NCT04323436

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

Terminated Phase 2 Results posted Last updated 9 October 2024

What this trial tests

Phase 2 trial testing Spartalizumab in Carcinoma, Non-Small-Cell Lung in 31 participants. Terminated before completion.

Timeline

19 August 2020

Primary endpoint
14 December 2022

26 January 2023

Quick facts

Lead sponsor	Novartis Pharmaceuticals
Phase	Phase 2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	31
Start date	19 August 2020
Primary completion	14 December 2022
Estimated completion	26 January 2023
Sites	15 locations across France, Italy, Japan, Belgium, Germany, South Korea, Canada, United States

Drugs / interventions tested

• Spartalizumab — full drug profile →
• Capmatinib (CAPMATINIB) — full drug profile →
• spartalizumab placebo — full drug profile →

Conditions studied

• Carcinoma, Non-Small-Cell Lung — all drugs for Carcinoma, Non-Small-Cell Lung →

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

18 and older, any sex, with Carcinoma, Non-Small-Cell Lung. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Run-in Part: Overall Response Rate (ORR) by Investigator Assessment as Per RECIST 1.1 Primary · Up to approximately 2 years and 4 months

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.

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	35.5	19.2 – 54.6

Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib Secondary · From first dose of capmatinib to last dose, up to 2.4 years

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

At least one dose reduction

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	19

At least one dose interruption

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	20

Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab Secondary · From first dose of spartalizumab to last dose, up to 0.9 years

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.

At least one dose reduction

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	0

At least one dose interruption

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	7

Run-in Part: Dose Intensity of Capmatinib Secondary · From first dose of capmatinib to last dose, up to 2.4 years

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

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	595.9	± 173.6

Run-in Part: Dose Intensity of Spartalizumab Secondary · From first dose of spartalizumab to last dose, up to 0.9 years

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).

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	365.6	± 51.5

Run-in Part: Disease Control Rate (DCR) by Investigator Assessment as Per RECIST 1.1 Secondary · Up to approximately 2 years and 4 months

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 di

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	77.4	58.9 – 90.4

Run-in Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1 Secondary · Up to approximately 2 years and 5 months

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 o

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	16.5	7.4 – NA

Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Capmatinib Secondary · pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.

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.

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	2730	± 74.3

Run-in Part: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib Secondary · pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.

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.

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	1.75	1.00 – 3.92

Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Capmatinib Secondary · pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.

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.

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	12900	± 96.1

Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib Secondary · pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.

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

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	10000	± 61.8

Run-in Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab Secondary · pre-infusion and 1, 72, 168, 336 and 672 hours after completion of the spartalizumab infusion on Cycle 3 Day 1. The duration of the infusion was approximately 30 minutes. The duration of one cycle was 28 days.

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.

Group	Value	95% CI
Run-in Part: Capmatinib 400 mg BID + Spartalizumab 400 mg Q4W	135	± 28.4

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were collected from first dose of spartalizumab+capmatinib (or capmatinib single agent for enrolled patients who had not started study treatment at the time of spartalizumab discontinuation) to 150 days after last dose of spartalizumab or 30 days after last dose of capmatinib, whichever was longer, up to approximately 2 years and 5 months.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

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

Serious: 11/28 (39%)

Deaths: 4/28

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

Serious: 8/28 (29%)

Deaths: 0/28

Run-in Part: Capmatinib 400mg BID Only

Serious: 1/3 (33%)

Deaths: 0/3

Serious adverse events (29 terms)

Reaction	System	Run-in Part: Capmatinib 40…	Run-in Part: Capmatinib 40…	Run-in Part: Capmatinib 40…
Pancreatitis	Gastrointestinal disorders	—	—	—
General physical health deterioration	General disorders	—	—	—
Medical device site haemorrhage	General disorders	—	—	—
Oedema	General disorders	—	—	—
Oedema peripheral	General disorders	—	—	—
Pyrexia	General disorders	—	—	—
Drug-induced liver injury	Hepatobiliary disorders	—	—	—
Hepatic function abnormal	Hepatobiliary disorders	—	—	—
Hepatitis	Hepatobiliary disorders	—	—	—
Hepatotoxicity	Hepatobiliary disorders	—	—	—
Clostridium colitis	Infections and infestations	—	—	—
Gastroenteritis rotavirus	Infections and infestations	—	—	—
Osteomyelitis	Infections and infestations	—	—	—
Pneumonia	Infections and infestations	—	—	—
Respiratory tract infection	Infections and infestations	—	—	—
Streptococcal infection	Infections and infestations	—	—	—
Infusion related reaction	Injury, poisoning and procedural complications	—	—	—
Joint dislocation	Injury, poisoning and procedural complications	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—
Brain oedema	Nervous system disorders	—	—	—
Encephalopathy	Nervous system disorders	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—

Other adverse events (68 terms — click to expand)

Reaction	System	Run-in Part: Capmatinib 40…	Run-in Part: Capmatinib 40…	Run-in Part: Capmatinib 40…
Oedema peripheral	General disorders	—	—	—
Blood creatinine increased	Investigations	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Lipase increased	Investigations	—	—	—
Hypoalbuminaemia	Metabolism and nutrition disorders	—	—	—
Oedema	General disorders	—	—	—
Amylase increased	Investigations	—	—	—
Blood creatine phosphokinase increased	Investigations	—	—	—
Weight increased	Investigations	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—
Face oedema	General disorders	—	—	—
Fatigue	General disorders	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—
Weight decreased	Investigations	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—
Gastritis	Gastrointestinal disorders	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—
Chest pain	General disorders	—	—	—
COVID-19	Infections and infestations	—	—	—
Gastroenteritis	Infections and infestations	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—
Blood bilirubin increased	Investigations	—	—	—
Blood lactate dehydrogenase increased	Investigations	—	—	—
Gamma-glutamyltransferase increased	Investigations	—	—	—

Most-reported serious reactions: Pancreatitis, General physical health deterioration, Medical device site haemorrhage, Oedema, Oedema peripheral, Pyrexia, Drug-induced liver injury, Hepatic function abnormal.

Data from ClinicalTrials.gov NCT04323436 adverse events section.

Sponsor's own description

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

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation.
   Wu M, Huang Q, Xie Y, Wu X, et al · · 2022 · cited 336× · PMID 35279217 · DOI 10.1186/s13045-022-01242-2
2. Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy.
   Boyero L, Sánchez-Gastaldo A, Alonso M, Noguera-Uclés JF, et al · · 2020 · cited 78× · PMID 33322522 · DOI 10.3390/cancers12123729
3. Current and future treatment options for <i>MET</i> exon 14 skipping alterations in non-small cell lung cancer.
   Hong L, Zhang J, Heymach JV, Le X. · · 2021 · cited 50× · PMID 33643443 · DOI 10.1177/1758835921992976
4. A narrative review of MET inhibitors in non-small cell lung cancer with <i>MET</i> exon 14 skipping mutations.
   Santarpia M, Massafra M, Gebbia V, D'Aquino A, et al · · 2021 · cited 44× · PMID 33889528 · DOI 10.21037/tlcr-20-1113
5. Therapeutic strategies in METex14 skipping mutated non-small cell lung cancer.
   Drusbosky LM, Dawar R, Rodriguez E, Ikpeazu CV. · · 2021 · cited 40× · PMID 34425853 · DOI 10.1186/s13045-021-01138-7
6. Trial Watch: combination of tyrosine kinase inhibitors (TKIs) and immunotherapy.
   Petrazzuolo A, Maiuri MC, Zitvogel L, Kroemer G, et al · · 2022 · cited 23× · PMID 35655707 · DOI 10.1080/2162402x.2022.2077898
7. Targeting MET in Non-Small Cell Lung Cancer (NSCLC): A New Old Story?
   Spagnolo CC, Ciappina G, Giovannetti E, Squeri A, et al · · 2023 · cited 21× · PMID 37373267 · DOI 10.3390/ijms241210119
8. Unveiling the Role of HGF/c-Met Signaling in Non-Small Cell Lung Cancer Tumor Microenvironment.
   Yao S, Liu X, Feng Y, Li Y, et al · · 2024 · cited 16× · PMID 39201787 · DOI 10.3390/ijms25169101