Study of Safety and Efficacy of EGFR-TKI EGF816 in Combination With cMET Inhibitor INC280 in Adult Patients With EGFR Mutated Non Small Cell Lung Cancer.

• ClinicalTrials.gov Identifier: NCT02335944
• Recruitment Status: Terminated
• First Posted: January 12, 2015
• Results First Posted: June 18, 2023
• Last Update Posted: June 18, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

The purpose of this study was to determine the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) of nazartinib (EGF816) in combination with capmatinib (INC280) and to estimate the preliminary anti-tumor activity of nazartinib in combination with capmatinib in participants with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.

Condition or disease	Intervention/treatment	Phase
Non Small Cell Lung Cancer	Drug: Capmatinib; Drug: Nazartinib	Phase 1; Phase 2

Detailed Description:

This study was designed as a Phase Ib/II, multi-center, open-label study starting with a Phase Ib dose escalation part followed by a Phase II expansion part. Oral nazartinib (once daily) and capmatinib (twice daily) was administered on a continuous schedule until participant experienced unacceptable toxicity, progressive disease (PD) and/or treatment was discontinued at the discretion of the investigator or withdrawal of consent/opposition to use data/biological samples. Study treatment could be continued beyond Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) defined PD, in the judgment of the investigator, when there was evidence of clinical benefit and the subject wished to continue with the study treatment.

In Phase Ib part, participants with NSCLC harboring EGFR activating mutations were enrolled. At the end of the Phase Ib part, once the MTD or RP2D of nazartinib in combination with capmatinib was declared, additional participants with NSCLC were enrolled in the Phase II part in order to assess the preliminary anti-tumor activity of nazartinib in combination with capmatinib. Participants with locally advanced or metastatic NSCLC were assigned into different groups according to their resistance mechanisms.

As per the Protocol amendment 7, an additional group (Group 5) was included into study CINC280X2105C, which was intended to support study CINC280L12301. After thorough and careful assessment of study CINC280L12301 enrollment status, projected study completion timelines, and the changing clinical landscape, Novartis made the decision to discontinue the study. Importantly, this decision was not driven by safety concerns; no new safety signals were observed in the study participants or in the ongoing capmatinib program. As such, Group 5 data was no longer needed and the new arm in study CINC280X2105C was not opened as planned.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 177 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib/II, Multicenter, Open-label Study of EGF816 in Combination With INC280 in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer.
• Actual Study Start Date: January 13, 2015
• Actual Primary Completion Date: November 10, 2020
• Actual Study Completion Date: November 10, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase IB part- NSCLC with EGFR activating mutations; NSCLC participants who have previously documented EGFR mutation and progressed on EGFR TKI treatment. Participants were treated at a starting dose of 50 mg once a day for EGF816 and 200 mg twice a day for INC280 in fasted state	Drug: Capmatinib; In the Phase 1, capmatinib was administered orally, twice per day, at a dose of 200 mg or 400 mg, in fasted state. In the Phase II, participants received capmatinib at the RP2D (400 mg twice per day) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: INC280; Drug: Nazartinib; In the Phase 1, nazartinib was administered orally, once a day, at a dose of 50 mg, 75 mg, 100 mg or 150 mg in fasted state. In the Phase II, participants received nazartinib at the RP2D (100 mg once daily) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: EGF816
Experimental: Phase II- Group 1 (EGFRmut, any T790M, any MET, 2/4L antineoplastic, EGFR TKI resistant); NSCLC participants with previously documented activating EGFR mutation, with any T790M and MET dysregulation status, who received one to three lines of systemic antineoplastic therapy prior to study entry including one line maximum of first or second generation EGFR TKI and who progressed on this EGFR TKI treatment line. Participants were treated at the RP2D of INC280 and EGF816 in fasted state	Drug: Capmatinib; In the Phase 1, capmatinib was administered orally, twice per day, at a dose of 200 mg or 400 mg, in fasted state. In the Phase II, participants received capmatinib at the RP2D (400 mg twice per day) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: INC280; Drug: Nazartinib; In the Phase 1, nazartinib was administered orally, once a day, at a dose of 50 mg, 75 mg, 100 mg or 150 mg in fasted state. In the Phase II, participants received nazartinib at the RP2D (100 mg once daily) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: EGF816
Experimental: Phase II- Group 2 (EGFRmut, de novo T790M, any MET, 1/3L antineoplastic, EGFR TKI naïve); NSCLC participants harboring T790M mutation in de novo setting, irrespective of the activating mutation status who are treatment naïve or received maximum 2 lines of systemic antineoplastic therapy prior to study entry, but no therapy known to inhibit EGFR. Participants were treated at the RP2D of INC280 and EGF816 in fasted state	Drug: Capmatinib; In the Phase 1, capmatinib was administered orally, twice per day, at a dose of 200 mg or 400 mg, in fasted state. In the Phase II, participants received capmatinib at the RP2D (400 mg twice per day) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: INC280; Drug: Nazartinib; In the Phase 1, nazartinib was administered orally, once a day, at a dose of 50 mg, 75 mg, 100 mg or 150 mg in fasted state. In the Phase II, participants received nazartinib at the RP2D (100 mg once daily) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: EGF816
Experimental: Phase II- Group 3 (EGFRmut, T790M negative, any MET, 1L antineoplastic); NSCLC participants with previously documented EGFR activating mutation, T790M negative, and any MET status who never received any prior line of systemic antineoplastic systemic therapy prior to study entry. Participants were treated at the RP2D of INC280 and EGF816 in fasted state	Drug: Capmatinib; In the Phase 1, capmatinib was administered orally, twice per day, at a dose of 200 mg or 400 mg, in fasted state. In the Phase II, participants received capmatinib at the RP2D (400 mg twice per day) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: INC280; Drug: Nazartinib; In the Phase 1, nazartinib was administered orally, once a day, at a dose of 50 mg, 75 mg, 100 mg or 150 mg in fasted state. In the Phase II, participants received nazartinib at the RP2D (100 mg once daily) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: EGF816
Experimental: Phase II- Group 4 (EGFRmut, any T790M, any MET, 1L (treatment naïve) 2-3L antineoplastic); NSCLC participants with previously documented EGFR activating mutations and any T790M and MET status who were treatment naïve or failed maximum 2 prior lines of any systemic antineoplastic therapy for advanced disease. Participants were treated at the RP2D of INC280 and EGF816 in fed state	Drug: Capmatinib; In the Phase 1, capmatinib was administered orally, twice per day, at a dose of 200 mg or 400 mg, in fasted state. In the Phase II, participants received capmatinib at the RP2D (400 mg twice per day) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: INC280; Drug: Nazartinib; In the Phase 1, nazartinib was administered orally, once a day, at a dose of 50 mg, 75 mg, 100 mg or 150 mg in fasted state. In the Phase II, participants received nazartinib at the RP2D (100 mg once daily) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: EGF816
Experimental: Phase II- Group 5 (EGFRmut, T790M-, MET GCN≥5, 2L, EGFR TKI resistant); NSCLC participants with previously documented EGFR activating mutation, T790M negative, acquired MET amplification who have progressed on one prior line of therapy for advanced/metastatic NSCLC disease. Participants were to start with INC280 monotherapy (twice a day) and would have had the opportunity to continue to combination of EGF816 (once a day) and INC280 (twice a day) based on radiological disease progression evaluation by investigator's assessment per RECIST 1.1	Drug: Capmatinib; In the Phase 1, capmatinib was administered orally, twice per day, at a dose of 200 mg or 400 mg, in fasted state. In the Phase II, participants received capmatinib at the RP2D (400 mg twice per day) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: INC280; Drug: Nazartinib; In the Phase 1, nazartinib was administered orally, once a day, at a dose of 50 mg, 75 mg, 100 mg or 150 mg in fasted state. In the Phase II, participants received nazartinib at the RP2D (100 mg once daily) in fasted state (Groups 1, 2 and 3) or fed state (Group 4). Participants in Phase II Group 5 were to start with capmatinib monotherapy (fasted or fed state) and then would have had the opportunity to continue with the combination of nazartinib and capmatinib (fasted or fed state).; Other Name: EGF816

Outcome Measures

Primary Outcome Measures :

1. Phase Ib: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Up to first 28 days of treatment ]
   Number of participants with DLTs in the Phase Ib part. A DLT is defined as an AE or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment with EGF816 in combination with INC280 during the escalation part of the study (Phase Ib)
2. Phase II Group 1, 2 and 3: Overall Response Rate (ORR) by Investigator's Assessment Per RECIST 1.1 [ Time Frame: Up to approximately 4 years ]

   ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) determined by investigator's assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). ORR was assessed in Group 1, 2 and 3 (Phase II part).

   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 diameters of all target lesions, taking as reference the baseline sum of diameters.

3. Phase II Group 4: Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) [ Time Frame: From start of treatment up to 30 days after last dose of study treatment, assessed up to 3.7 years ]
   Number of participants in Group 4 (Phase II part) with AEs and SAEs. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Any untoward event resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE.
4. Phase II Group 4: Number of Participants With Dose Reductions and Dose Interruptions of INC280 and EGF618 [ Time Frame: From start of treatment until end of treatment, assessed up to 3.6 years ]
   Number of participants with at least one dose reduction of INC280, at least one dose interruption of INC280, at least one dose reduction of EGF816 and at least one dose interruption of EGF816 in the Group 4 (Phase II part).
5. Phase II Group 4: Dose Intensity [ Time Frame: From start of treatment until end of treatment, assessed up to 3.6 years ]
   Dose intensity, defined as the ratio of total dose received and actual duration, for participants in Group 4 (Phase II part)
6. Phase II Group 5: ORR Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy [ Time Frame: Up to approximately 3 years (while on INC280 monotherapy) ]

   ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for participants in Group 5 (Phase II part) while on treatment with INC280 monotherapy.

   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 diameters of all target lesions, taking as reference the baseline sum of diameters.

Secondary Outcome Measures :

1. Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of INC280 and EGF618 [ Time Frame: From start of treatment until end of treatment, assessed up to approximately 5 years ]
   Number of participants in Phase Ib with at least one dose reduction of INC280, at least one dose interruption of INC280, at least one dose reduction of EGF816 and at least one dose interruption of EGF816 .
2. Phase II Group 1, 2 and 3: Number of Participants With Dose Reductions and Dose Interruptions of INC280 and EGF618 [ Time Frame: From start of treatment until end of treatment, assessed up to approximately 4 years ]
   Number of participants in Groups 1, 2 and 3 (Phase II part) with at least one dose reduction of INC280, at least one dose interruption of INC280, at least one dose reduction of EGF816 and at least one dose interruption of EGF816 .
3. Phase Ib: Dose Intensity [ Time Frame: From start of treatment until end of treatment, assessed up to approximately 5 years ]
   Dose intensity, defined as the ratio of total dose received and actual duration, in Phase Ib participants
4. Phase II Group 1, 2 and 3: Dose Intensity [ Time Frame: From start of treatment until end of treatment, assessed up to approximately 4 years ]
   Dose intensity, defined as the ratio of total dose received and actual duration, in Group 1, 2 and 3 (Phase II)
5. Phase Ib: Overall Response Rate (ORR) Per RECIST 1.1 Based on Investigator's Assessment [ Time Frame: Up to approximately 5 years ]

   ORR is defined as percentage of participants with best overall response of PR+CR determined by Investigator's assessment in accordance to RECIST 1.1. ORR was assessed in Phase Ib participants.

   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 diameters of all target lesions, taking as reference the baseline sum of diameters.

6. Phase II Group 4: Overall Response Rate (ORR) Per RECIST 1.1 Based on Investigator's Assessment [ Time Frame: Up to approximately 4 years ]
   ORR is defined as percentage of participants with best overall response of PR+CR determined by Investigator's assessment in accordance to RECIST 1.1. ORR was assessed in Group 4 (Phase II) 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 diameters of all target lesions, taking as reference the baseline sum of diameters.
7. Phase Ib: Progression Free Survival (PFS) Per RECIST 1.1 Based on Investigator's Assessment [ Time Frame: From date of first dose to first documented disease progression or death, assessed up to approximately 5 years ]
   PFS is defined as time from date of first dose of study treatment to date of first documented disease progression determined by Investigator assessment in accordance to RECIST 1.1.or death due to any cause. The PFS distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant has not had an event, PFS is censored at the date of last adequate tumor assessment. PFS was assessed in Phase Ib participants
8. Phase II Groups 1, 2, 3 and 4: Progression Free Survival (PFS) Per RECIST 1.1 Based on Investigator's Assessment [ Time Frame: From date of first dose to first documented disease progression or death, assessed up to approximately 4 years ]
   PFS is defined as time from date of first dose of study treatment to date of first documented disease progression determined by Investigator assessment in accordance to RECIST 1.1.or death due to any cause. The PFS distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant has not had an event, PFS is censored at the date of last adequate tumor assessment. PFS was assessed in Group 1, 2, 3 and 4 (Phase II)
9. Phase Ib: Time to Response (TTR) Per RECIST 1.1 Based on Investigator's Assessment [ Time Frame: From the date of the first dose to the date of first documented response, up to approximately 5 years ]

   TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to RECIST 1.1. The TTR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant has not had an event, duration was censored at the date of last adequate tumor assessment. TTR was assessed in Phase Ib participants.

   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 diameters of all target lesions, taking as reference the baseline sum of diameters.

10. Phase II Groups 1, 2, 3 and 4: Time to Response (TTR) Per RECIST 1.1 Based on Investigator's Assessment [ Time Frame: From the date of the first dose to the date of first documented response, up to approximately 4 years ]
    TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to RECIST 1.1. The TTR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant has not had an event, duration was censored at the date of last adequate tumor assessment. TTR was assessed in Group 1, 2, 3 and 4 (Phase II) 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 diameters of all target lesions, taking as reference the baseline sum of diameters.
11. Phase Ib: Duration of Response (DOR) Per RECIST 1.1 Based on Investigator's Assessment [ Time Frame: From date of first documented response to first documented disease progression or death, assessed up to approximately 5 years ]
    DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression determined by Investigator assessment in accordance to RECIST 1.1 or death due to underlying cancer. The DOR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant has not had an event, duration was censored at the date of last adequate tumor assessment. DOR was assessed in Phase Ib participants 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 diameters of all target lesions, taking as reference the baseline sum of diameters.
12. Phase II Groups 1, 2, 3 and 4: Duration of Response (DOR) Per RECIST 1.1 Based on Investigator's Assessment [ Time Frame: From date of first documented response to first documented disease progression or deaths, assessed up to approximately 4 years ]
    DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression determined by Investigator assessment in accordance to RECIST 1.1 or death due to underlying cancer. The DOR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant has not had an event, duration was censored at the date of last adequate tumor assessment. DOR was assessed in Group 1, 2, 3 and 4 (Phase II) 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 diameters of all target lesions, taking as reference the baseline sum of diameters.
13. Phase Ib: Disease Control Rate (DCR) Per RECIST 1.1 Based on Investigator's Assessment [ Time Frame: Up to approximately 5 years ]
    DCR is defined as the percentage of participants with best overall response of CR, PR, or stable disease (SD) determined by Investigator assessment in accordance to RECIST 1.1. DCR was assessed in Phase Ib participants 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 diameters 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.
14. Phase II Group 1, 2 3 and 4: Disease Control Rate (DCR) Per RECIST 1.1 Based on Investigator's Assessment [ Time Frame: Up to approximately 4 years ]
    DCR is defined as the percentage of participants with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to RECIST 1.1. DCR was assessed in Group 1, 2, 3 and 4 (Phase II) 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 diameters 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.
15. Phase Ib: Overall Survival (OS) [ Time Frame: From date of first dose to death, assessed up to approximately 5 years ]
    OS is defined as the time from first dose of the study treatment to the date of death due to any cause. The OS distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant was not known to have died, survival was censored at the date of last contact. OS was assessed in Phase Ib participants
16. Phase II Groups 1, 2, 3 and 4: Overall Survival (OS) [ Time Frame: From date of first dose to death, assessed up to approximately 4 years ]
    OS is defined as the time from first dose of the study treatment to the date of death due to any cause. The OS distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant was not known to have died, survival was censored at the date of last contact. OS was assessed in Group 1, 2, 3 and 4
17. Phase Ib: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 12 Hours (AUC0-12) of INC280 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods.
18. Phase Ib: Peak Plasma Concentration (Cmax) of INC280 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods.
19. Phase Ib: Time to Reach Maximum Concentration (Tmax) of INC280 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)
20. Phase II Groups 3 and 4: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 12 Hours (AUC0-12) of INC280 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods.
21. Phase II Groups 3 and 4: Peak Plasma Concentration (Cmax) of INC280 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods.
22. Phase II Groups 3 and 4: Time to Reach Maximum Concentration (Tmax) of INC280 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)
23. Phase Ib: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) of EGF816 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods.
24. Phase Ib: Peak Plasma Concentration (Cmax) of EGF816 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods.
25. Phase Ib: Time to Reach Maximum Concentration (Tmax) of EGF816 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)
26. Phase II Groups 3 and 4: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) of EGF816 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods.
27. Phase II Groups 3 and 4: Peak Plasma Concentration (Cmax) of EGF816 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods.
28. Phase II Groups 3 and 4: Time to Reach Maximum Concentration (Tmax) of EGF816 [ Time Frame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days) ]
    Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)
29. Phase II Group 5: Duration of Response (DOR) Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy [ Time Frame: From date of first documented response to the date of first documented disease progression or death, assessed up to approximately 3 years (while on INC280 monotherapy) ]

    DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1 for participants in Group 5 (Phase II) while on INC280 monotherapy treatment.

    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 diameters of all target lesions, taking as reference the baseline sum of diameters.

30. Phase II Group 5: Disease Control Rate (DCR) Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy [ Time Frame: Up to approximately 3 years (while on INC280 monotherapy) ]

    DCR is defined as the percentage of participants with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to RECIST 1.1 for participants in Group 5 (Phase II) while on INC280 monotherapy treatment.

    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 diameters 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.

31. Phase II Group 5: Progression Free Survival (PFS) Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy [ Time Frame: Up to approximately 3 years (while on INC280 monotherapy) ]
    PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1 for participants in Group 5 (Phase II) while on INC280 monotherapy treatment.
32. Phase II Group 5: Number of Participants With Dose Modifications for INC280 Monotherapy as Well as INC280 in Combination With EGF816 Therapy [ Time Frame: From start of treatment until end of treatment, up to approximately 3 years ]
    Number of participants with dose modifications for INC280 monotherapy as well as INC280 in combination with EGF816 therapy
33. Phase II Group 5: Dose Intensity for INC280 Monotherapy as Well as INC280 in Combination With EGF816 Therapy [ Time Frame: From start of treatment until end of treatment, up to approximately 3 years ]
    Dose intensity is defined as the ratio of total dose received and actual duration for INC280 monotherapy as well as INC280 in combination with EGF816 therapy in Group 5 (Phase II)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion criteria:

- Participants in Phase Ib and Phase II Groups 1 to 4: histologically documented, locally advanced or recurrent (stage IIIB who were not eligible for combined modality treatment) or metastatic (Stage IV) NSCLC.

Participants in Phase II Group 5: stage IIIB/IIIC (not amenable to curative surgery, chemoradiation or radiation) or stage IV NSCLC

• Participants in Phase Ib and Phase II Groups 1 to 4: locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR T790M mutation (or other rare activating mutations that confer sensitivity to 1st and 2nd generation EGFR inhibitors (e.g. L861Q, G719X, S768I), or a characterized de novo EGFRT790M mutation.
• Presence of at least one measurable lesion according to RECIST v.1.1
• ECOG performance status ≤1
• Participants had to be screened for HBV. Participants who were either HBsAg positive or HBV-DNA positive had to be willing and able to take antiviral therapy 1-2 weeks prior to 1st dose of EGF816 treatment and continue on antiviral therapy for at least 4 weeks after the last dose of EGF816.
• Participants had to be screened for HCV. Participants had to have negative hepatitis C antibody (HCV Ab) or were HCV Ab positive but with an undetectable level of HCV-RNA. Note: participants with detectable HCV-RNA were not eligible for the study.
• Phase Ib only: documented progression of disease according to RECIST v1.1 while on continuous treatment with EGFR TKI (e.g.: erlotinib, gefitinib or afatinib).
• Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant) only: Participants demonstrated a documented clinical benefit (CR (any duration), PR (any duration), or SD for at least 6 months) on prior EGFR TKI (e.g. erlotinib, gefitinib or afatinib, and subsequently demonstrated progression according to RECIST v1.1.
• Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve) only: Advanced NSCLC participants who were not previously treated with any therapy known to inhibit EGFR and harbor de novo T790M mutation .
• Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic) only: participants had to harbor an EGFR activating mutation and had to be naïve from any line of systemic antineoplastic therapy in the advanced setting.
• Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1L (treatment-naïve), 2//3L antineoplastic): All participants had to harbor an EGFR activating mutation and 2/3L participants had to have failed (defined as intolerance to treatment or documented disease progression) a maximum of 2 prior lines of antineoplastic therapy in the advanced setting

• Phase II Group 5 only: Histologically or cytologically confirmed diagnosis of NSCLC (excluding squamous cell carcinoma) with all the following:

  1. EGFR mutations known to be associated with EGFR TKI sensitivity. This had to be assessed as part of the participant standard of care by a validated test for EGFR mutations, as per local regulations. Exon 19 del, L858R, either alone or in combination with other EGFR sensitivity mutation assessed by a Clinical Laboratory Improvement Amendments (CLIA) certified USA laboratory or an accredited local laboratory outside the USA had to be documented in the participant source documents before the participant consented for pre-screening for MET amplification status.
  2. EGFR T790M negative status for participants who had progressed on first or second generation EGFR TKI, or third generation EGFR TKI other than osimertinib, as per tissue-based result from a CLIA-certified USA laboratory or an accredited local laboratory outside of the USA, by a validated test according to local regulations.
  3. MET gene amplification defined as: Gene copy number (GCN) ≥ 5 per tissue-based result from a CLIA-certified USA laboratory or an accredited local laboratory outside of the USA by a test that is validated according to local regulations with results documented in the participant source documents.
  4. Histological transformation from NSCLC into small cell lung cancer (SCLC) following previous EGFR TKI treatment were excluded.
• Participants had to have progressed on one prior line of therapy either to first/second generation EGFR TKIs, osimertinib or other third generation EGFR TKIs for advanced/metastatic disease (stage IIIB/IIIC [not amenable to curative surgery, chemoradiation or radiation or stage IV NSCLC).
• Participants had to have a life expectancy of at least 3 months.

Key exclusion Criteria:

• Phase Ib:

  • More than one previous treatment line with erlotinib, gefitinib or afatinib
  • Previous treatment with any investigational agent known to inhibit EGFR (mutant or wild-type)
  • Participants who had received more than three prior lines of antineoplastic therapies (including EGFR TKI) in advanced setting.

• Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant):

  • More than 3 prior lines of systemic antineoplastic therapies (including EGFR TKI) in the advanced setting
  • More than 1 previous treatment line with 1st or 2nd generation EGFR TKI (e.g. erlotinib, gefitinib, afatinib) in the advanced setting
  • Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
  • Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).

• Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve):

  • More than two previous treatment lines of systemic antineoplastic therapies in the advanced setting
  • Previous treatment with an investigational or marketed agent that inhibits EGFR. EGFR inhibitors include (but not limited to) all generations of EGFR TKI (e.g.erlotinib, gefitinib, afatinib, AZD9291, CO-1686, ASP8273, EGF816) or other anti-EGFR or EGFR monoclonal antibody therapy or dual TKI inhibitors.

• Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic):

  • De novo EGFR T790M mutation identified by central assessment
  • Previous treatment with any systemic antineoplastic therapy in the advanced setting (NSCLC stage IIIB or IV. Participants who received only one cycle of antineoplastic therapy in the advanced setting were allowed).

• Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1/3L antineoplastic):

  • More than 2 prior lines of systemic antineoplastic therapies in the advanced setting
  • Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. AZD9291, CO-1686, ASP8273, EGF816)
  • Previous treatment with an investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
  • Previous treatment with a c-MET inhibitor or HGF-targeting therapy.
  • Participants with symptomatic brain metastases.
• Phase II Group 5: Participants with symptomatic central nervous system (CNS) metastases who were neurologically unstable or had required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
• Presence or history of another malignancy. Exception: Participants who had been disease-free for 3 years, or participants with a history of adequately treated in-situ carcinoma of the uterine cervix, completely resected basal or squamous cell carcinoma, non-melanomatous cancer of skin, history of stage IA melanoma that had been cured, were eligible.

For Phase II Group 5: Presence or history of a malignant disease other than NSCLC that had been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.

• Undergone a bone marrow or solid organ transplant.
• Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory).

For Group 5: Participants with known history of testing positive for human immunodeficiency virus (HIV) infection, and with a history of Acquired ImmunoDeficiency Syndrome (AIDS) defining opportunistic infections in the last 12 months prior to the first dose of study treatment had to be excluded

• Participants receiving concomitant immunosuppressive agents or chronic corticosteroids used at the time of study entry except for control of brain metastases, topical applications, inhaled sprays, eye drops or local injections
• Participants with clinically significant, uncontrolled cardiovascular disease
• Presence or history of interstitial lung disease or interstitial pneumonitis
• Participants who had not recovered from all toxicities related to prior anticancer therapies to grade ≤1 (CTCAE v 4.03)
• Participants who had out of range laboratory values
• Participants who received live vaccines

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital Mass General

Boston, Massachusetts, United States, 02114

Australia, Victoria

Novartis Investigative Site

Melbourne, Victoria, Australia, 3000

Canada, Alberta

Novartis Investigative Site

Edmonton, Alberta, Canada, T6G 1Z2

France

Novartis Investigative Site

Marseille Cedex 05, France, 13885

Germany

Novartis Investigative Site

Heidelberg, Baden-Württemberg, Germany, 69126

Novartis Investigative Site

Koeln, Nordrhein-Westfalen, Germany, 50937

Italy

Novartis Investigative Site

Bologna, BO, Italy, 40138

Novartis Investigative Site

Modena, MO, Italy, 41124

Novartis Investigative Site

Perugia, PG, Italy, 06129

Korea, Republic of

Novartis Investigative Site

Seoul, Korea, Korea, Republic of, 05505

Norway

Novartis Investigative Site

Oslo, Norway, NO 0424

Singapore

Novartis Investigative Site

Singapore, Singapore, 119228

Novartis Investigative Site

Singapore, Singapore, 168583

Spain

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site

La Coruna, Galicia, Spain, 15006

Novartis Investigative Site

Las Palmas De Gran Canarias, Las Palmas De Gran Canaria, Spain, 35016

Novartis Investigative Site

Madrid, Spain, 28009

Novartis Investigative Site

Madrid, Spain, 28041

Taiwan

Novartis Investigative Site

Taipei, Taiwan ROC, Taiwan, 10041

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Study Protocol  [PDF] October 20, 2021

Statistical Analysis Plan  [PDF] June 9, 2022

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jia Y, Juarez J, Li J, Manuia M, Niederst MJ, Tompkins C, Timple N, Vaillancourt MT, Pferdekamper AC, Lockerman EL, Li C, Anderson J, Costa C, Liao D, Murphy E, DiDonato M, Bursulaya B, Lelais G, Barretina J, McNeill M, Epple R, Marsilje TH, Pathan N, Engelman JA, Michellys PY, McNamara P, Harris J, Bender S, Kasibhatla S. EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor. Cancer Res. 2016 Mar 15;76(6):1591-602. doi: 10.1158/0008-5472.CAN-15-2581. Epub 2016 Jan 29.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02335944
• Other Study ID Numbers: CINC280X2105C; 2014-000726-37 ( EudraCT Number )
• First Posted: January 12, 2015
• Results First Posted: June 18, 2023
• Last Update Posted: June 18, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

non small cell lung cancer; NSCLC; EGF816; INC280; tyrosine kinase inhibitor; c-MET

Additional relevant MeSH terms:

Nazartinib; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Antineoplastic Agents