 days

Population: Docetaxel PAS in safety run-in part: all subjects who received at least one dose of canakinumab in the safety run-in part and have at least one evaluable docetaxel PK concentration. Number analyzed represents participants evaluable at specified time points

Venous whole blood samples were collected for pharmacokinetics characterization. Cmax of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.

Time frame: Cycle 1 Day 1 and Cycle 2 Day 1 at pre-infusion, end of infusion, and 2, 4, 6 and 8 hours post-dose. Each cycle is 21 days

Population: Docetaxel PAS in safety run-in part: all subjects who received at least one dose of canakinumab in the safety run-in part and have at least one evaluable docetaxel PK concentration. Number analyzed represents participants evaluable at specified time points

Venous whole blood samples were collected for pharmacokinetics characterization. Cmax of canakinumab was calculated from canakinumab plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics.

Time frame: Cycle 1 Day 1 at pre-dose and end of infusion and 24, 48, 168 and 336 hours (h) post-infusion. Each cycle is 21 days

Population: Canakinumab pharmacokinetic analysis set (PAS) in safety run-in part: all subjects who received at least one dose of canakinumab in the safety run-in part and have at least one evaluable canakinumab pharmacokinetic (PK) concentration. Only participants with an evaluable PK sample collected at each timepoint were included in this analysis.

Venous whole blood samples were collected for pharmacokinetics characterization. Tmax of canakinumab was calculated from canakinumab plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. Actual recorded sampling times were considered for the calculations.

Time frame: Cycle 1 Day 1 at pre-dose and end of infusion and 24, 48, 168 and 336 hours (h) post-infusion. Each cycle is 21 days

Population: Canakinumab PAS in safety run-in part: all subjects who received at least one dose of canakinumab in the safety run-in part and have at least one evaluable canakinumab PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in this analysis

Venous whole blood samples were collected for pharmacokinetics characterization. Tmax of docetaxel was calculated from docetaxel plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. Actual recorded sampling times were considered for the calculations.

Time frame: Cycle 1 Day 1 and Cycle 2 Day 1 at pre-infusion, end of infusion, and 2, 4, 6 and 8 hours post-dose. Each cycle is 21 days

Population: Docetaxel PAS in safety run-in part: all subjects who received at least one dose of canakinumab in the safety run-in part and have at least one evaluable docetaxel PK concentration. Number analyzed represents participants evaluable at specified time points

Pre-treatment deaths were collected from screening to the first day of treatment, for a maximum duration of 28 days. On-treatment deaths due to any cause were collected from first dose of study treatment to 130 days after the last dose of study treatment. Post-treatment survival follow-up deaths were collected from day 131 after last dose of study treatment to end of study. All deaths refer to the sum of pre-treatment, on-treatment and post-treatment deaths.

Time frame: Pre-treatment: up to 28 days before Day 1;On-treatment: up to approximately 10 months (safety run-in) or 25 months (randomized); post-treatment survival follow-up deaths: Up to approximately 16 months (safety run in) or 25 months (randomized)

Population: Safety run-in part: FAS including all subjects to whom study treatment was assigned.~Randomized part: FAS including all participants to whom study treatment was assigned by randomization