Non-small Cell Lung Cancer
Conditions
Keywords
Mesenchymal Epithelial Transition (MET), MET exon 14 skipping mutation, High MET amplification, Neoadjuvant, Prior to surgery, Adjuvant, After surgery, INC280, MET inhibition, adult, capmatinib
Brief summary
This study was planned to determine if neoadjuvant capmatinib could improve the major pathological response (MPR) in patients with Stage IB-IIIA, N2 and selected IIIB (T3N2 or T4N2) lung cancers with Mesenchymal Epithelial Transition (MET) exon 14 mutations and/or high MET amplification beyond those achieved with surgery, chemotherapy, and radiation. Treatment was to be continued with capmatinib in the adjuvant setting to evaluate the potential clinical benefit of extended therapy. The purpose of this study is to determine if neoadjuvant capmatinib can improve outcomes in participants with stages I-IIIA non-small cell lung cancer with MET exon 14 mutations and/or high MET amplification beyond those achieved with surgery, chemotherapy, and radiation.
Detailed description
This was a Phase II, two cohort, two stage study of capmatinib given for 8 weeks (2 cycles) prior to surgical resection, followed by three-year capmatinib treatment in adjuvant setting. Surgery had to be performed up to 2 weeks after the last dose of neoadjuvant study treatment. There were 2 molecularly defined cohorts enrolled in parallel: * Cohort A: MET exon 14 skipping mutations, irrespective of MET GCN or * Cohort B: high level MET amplification (MET: GCN ≥ 10 by FISH or FoundationOne CDx NGS using tumor tissue). Approximately 42 participants were aimed to be enrolled in the study, with 21 participants per cohort. This was planned to obtain 38 evaluable participants, 19 per each cohort. Participants who had both MET exon 14 skipping mutations and high-level MET amplification were planned to be enrolled into Cohort A. An evaluable subject received the neoadjuvant treatment and subsequently underwent surgery, resulting in a pathological response. The study recruitment was prematurely discontinued due to significant recruitment challenges leading to termination of the study. The challenges included the rarity of the mutation and site initiation delays caused by staff shortages associated with COVID-19. As a result, only 4 subjects were enrolled and treated in Cohort A.
Interventions
DRUGcapmatinib
150 mg and 200 mg tablets for oral administration
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: 1. Adult ≥ 18 years of age at the time of informed consent. 2. Histologically confirmed NSCLC Stage IB-IIIA, N2 and selected IIIB (T3N2 or T4N2) (per AJCC 8th edition), deemed suitable for primary resection by treating surgeon (T4 tumors with mediastinal organ invasion were not eligible for enrollment). 3. Participant must have MET exon 14 mutation and/or high-level MET amplification (MET: GCN ≥ 10) as determined by a CLIA certified laboratory. High level MET amplification must be identified by FISH in a CLIA certified laboratory or FoundationOne CDx NGS (other NGS-based methods without adjusting for tumor content % cannot be accepted). 4. Participants must be eligible for surgery and scheduled for surgical resection within approximately 2 weeks after the last dose of neoadjuvant study treatment. 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Key
Exclusion criteria
1. Participants with unresectable or metastatic disease. All participants should have brain imaging (either MRI brain or CT brain with contrast) prior to enrollment to exclude brain metastasis. 2. Presence or history of a malignant disease that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type. 3. Prior treatment with any MET inhibitor or HGF-targeting therapy. 4. Participants with other known oncogenic driver alterations. 5. Prior systemic anti-cancer therapy (chemotherapy, immunotherapy, biologic therapy, vaccine) or investigational agents for NSCLC. 6. Participants with known hypersensitivity to capmatinib and any of the excipients of capmatinib (crospovidone, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, magnesium stearate, colloidal silicon dioxide, and various coating premixes). Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response (MPR) Rate | Baseline up to time of surgery (approximately 8 to 10 weeks after first dose) | The primary efficacy variable was MPR rate, defined as the proportion of participants with ≤ 10% residual viable cancer cells. MPR rate was to be assessed via local review for primary analysis. MPR assessment in tumor samples was collected at time of resection. Due to low number of participants and limited data, analysis related to the primary endpoint was not performed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Baseline up to time of surgery (approximately 8 - 10 weeks after first dose) | Overall Response Rate (ORR) was defined as the percentage participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response ( PR) according to RECIST v1.1. BOR was the observed response at the assessment performed prior to surgery via local review. |
| Complete Pathologic Response (pCR) Rate | Baseline up to time of surgery (approximately. 8- 10 weeks after first dose) | Complete pathologic response (pCR) rate ws defined as the percentage of participants with no residual viable cancer cells. pCR rate was assessed via both central and local review. |
| Disease Free Survival (DFS) | From time of surgery to Months 24, 36, and 60 | Disease Free Survival (DFS) was defined as the time from the date of first adjuvant treatment to the date of the first documented disease recurrence as assessed by local investigator radiologically or death due to any cause. In case of non-conclusive radiological evidence, a biopsy was to be performed to confirm recurrence and used as DFS event. DFS events were assessed locally. |
| Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria | Baseline up to 30 days after last dose of study medication, assessed up to approximately 20 months | An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. Treatment emergent Adverse Event (TEAEs) in this study were events that started after the first dose of study treatment and until 30 days after the last dose of study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 30 days after the last study treatment. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 3 centers in the USA.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A (MET Exon 14 Skipping Mutations) The study treatment started on Cycle 1 Day 1 with the first administration of capmatinib 400 mg twice a day (b.i.d.). The participants were planned to receive study treatment for a maximum of 3 years following surgery or until early discontinuation. | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Cohort A (MET Exon 14 Skipping Mutations) |
|---|---|
| Age, Continuous | 78.25 Years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 4 |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 3 / 4 |
Outcome results
Primary
Major Pathological Response (MPR) Rate
The primary efficacy variable was MPR rate, defined as the proportion of participants with ≤ 10% residual viable cancer cells. MPR rate was to be assessed via local review for primary analysis. MPR assessment in tumor samples was collected at time of resection. Due to low number of participants and limited data, analysis related to the primary endpoint was not performed.
Time frame: Baseline up to time of surgery (approximately 8 to 10 weeks after first dose)
Population: All enrolled participants with tumor tissue samples
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A (MET Exon 14 Skipping Mutations) | Major Pathological Response (MPR) Rate | Responder as per local review | 1 Participants |
| Cohort A (MET Exon 14 Skipping Mutations) | Major Pathological Response (MPR) Rate | Responder as per central review | 0 Participants |
Secondary
Complete Pathologic Response (pCR) Rate
Complete pathologic response (pCR) rate ws defined as the percentage of participants with no residual viable cancer cells. pCR rate was assessed via both central and local review.
Time frame: Baseline up to time of surgery (approximately. 8- 10 weeks after first dose)
Population: All enrolled participants with tumor tissue samples
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A (MET Exon 14 Skipping Mutations) | Complete Pathologic Response (pCR) Rate | 0 Participants |
Secondary
Disease Free Survival (DFS)
Disease Free Survival (DFS) was defined as the time from the date of first adjuvant treatment to the date of the first documented disease recurrence as assessed by local investigator radiologically or death due to any cause. In case of non-conclusive radiological evidence, a biopsy was to be performed to confirm recurrence and used as DFS event. DFS events were assessed locally.
Time frame: From time of surgery to Months 24, 36, and 60
Population: All enrolled participants. Due to early discontinuation of the study, no participants reached month 24 (no data was collected/analyzed for the endpoint).
Secondary
Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. Treatment emergent Adverse Event (TEAEs) in this study were events that started after the first dose of study treatment and until 30 days after the last dose of study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 30 days after the last study treatment.
Time frame: Baseline up to 30 days after last dose of study medication, assessed up to approximately 20 months
Population: All enrolled participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A (MET Exon 14 Skipping Mutations) | Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria | Adverse Events (AEs) | 4 Participants |
| Cohort A (MET Exon 14 Skipping Mutations) | Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria | AEs leading to study treatment discontinuation | 2 Participants |
| Cohort A (MET Exon 14 Skipping Mutations) | Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria | AEs leading to dose adjustment and/or interruption | 4 Participants |
| Cohort A (MET Exon 14 Skipping Mutations) | Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria | SAEs related to study treatment | 0 Participants |
| Cohort A (MET Exon 14 Skipping Mutations) | Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria | Serious Adverse Events (SAEs) | 3 Participants |
| Cohort A (MET Exon 14 Skipping Mutations) | Number of Adverse Events and Serious Adverse Events as Assessed by CTCAE Criteria | Fatal SAEs | 1 Participants |
Secondary
Overall Response Rate (ORR)
Overall Response Rate (ORR) was defined as the percentage participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response ( PR) according to RECIST v1.1. BOR was the observed response at the assessment performed prior to surgery via local review.
Time frame: Baseline up to time of surgery (approximately 8 - 10 weeks after first dose)
Population: All enrolled participants with tumor tissue samples
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A (MET Exon 14 Skipping Mutations) | Overall Response Rate (ORR) | 1 Participants |