This Study Will Evaluate the Effect of Canakinumab or Pembrolizumab Given as Monotherapy or in Combination as Neo-adjuvant Treatment for Subjects With Early Stages NSCLC.

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the major pathological response (MPR) rate of canakinumab given as a neoadjuvant treatment, either as single agent or in combination with pembrolizumab, in addition to evaluate the MPR of pembrolizumab as a single agent and the dynamic of the tumor microenvironment changes on treatment.

Detailed Description
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This was a randomized, phase II, open-label study evaluating canakinumab, an anti-IL-1β monoclonal antibody, or pembrolizumab, a monoclonal antibody designed to block the PD-1 receptor, as monotherapy or in combination as neoadjuvant therapy. The study population included adult subjects with resectable non-small cell lung cancer (NSCLC) planned for surgery in approximately 4-6 weeks. Subjects were treated for a maximum duration of 6 weeks (2 cycles) until surgery, progression, unacceptable toxicity or discontinuation from the study treatment for any other reason. Subjects were randomized in a 2:2:1 ratio to one of the 3 treatment arms (canakinumab alone or canakinumab in combination with pembrolizumab or pembrolizumab alone). Surgery was performed between 4 to 6 weeks after the first dose of study treatment. All randomized subjects were followed for safety for up to 130 days following the last dose of study treatment (safety follow-up period).

Official Title
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A Randomized, Open-label, Phase II Study of Canakinumab or Pembrolizumab as Monotherapy or in Combination as Neoadjuvant Therapy in Subjects With Resectable Non-small Cell Lung Cancer (CANOPY-N)

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Canakinumab
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria: Histologically confirmed NSCLC stage IB-IIIA (per AJCC 8th edition), deemed suitable for primary resection by treating surgeon, except for N2 and T4 tumors. Subject must have been eligible for surgery and with a planned surgical resection in approximately 4-6 weeks (after the first dose of study treatment). A mandatory newly obtained tissue biopsy from primary site was required for study enrollment. An archival biopsy was also acceptable if obtained up to 5 months before first day of study treatment and if the subject did not go through antineoplastic systemic therapies between biopsy collection date and beginning of study treatment. Eastern Cooperative oncology group (ECOG) performance status of 0 or 1. Key exclusion criteria: Subjects with unresectable or metastatic disease. History of severe hypersensitivity reactions to monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction Subjects who received prior systemic therapy (including chemotherapy, other anti-cancer therapies and any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) in the past 3 years before screening Active autoimmune disease that has required systemic treatment in the past 2 years prior to randomization. Control of the disorder with replacement therapy was permitted Subject with suspected or proven immunocompromised state or infections

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Canakinumab monotherapy<br>Participants received 200 mg of canakinumab once every 3 weeks for a maximum duration of 6 weeks prior to surgery | Drug: Canakinumab<br>* 200 mg of canakinumab administered via subcutaneous injections once every 3 weeks for a maximum duration of 6 weeks<br>* Other names: ACZ885;|
| Experimental: Canakinumab + pembrolizumab<br>Participants received 200 mg of canakinumab in combination with 200 mg of pembrolizumab once every 3 weeks for a maximum duration of 6 weeks prior to surgery | Drug: Canakinumab<br>* 200 mg of canakinumab administered via subcutaneous injections once every 3 weeks for a maximum duration of 6 weeks<br>* Other names: ACZ885;Drug: Pembrolizumab<br>* 200 mg of pembrolizumab administered via infusion once every 3 weeks for a maximum duration of 6 weeks<br>|
| Experimental: Pembrolizumab monotherapy<br>Participants received 200 mg of pembrolizumab every 3 weeks for a maximum duration of 6 weeks prior to surgery | Drug: Pembrolizumab<br>* 200 mg of pembrolizumab administered via infusion once every 3 weeks for a maximum duration of 6 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Pathological Response (MPR) Rate at the Time of Surgery in Subjects Randomized to Canakinumab Monotherapy and in Combination With Pembrolizumab Based on Central Review | MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had >10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR was assessed at the time of surgery in all subjects randomized to canakinumab monotherapy and in combination with pembrolizumab based on central review. | At time of surgery (up to 6 weeks after first dose of study treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Canakinumab Antidrug Antibodies (ADA) Prevalence | Canakinumab ADA prevalence at baseline was calculated as the percentage of participants who had a canakinumab ADA positive result at baseline | Predose (0 hour) on Day 1 of Cycle 1 (Cycle=21 days) | 
| Canakinumab ADA Incidence | Canakinumab ADA incidence on treatment was calculated as the percentage of participants who were canakinumab treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and canakinumab 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) | From baseline (Predose on Day 1 of Cycle 1) up to 130 days after last dose of study treatment (assessed up to 24.6 weeks). Cycle = 21 days | 
| Pembrolizumab ADA Prevalence | Pembrolizumab ADA prevalence at baseline was calculated as the percentage of participants who had a pembrolizumab ADA positive result at baseline | Predose (0 hour) on Day 1 of Cycle 1 (Cycle = 21 days) | 
| Pembrolizumab ADA Incidence | Pembrolizumab ADA incidence on treatment was calculated as the percentage of participants who were pembrolizumab treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and pembrolizumab 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) | From baseline (Predose on Day 1 of Cycle 1) up to 26 days after last dose of study treatment (assessed up to 10.7 weeks). Cycle = 21 days | 
| Overall Response Rate (ORR) Based on Local Investigator Assessment Using RECIST v1.1 | ORR is defined as the percentage of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per local investigator's assessment by RECIST 1.1. 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 | From date of randomization to date of surgery, assessed up to 6 weeks | 
| Serum Canakinumab Concentration | Canakinumab serum concentrations were determined at the specified time points. | Predose (0 hour) on Day 1 of Cycles 1 and 2 (Cycle =21 days) | 
| Serum Pembrolizumab Concentration | Pembrolizumab serum concentrations were determined at the specified time points. | Predose (0 hour) and 0.5 hours post dose on Day 1 of Cycle 1 and predose on Cycle 2 (Cycle =21 days) | 
| Surgical Feasibility Rate | Surgical feasibility rate was defined as the percentage of subjects who underwent surgery following study treatment. | Up to 6 weeks after first dose | 
| Major Pathological Response (MPR) Rate at the Time of Surgery in Subjects Randomized to Pembrolizumab Monotherapy Based on Central Review | MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had >10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR was assessed at the time of surgery in all subjects randomized to pembrolizumab monotherapy arm based on central review. | At time of surgery (up to 6 weeks after first dose) | 
| Difference in Major Pathological Response (MPR) Rate Between the Canakinumab Plus Pembrolizumab Arm and the Pembrolizumab Arm Based on Central Review | MPR was defined as the percentage of participants with ≤10% residual viable tumor cells on surgical samples. MPR was assessed at the time of surgery based on central review. The difference in MPR rate between the canakinumab plus pembrolizumab arm and the pembrolizumab arm based on central review along with the Chang and Zhang confidence interval was assessed. | At time of surgery (up to 6 weeks after first dose of study treatment) | 
| Major Pathological Response (MPR) Rate at the Time of Surgery in All Subjects Based on Local Review | MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had >10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR was assessed at the time of surgery in all subjects based on local review. | At time of surgery (up to 6 weeks after first dose) | 
| Major Pathological Response (MPR) Rate Based on the Levels of Biomarkers | MPR was defined as the percentage of participants with major pathological response (defined as ≤10% residual viable tumor cells on surgical samples). Any participant who had >10% residual viable cancer cells, or started new antineoplastic therapy prior to surgery, or did not have the surgery performed, or had the surgery performed but with unevaluable MPR result, was considered as a non-responder. MPR rate was analyzed by the biomarker subgroups at baseline. Biomarkers included PD-L1, CD8, hs-CRP and hs-IL-6. | From date of randomization up to 6 weeks after first dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MPR, CD8, non-small cell lung cancer, ACZ885, canakinumab, pembrolizumab, NSCLC, non small cell lung cancer, early stage NSCLC, squamous, non-squamous,, major pathological response, hs-CRP, PD-L1, hsCRP, surgery, neo-adjuvant, neo adjuvant, hs-IL-6, CANOPY