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.

Phase 2TerminatedNCT03968419

Novartis Pharmaceuticals88 enrolled

Overview

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.

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Non-small Cell Lung Cancer

Interventions

CanakinumabDRUG

200 mg of canakinumab administered via subcutaneous injections once every 3 weeks for a maximum duration of 6 weeks

PembrolizumabDRUG

200 mg of pembrolizumab administered via infusion once every 3 weeks for a maximum duration of 6 weeks

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (29)

Outcomes

Primary Outcomes

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.

Time frame: At time of surgery (up to 6 weeks after first dose of study treatment)

Secondary Outcomes

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

Time frame: 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)

Time frame: 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

Time frame: Predose (0 hour) on Day 1 of Cycle 1 (Cycle = 21 days)

Data from ClinicalTrials.gov

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UCLA Oncology Hematology

La Jolla, California, United States

University of Kansas Medical Center Neurology Dept.

Kansas City, Kansas, United States

SUNY - Upstate Medical University

Syracuse, New York, United States

Methodist Hospital / Methodist Cancer Center

Houston, Texas, United States

Novartis Investigative Site

Brussels, Belgium

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Montpellier, Herault, France

Novartis Investigative Site

Bron, France

Novartis Investigative Site

Paris, France

Novartis Investigative Site

Bad Berka, Germany

...and 19 more locations

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)

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: From date of randomization up to 6 weeks after first dose