Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The purpose of this study is to assess the efficacy of the amivantamab and lazertinib combination, compared with osimertinib, in participants with epidermal growth factor receptor (EGFR) mutation (Exon 19 deletions \[Exon 19del\] or Exon 21 L858R substitution) positive, locally advanced or metastatic non-small cell lung cancer (NSCLC).
Interventions
DRUGAmivantamab
Participants will receive amivantamab intravenously.
DRUGOsimertinib
Participants will receive osimertinib capsules orally.
DRUGLazertinib
Participants will receive lazertinib tablets orally.
DRUGPlacebo
Participants will receive matching placebo orally.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Only Arm B and C will be masked to all (Double-blind).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must have newly diagnosed histologically or cytologically confirmed, locally advanced or metastatic non-small cell lung cancer (NSCLC) that is treatment naive and not amenable to curative therapy including surgical resection or chemoradiation * The tumor harbors exon 19 deletions (Exon 19del) or Exon 21 L858R substitution, as detected by an food and drug administration (FDA)-approved or other validated test in a clinical laboratory improvement amendments (CLIA) certified laboratory (sites in the United states \[US\]) or an accredited local laboratory (sites outside of the US) in accordance with site standard of care * Mandatory submission of unstained tissue from tumor (in a quantity sufficient to allow for central analysis of EGFR mutation status and blood (for circulating tumor deoxyribonucleic acid \[ctDNA\], digital droplet polymerase chain reaction \[ddPCR\], and pharmacogenomic analysis) * Any toxicities from prior anticancer therapy must have resolved to common terminology criteria for adverse events (CTCAE) Grade 1 or baseline level * Participant must have at least 1 measurable lesion, according to response evaluation criteria in solid tumors (RECIST) v1.1 that has not been previously irradiated. Measurable lesions should not have been biopsied during screening, but if only 1 non-irradiated measurable lesion exists, it may undergo a diagnostic biopsy and be acceptable as a target lesion, provided the baseline tumor assessment scans are performed at least 14 days after the biopsy
Exclusion criteria
* Participant has received any prior systemic treatment at any time for locally advanced Stage III or metastatic Stage IV disease (adjuvant or neoadjuvant therapy for Stage I or II disease is allowed, if administered more than 12 months prior to the development of locally advanced or metastatic disease) * Participant has an active or past medical history of leptomeningeal disease * Participant with untreated spinal cord compression. A participant that has been definitively treated with surgery or radiation and has a stable neurological status for at least 2 weeks prior to randomization is eligible provided they are off corticosteroid treatment or receiving low-dose corticosteroid treatment less than or equal to (\<=) 10 milligrams per day (mg/day) prednisone or equivalent * Participant has an active or past medical history of interstitial lung disease (ILD)/pneumonitis, including drug-induced or radiation ILD/pneumonitis * Participant has known allergy, hypersensitivity, or intolerance to the excipients used in formulation of amivantamab, lazertinib, or osimertinib, or any contraindication to the use of osimertinib * Participant has symptomatic brain metastases. A participant with asymptomatic or previously treated and stable brain metastases may participate in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Blinded Independent Central Review (BICR) | From randomization to either disease progression or death whichever occurs first (up to 32.8 months) | PFS was defined as the time from randomization until the date of objective disease progression based on BICR using RECIST version 1.1 or death (by any cause) the absence of progression, whichever came first. Disease progression was defined using RECIST 1.1 as a 20 percent (%) increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 millimeters (mL). Participants who have not progressed or have not died at the time of analysis were censored at the time of the latest date of their last evaluable RECIST version 1.1 assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Approximately 60 months (time from the date of randomization until the date of death due to any cause) | Overall Survival is defined as the time from the date of randomization to the date of participant's death due to any cause. |
| Objective Response Rate (ORR) | Approximately 32.8 months | ORR is defined as the percentage of participants who achieve either a complete response (CR) or partial response (PR) as defined by BICR using RECIST v1.1 criteria. |
| Duration of Response (DOR) | Approximately 32.8 months | DOR is defined as the time from the date of first documented response (CR or PR) until the date of documented progression or death, whichever comes first, only for participants who achieve CR or PR as determined by the investigator using RECIST v1.1 criteria. |
| Time to Symptomatic Progression (TTSP) | Approximately 60 months | TTSP is defined as the time from randomization to documentation in the electronic case report form (eCRF) of any of the following (whichever occurs earlier): onset of new symptoms or symptom worsening that is considered by the investigator to be related to lung cancer and requires either a change in anticancer treatment and/or clinical intervention to manage symptoms. |
| Intracranial PFS | Approximately 60 months | Intracranial PFS is defined as the time from randomization until the date of objective intracranial disease progression or death, whichever comes first, based on BICR using RECIST v1.1. |
| Incidence and Severity of Adverse Events (AEs) | Approximately 60 months | Incidence and severity of treatment emergent adverse events (TEAEs) will be reported. Any adverse event occurring at or after the initial administration of study treatment through the day of last dose plus 30 days, or until the start of subsequent anticancer therapy (if earlier), is considered to be treatment emergent. |
| Number of Participants With Clinical Laboratory Abnormalities | Approximately 60 months | Number of participants with clinical laboratory abnormalities (serum chemistry, hematology, blood coagulation, and urine samples) will be reported. |
| Number of Participants With Vital Signs Abnormalities | Approximately 60 months | Number of participants with vital signs abnormalities (temperature, heart rate, respiratory rate, oxygen saturation, blood pressure) will be reported. |
| Number of Participants With Physical Examination Abnormalities | Approximately 60 months | Number of participants with physical examination abnormalities will be reported. |
| Serum Concentration of Amivantamab | Approximately 60 months | Serum samples will be analyzed to determine concentrations of Amivantamab. |
| Plasma Concentration of Lazertinib | Approximately 60 months | Plasma samples will be analyzed to determine concentrations of Lazertinib. |
| Number of Participants With Anti-Amivantamab Antibodies | Approximately 60 months | Number of participants with antibodies to amivantamab will be reported. |
| Change From Baseline in Non-Small Cell Lung Cancer - Symptom Assessment Questionnaire (NCSLC-SAQ) | Baseline up to approximately 60 months | The NSCLC-SAQ contains 7 items that assess cough, pain, dyspnea, fatigue, and poor appetite over a 7-day recall period. Each multi-item scale and individual item will be summarized using count and percent by visit. |
| Progression-Free Survival After First Subsequent Therapy (PFS2) | Approximately 60 months | The PFS2 is defined as the time from randomization until the date of second objective disease progression, after initiation of subsequent anticancer therapy, based on investigator assessment (after that used for PFS) or death, whichever comes first. |
| Change From Baseline in European Organization of Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) | Baseline up to approximately 60 months | EORTC-QLQ-C30 is a core 30-item questionnaire for evaluating the health-related quality of life (HRQoL) of participants participating in cancer clinical studies. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, France, Germany, Hungary, India, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Russia, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORJanssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Participant flow
Pre-assignment details
Currently, results posted till cut-off date 11-Aug-2023 (primary completion date). After analyzing primary analysis of progression free survival, participants were transitioned to an open-label extension (OLE) phase. Participants who continue to benefit from study treatment(s), as determined by investigator, may continue to receive access to study treatment(s) within study by transferring to long-term extension phase. OLE phase is still ongoing and results will be posted upon study completion.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Arm A (Open-label): Amivantamab + Lazertinib Participants received combination therapy of amivantamab 1050 milligrams (mg) for body weight (BW) less than (\<) 80 kilograms (kg) or 1400 mg for BW greater than or equal to (\>=) 80 kg intravenous (IV) infusion once weekly in 28-day treatment cycles: at Cycle 1 Days 1/2 (split dose, Day 1: 350 mg regardless of BW; Day 2: 700 mg or 1050 mg \[if BW \>=80 kg\]), 8, 15, and 22 and then once every 2 weeks (at Day 1 and 15) from Cycle 2 onwards; and lazertinib 240 mg (3 tablets of 80 mg) orally once daily. Participants continued treatment until disease progression, participant consent withdrawal, adverse event, investigator's decision, or initiation of new systemic anti-cancer treatment. | 429 |
| Active Comparator: Arm B (Double-blind): Osimertinib+Placebo Matching Lazertinib Participants received osimertinib 80 mg capsule orally once daily along with 3 tablets of matching placebo of lazertinib 240 mg tablets orally once daily from Cycle 1 Day 1 until disease progression, participant consent withdrawal, adverse event, investigator's decision, or initiation of new systemic anti-cancer treatment. | 429 |
| Experimental: Arm C (Double-blind): Lazertinib+Placebo Matching Osimertinib Participants received lazertinib 240 mg (3 tablets of 80 mg) orally once daily along with single capsule of matching placebo of osimertinib 80 mg orally once daily from Cycle 1 Day 1 until disease progression, participant consent withdrawal, adverse event, investigator's decision, or initiation of new systemic anti-cancer treatment. | 216 |
| Total | 1,074 |
Baseline characteristics
| Characteristic | Experimental: Arm A (Open-label): Amivantamab + Lazertinib | Active Comparator: Arm B (Double-blind): Osimertinib+Placebo Matching Lazertinib | Experimental: Arm C (Double-blind): Lazertinib+Placebo Matching Osimertinib | Total |
|---|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 10.63 | 61.9 years STANDARD_DEVIATION 11.52 | 61.3 years STANDARD_DEVIATION 10.69 | 62.1 years STANDARD_DEVIATION 11.01 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 56 Participants | 45 Participants | 24 Participants | 125 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 371 Participants | 382 Participants | 190 Participants | 943 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 7 Participants | 7 Participants | 4 Participants | 18 Participants |
| Race (NIH/OMB) Asian | 250 Participants | 251 Participants | 128 Participants | 629 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 3 Participants | 4 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 164 Participants | 165 Participants | 79 Participants | 408 Participants |
| Region of Enrollment ARGENTINA | 8 Participants | 11 Participants | 6 Participants | 25 Participants |
| Region of Enrollment AUSTRALIA | 5 Participants | 7 Participants | 1 Participants | 13 Participants |
| Region of Enrollment BELGIUM | 2 Participants | 4 Participants | 1 Participants | 7 Participants |
| Region of Enrollment BRAZIL | 38 Participants | 22 Participants | 9 Participants | 69 Participants |
| Region of Enrollment CANADA | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment CHINA | 81 Participants | 79 Participants | 43 Participants | 203 Participants |
| Region of Enrollment FRANCE | 12 Participants | 11 Participants | 6 Participants | 29 Participants |
| Region of Enrollment GERMANY | 2 Participants | 5 Participants | 2 Participants | 9 Participants |
| Region of Enrollment HUNGARY | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Region of Enrollment INDIA | 6 Participants | 16 Participants | 3 Participants | 25 Participants |
| Region of Enrollment ISRAEL | 3 Participants | 3 Participants | 2 Participants | 8 Participants |
| Region of Enrollment ITALY | 11 Participants | 8 Participants | 5 Participants | 24 Participants |
| Region of Enrollment JAPAN | 29 Participants | 32 Participants | 17 Participants | 78 Participants |
| Region of Enrollment MALAYSIA | 27 Participants | 23 Participants | 10 Participants | 60 Participants |
| Region of Enrollment MEXICO | 12 Participants | 14 Participants | 5 Participants | 31 Participants |
| Region of Enrollment NETHERLANDS | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Region of Enrollment POLAND | 7 Participants | 6 Participants | 0 Participants | 13 Participants |
| Region of Enrollment PORTUGAL | 4 Participants | 2 Participants | 2 Participants | 8 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 17 Participants | 15 Participants | 8 Participants | 40 Participants |
| Region of Enrollment SOUTH KOREA | 63 Participants | 68 Participants | 33 Participants | 164 Participants |
| Region of Enrollment SPAIN | 26 Participants | 33 Participants | 15 Participants | 74 Participants |
| Region of Enrollment TAIWAN | 24 Participants | 15 Participants | 13 Participants | 52 Participants |
| Region of Enrollment THAILAND | 15 Participants | 9 Participants | 5 Participants | 29 Participants |
| Region of Enrollment TURKEY | 15 Participants | 21 Participants | 4 Participants | 40 Participants |
| Region of Enrollment UKRAINE | 10 Participants | 11 Participants | 10 Participants | 31 Participants |
| Region of Enrollment UNITED KINGDOM | 2 Participants | 7 Participants | 2 Participants | 11 Participants |
| Region of Enrollment UNITED STATES | 7 Participants | 5 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male Female | 275 Participants | 251 Participants | 136 Participants | 662 Participants |
| Sex: Female, Male Male | 154 Participants | 178 Participants | 80 Participants | 412 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 96 / 421 | 116 / 428 | 56 / 213 |
| other Total, other adverse events | 419 / 421 | 409 / 428 | 210 / 213 |
| serious Total, serious adverse events | 205 / 421 | 143 / 428 | 75 / 213 |
Outcome results
Primary
Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Blinded Independent Central Review (BICR)
PFS was defined as the time from randomization until the date of objective disease progression based on BICR using RECIST version 1.1 or death (by any cause) the absence of progression, whichever came first. Disease progression was defined using RECIST 1.1 as a 20 percent (%) increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 millimeters (mL). Participants who have not progressed or have not died at the time of analysis were censored at the time of the latest date of their last evaluable RECIST version 1.1 assessment.
Time frame: From randomization to either disease progression or death whichever occurs first (up to 32.8 months)
Population: Full analysis set (FAS) included all randomized participants, classified according to their assigned treatment arm regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental: Arm A (Open-label): Amivantamab + Lazertinib | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Blinded Independent Central Review (BICR) | 23.72 Months |
| Active Comparator: Arm B (Double-blind): Osimertinib+Placebo Matching Lazertinib | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Blinded Independent Central Review (BICR) | 16.59 Months |
| Experimental: Arm C (Double-blind): Lazertinib+Placebo Matching Osimertinib | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Blinded Independent Central Review (BICR) | 18.46 Months |
p-value: 0.000295% CI: [0.58, 0.85]Log Rank
Secondary
Change From Baseline in European Organization of Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)
EORTC-QLQ-C30 is a core 30-item questionnaire for evaluating the health-related quality of life (HRQoL) of participants participating in cancer clinical studies.
Time frame: Baseline up to approximately 60 months
Secondary
Change From Baseline in Non-Small Cell Lung Cancer - Symptom Assessment Questionnaire (NCSLC-SAQ)
The NSCLC-SAQ contains 7 items that assess cough, pain, dyspnea, fatigue, and poor appetite over a 7-day recall period. Each multi-item scale and individual item will be summarized using count and percent by visit.
Time frame: Baseline up to approximately 60 months
Secondary
Duration of Response (DOR)
DOR is defined as the time from the date of first documented response (CR or PR) until the date of documented progression or death, whichever comes first, only for participants who achieve CR or PR as determined by the investigator using RECIST v1.1 criteria.
Time frame: Approximately 32.8 months
Secondary
Incidence and Severity of Adverse Events (AEs)
Incidence and severity of treatment emergent adverse events (TEAEs) will be reported. Any adverse event occurring at or after the initial administration of study treatment through the day of last dose plus 30 days, or until the start of subsequent anticancer therapy (if earlier), is considered to be treatment emergent.
Time frame: Approximately 60 months
Secondary
Intracranial PFS
Intracranial PFS is defined as the time from randomization until the date of objective intracranial disease progression or death, whichever comes first, based on BICR using RECIST v1.1.
Time frame: Approximately 60 months
Secondary
Number of Participants With Anti-Amivantamab Antibodies
Number of participants with antibodies to amivantamab will be reported.
Time frame: Approximately 60 months
Secondary
Number of Participants With Clinical Laboratory Abnormalities
Number of participants with clinical laboratory abnormalities (serum chemistry, hematology, blood coagulation, and urine samples) will be reported.
Time frame: Approximately 60 months
Secondary
Number of Participants With Physical Examination Abnormalities
Number of participants with physical examination abnormalities will be reported.
Time frame: Approximately 60 months
Secondary
Number of Participants With Vital Signs Abnormalities
Number of participants with vital signs abnormalities (temperature, heart rate, respiratory rate, oxygen saturation, blood pressure) will be reported.
Time frame: Approximately 60 months
Secondary
Objective Response Rate (ORR)
ORR is defined as the percentage of participants who achieve either a complete response (CR) or partial response (PR) as defined by BICR using RECIST v1.1 criteria.
Time frame: Approximately 32.8 months
Secondary
Overall Survival (OS)
Overall Survival is defined as the time from the date of randomization to the date of participant's death due to any cause.
Time frame: Approximately 60 months (time from the date of randomization until the date of death due to any cause)
Secondary
Plasma Concentration of Lazertinib
Plasma samples will be analyzed to determine concentrations of Lazertinib.
Time frame: Approximately 60 months
Secondary
Progression-Free Survival After First Subsequent Therapy (PFS2)
The PFS2 is defined as the time from randomization until the date of second objective disease progression, after initiation of subsequent anticancer therapy, based on investigator assessment (after that used for PFS) or death, whichever comes first.
Time frame: Approximately 60 months
Secondary
Serum Concentration of Amivantamab
Serum samples will be analyzed to determine concentrations of Amivantamab.
Time frame: Approximately 60 months
Secondary
Time to Symptomatic Progression (TTSP)
TTSP is defined as the time from randomization to documentation in the electronic case report form (eCRF) of any of the following (whichever occurs earlier): onset of new symptoms or symptom worsening that is considered by the investigator to be related to lung cancer and requires either a change in anticancer treatment and/or clinical intervention to manage symptoms.
Time frame: Approximately 60 months