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Carcinoma, Bronchogenic

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Respiratory Tract Diseases

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Antineoplastic Agents

Spartalizumab

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

capmatinib in combination with spartalizumab

Capmatinib

spartalizumab placebo

A double-blind, placebo controlled, randomized, phase II study evaluating the efficacy and safety of capmatinib (INC280) and spartalizumab (PDR001) combination therapy versus capmatinib and placebo as first line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping (METΔex14) mutations

The purpose of this study was to evaluate the efficacy and safety of capmatinib in combination with spartalizumab in treatment naive patients with EGFR wild-type, ALK rearrangement negative advanced NSCLC, harboring METΔex14 mutations.

A run-in part (Part 1) was conducted to determine the anti-tumor activity and safety of capmatinib in combination with spartalizumab. Upon review of safety data and confirmation of anti-tumor activity in Part 1, the randomized part (Part 2) was planned to be initiated to compare the efficacy and safety of capmatinib plus spartalizumab to capmatinib plus placebo.

Combined treatment of METΔex14 mutated NSCLC with capmatinib and spartalizumab was expected to result in improved efficacy compared to each single agent due to direct targeting of an oncogenic driver (MET) as well as more efficient stimulation of an anti-tumor immune response than with PD-1 blockade alone.

The study enrollment was halted on 28-Jul-2021 per sponsor's decision. The enrollment halt decision was based on lack of tolerability observed in capmatinib and spartalizumab combination treatment in the run-in part (Part 1) of the trial.

Following the study enrollment halt during Part 1 (Run in Part), Part 2 was not initiated.

Immediately following the enrollment halt:

* All ongoing subjects were discontinued from spartalizumab treatment and continue to receive single agent capmatinib
* Enrolled subjects who had not started study treatment were to receive capmatinib single agent treatment from the start

Run-in part: single arm, open-label.

Randomized part: two-arms parallel assignment, double-blinded, placebo control

Study of Capmatinib and Spartalizumab/Placebo in Advanced NSCLC Patients With MET Exon 14 Skipping Mutations

A Double-blind, Placebo Controlled, Randomized, Phase II Study Evaluating the Efficacy and Safety of Capmatinib and Spartalizumab vs Capmatinib and Placebo as 1st Line Treatment for Advanced NSCLC Patients With MET exon14 Skipping Mutations

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Tumor response was based on local investigator assessment as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR).

For RECIST v1.1, 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.

PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. Tumor response based on blinded independent review committee (BIRC) assessment per RECIST v1.1.

Number of participants with at least one dose reduction of capmatinib and number of participants with at least one dose interruption of capmatinib.

Number of participants with at least one dose reduction of spartalizumab and number of participants with at least one dose interruption of spartalizumab. Dose reductions were not allowed for spartalizumab.

Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.

Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in days and then multiplied by the duration of one cycle (28 days).

DCR is defined as the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and non-CR/non-progressive disease (for subjects without target lesions). Tumor response was based on local investigator assessment per RECIST v1.1.

For RECIST v1.1, 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; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression).

PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on investigator assessment per RECIST v1.1. Progression is defined using RECIST v1.1 as at least 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm.

PFS was analyzed using Kaplan-Meier estimates.

Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.

PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose. Actual recorded sampling times were considered for the calculations.

PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUCtau calculation. A dosing interval (tau) is defined as 12 hours. The portion of area under the curve between 8 hours and 12 hours post-dose was calculated by extrapolation based on terminal elimination slop.

PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.

PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.

PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUCtau calculation. A dosing interval (tau) is defined as 28 days.

PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.

OS is defined as the time from date of start of treatment to date of death due to any cause.

Number of participants with at least one dose reduction of capmatinib and spartalizumab and number of participants with at least one dose interruption of capmatinib and spartalizumab.

Dose intensity is defined as the ratio of actual cumulative dose and duration of exposure.

PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. Tumor response based on investigator assessment per RECIST v1.1.

DCR is defined as the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and non-CR/non-progressive disease (for subjects without target lesions). Tumor response based on BIRC and local investigator assessment per RECIST v1.1.

ORR is defined as the percentage of participants with a best overall response of Complete Response (CR) and Partial Response (PR). Tumor response based on BIRC and local investigator assessment per RECIST v1.1.

DOR is defined as the time from the date of first documented response (CR or PR) to the first documented progression per RECIST 1.1 or death due to any cause.

TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR, which must be subsequently confirmed, according to RECIST 1.1.

The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items and is composed of both multi-item scales and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact) and a global health status/QoL scale. All scales and single-item measures range in score from 0 to 100. For the functional and the global QoL scales, a higher score indicates better health. For the symptom scales, a higher score indicates more symptom burden. The QLQ-C30 summary score (0-100) is calculated as the mean of 13 of the 15 QLQ-C30 scale and item scores (excluding global QoL and financial impact), with a higher score indicating a better health-related QoL.

EORTC QLQ-LC13 is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 13 items specifically related to lung cancer. The five domains of the LC13 include pain, dyspnea, coughing and hemoptysis, and are based on their presence over the past week. All but the pain domain are scored on a 4 point Likert scale ranging from "not at all" to "very much". Pain score is based on its presence, hence yes or no. Scores are averaged and transformed to 0 to 100. A higher score indicates a higher presence of symptoms.

The EQ-5D-5L is a standardized measure of health utility that provides a single index value for one's health status. The EQ-5D-5L contains one item for each of five dimensions of health-related quality of life (HRQOL) (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Response options for each item vary from having no problems to extreme problems. Subject responses to the five dimensions of HRQOL reflect a specific health state that corresponds to a population preference weight for that state on a continuous scale of 0 (death) to 1 (perfect health). A visual analog scale (ranging from 0 to 100) is also included to capture subject's rating of their overall health status. Higher scores of the EQ-5D-5L represent better health states.

EORTC QLQ-LC13 is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 13 items specifically related to lung cancer. The five domains of the LC13 include pain in chest, dyspnea, coughing and hemoptysis, and are based on their presence over the past week. All but the pain domain are scored on a 4 point Likert scale ranging from "not at all" to "very much". Pain score is based on its presence, hence yes or no. Scores are averaged and transformed to 0 to 100. A higher score indicates a higher presence of symptoms.

The time to definitive 10 points deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the corresponding scale score or death due to any cause.

The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact) and a global health status/QoL scale. All scales and single-item measures range in score from 0 to 100. For the functional and the global QoL scales, a higher score indicates better health. For the symptom scales, a higher score indicates more symptom burden.

The time to definitive 10 points deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the corresponding scale score or death due to any cause.

Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.

Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose.

Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods.

Immunogenicity (IG) evaluated in serum samples. The assay to quantify and assess the IG was a validated homogeneous enzyme-linked immunosorbent assay (ELISA).

Novartis Pharmaceuticals

Patients were analyzed according to the treatment they actually received.

Capmatinib 400 mg BID in combination with spartalizumab 400 mg Q4W before the discontinuation of spartalizumab

Run-in Part: Capmatinib 400mg BID + Spartalizumab 400mg Q4W (Prior Discontinuing Spartalizumab)

Capmatinib 400 mg BID in combination with spartalizumab 400 mg Q4W after the discontinuation of spartalizumab

Run-in Part: Capmatinib 400mg BID + Spartalizumab 400mg Q4W (After Discontinuing Spartalizumab)

Immediately following the discontinuation of spartalizumab (and enrollment halt), enrolled subjects who had not started study treatment received capmatinib single agent treatment from the start

Run-in Part: Capmatinib 400mg BID Only

Capmatinib 400 mg orally twice daily (BID) in combination with spartalizumab 400 mg intravenously every 28 days (Q4W) in the run-in part.

Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W

Capmatinib 400 mg orally twice daily (BID) in combination with spartalizumab 400 mg intravenously every 28 days (Q4W) in the randomized part.

Randomized Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W

Capmatinib 400 mg orally twice daily (BID) in combination with spartalizumab matching placebo intravenously every 28 days (Q4W) in the randomized part.

Randomized Part: Capmatinib 400 mg BID + Placebo

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

All patients to whom study treatment had been assigned and who received at least one dose of study treatment (i.e. at least one dose of any component of the study treatment that is capmatinib or spartalizumab). The randomized part of the study was not initiated.

Study Director

All patients to whom study treatment had been assigned and who received at least one dose of study treatment (i.e. at least one dose of any component of the study treatment that is capmatinib or spartalizumab) in the single arm run-in part. Patients were analyzed according to the treatment they were assigned to.

Run-in Part: Overall Response Rate (ORR) by Investigator Assessment as Per RECIST 1.1

All patients to whom study treatment had been assigned and who received at least one dose of study treatment in the randomized part. The randomized part of the study was not initiated and data was not collected.

Randomized Part: Progression-Free Survival (PFS) by BIRC as Per RECIST 1.1

At least one dose reduction

At least one dose interruption

All patients to whom study treatment had been assigned and who received at least one dose of capmatinib in the single arm run-in part. Patients were analyzed according to the treatment they were assigned to.

Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib

All patients to whom study treatment had been assigned and who received at least one dose of spartalizumab in the single arm run-in part. Patients were analyzed according to the treatment they were assigned to.

Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab

Run-in Part: Dose Intensity of Capmatinib

Run-in Part: Dose Intensity of Spartalizumab

Run-in Part: Disease Control Rate (DCR) by Investigator Assessment as Per RECIST 1.1

Run-in Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1

Patients in the capmatinib full pharmacokinetic analysis set (INC-FPAS) with an available value for the outcome measure. INC-FPAS consists of all patients who had an extensive PK sampling and provided a capmatinib evaluable PK profile on Cycle 3 Day 1.

Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Capmatinib

Run-in Part: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib

Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Capmatinib

Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib

Patients in the spartalizumab full pharmacokinetic analysis set (PDR-FPAS) with an available value for the outcome measure. PDR-FPAS consists of all patients who had an extensive PK sampling and provided a spartalizumab evaluable PK profile on Cycle 3.

Run-in Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab

Run-in Part: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab

Run-in Part: Area Under the Serum Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Spartalizumab

Run-in Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab

Randomized Part: Overall Survival (OS)

Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab

Randomized Part: Dose Intensity of Capmatinib and Spartalizumab

Randomized Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1

Randomized Part: Disease Control Rate (DCR) by BIRC and Investigator Assessment as Per RECIST 1.1

Randomized Part: Overall Response Rate (ORR) by BIRC and Investigator Assessment as Per RECIST 1.1

Randomized Part: Duration of Response (DOR) by BIRC and Investigator Assessment as Per RECIST 1.1

Randomized Part: Time to Response (TTR) by BIRC and Investigator Assessment as Per RECIST 1.1

Randomized Part: Change From Baseline in EORTC QLQ-C30

Randomized Part: Change From Baseline in EORTC QLQ-LC13

Randomized Part: Change From Baseline in EQ-5D-5L

Randomized Part: Time to Definitive 10 Points Deterioration Symptom Scores for Pain in Chest, Coughing and Dyspnea Per QLQ-LC13 Questionnaire

Randomized Part: Time to Definitive Deterioration in Global Health Status/QoL, Shortness of Breath and Pain Per EORTC QLQ-C30

Randomized Part: Maximum Observed Concentration (Cmax) of Capmatinib and Spartalizumab

Randomized Part: Time to Reach Maximum Concentration (Tmax) of Capmatinib and Spartalizumab

Randomized Part: Area Under the Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Capmatinib and Spartalizumab

Randomized Part: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib and Spartalizumab

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of Capmatinib and Spartalizumab/Placebo in Advanced NSCLC Patients With MET Exon 14 Skipping Mutations	NCT04323436	Carcinoma, Non-...	Spartalizumab Capmatinib spartalizumab p...	18 Years -	Novartis
Study of Capmatinib and Spartalizumab/Placebo in Advanced NSCLC Patients With MET Exon 14 Skipping Mutations	NCT04323436	Carcinoma, Non-...	Spartalizumab Capmatinib spartalizumab p...	18 Years -	Novartis

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