Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
The purpose of this study is to assess the efficacy of adding lazertinib to amivantamab, carboplatin, and pemetrexed (LACP/ACP-L dosing strategies) and amivantamab, carboplatin and pemetrexed (ACP) compared with carboplatin and pemetrexed (CP) in participants with locally advanced or metastatic epidermal growth factor receptor (EGFR) Exon 19del or Exon 21 L858R substitution non-small cell lung cancer (NSCLC) after osimertinib failure. The purpose of the extension cohort is to further describe the safety and efficacy for the ACP-L dosing schedule versus ACP with additional data. After completion of the primary analysis, the study may eventually transition to an open-label extension (OLE) or long-term extension (LTE) phase during which participants will have the option to continue their assigned treatment.
Interventions
DRUGLazertinib
Lazertinib will be administered orally.
DRUGAmivantamab
Amivantamab will be administered as an IV infusion.
DRUGPemetrexed
Pemetrexed will be administered as an IV infusion.
DRUGCarboplatin
Carboplatin will be administered as an IV infusion.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must have at least 1 measurable lesion, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, that has not been previously irradiated * Participant must have histologically or cytologically confirmed, locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC), characterized at or after the time of locally advanced or metastatic disease diagnosis by either epidermal growth factor receptor (EGFR) Exon 19del or Exon 21 L858R mutation * A participant with a history of brain metastases must have had all lesions treated as clinically indicated (that is, no current indication for further definitive local therapy). Any definitive local therapy to brain metastases must have been completed at least 14 days prior to randomization and the participant can be receiving no greater than10 milligrams (mg) prednisone or equivalent daily for the treatment of intracranial disease * Participant must have Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 * Any toxicities from prior systemic anticancer therapy must have resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Grade 1 or baseline level (except for alopecia \[any grade\], Grade \<= 2 peripheral neuropathy, or Grade \<= 2 hypothyroidism stable on hormone replacement) * A participant of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study * Participant must have progressed on or after osimertinib monotherapy as the most recent line of treatment. Osimertinib must have been administered as either the first-line treatment for locally advanced or metastatic disease or in the second- line setting after prior treatment with first- or second-generation EGFR tyrosine kinase inhibitor (TKI) as a monotherapy. Participants who received either neoadjuvant and/or adjuvant treatment of any type are eligible if progression to locally advanced or metastatic disease occurred at least 12 months after the last dose of such therapy and then the participant progressed on or after osimertinib in the locally advanced or metastatic setting. Treatment with osimertinib must be discontinued at least 8 days (4 half-lives) prior to randomization (that is last dose no later than Day -8)
Exclusion criteria
* Participant received radiotherapy for palliative treatment of NSCLC less than 14 days prior to randomization * Participant with symptomatic or progressive brain metastases * Participant has history of or current evidence of leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation * Participant has known small cell transformation * Participant has a medical history of interstitial lung disease (ILD), including drug-induced ILD or radiation pneumonitis * Participant has a history of clinically significant cardiovascular disease including, but not limited to diagnosis of deep vein thrombosis or pulmonary embolism within 4 weeks prior to randomization; myocardial infarction; unstable angina; stroke; transient ischemic attack; coronary/peripheral artery bypass graft; or acute coronary syndrome. Participant has a significant genetic predisposition to venous thromboembolic events. Participant has a prior history of venous thromboembolic events and is not on appropriate therapeutic anticoagulation as per National Comprehensive Cancer Network or local guidelines
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Main Study: 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 occurred first (up to 1 year 7 months) | PFS is defined as the time from randomization until the date of objective disease progression or death, whichever came first, as assessed by BICR according to RECIST version 1.1. Progressed disease: Sum of diameters increased by greater than or equal to (\>=)20 percent (%) and \>=5 millimeter (mm) from nadir (including baseline if it was smallest sum). |
| Main Study + Extension Cohort: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | up to 4 years 10 months | Follow-up for the extension cohort is still ongoing and thus results from the analysis that includes the extension cohort will be reported up on study completion. |
| Main Study + Extension Cohort: Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review | Up to 4 years 10 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Main Study+ Extension Cohort: Objective Response Rate as Assessed by Blinded Independent Central Review | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Overall Survival | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Duration of Response as Assessed by Blinded Independent Central Review | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Time to Subsequent Therapy | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Progression-free Survival (PFS) After First Subsequent Therapy (PFS2) | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Time to Symptomatic Progression | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Intracranial Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review | Up to 4 years 10 months |
| Main Study: Number of Participants With Adverse Events (AEs) | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Number of Participants With Adverse Events (AEs) by Severity | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Number of Participants With Clinical Laboratory Abnormalities | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Serum Concentration of Amivantamab | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Plasma Concentration of Lazertinib | Up to 4 years 10 months |
| Main Study + Extension Cohort: Number of Participants With Serum Anti-amivantamab Antibodies | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Change From Baseline With Non-Small Cell Lung Cancer - Symptom Assessment Questionnaire (NSCLC-SAQ) | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Change From Baseline With European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) | Up to 4 years 10 months |
| Main Study+ Extension Cohort: Change From Baseline With Patient-Reported Outcomes Measurement Information System -Physical Function (PROMIS-PF) | Up to 4 years 10 months |
Countries
Argentina, Belgium, Brazil, Bulgaria, Canada, China, Czechia, Denmark, France, Germany, Hong Kong, India, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Russia, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORJanssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Participant flow
Recruitment details
A total of 657 participants were enrolled in the main study. During the study, a separate open-label randomized extension cohort was added. A total of 119 participants were enrolled into the extension cohort. Main study results are alone reported for primary completion date (PCD; 10-July-2023).
Pre-assignment details
At the time of PCD, extension cohort enrollment was still ongoing. As per protocol, extension cohort analysis was not included as part of main study primary analysis. Currently no information other than total count of participants for extension cohort is available and for reporting purpose extension cohort arms (A2 and C2) have been combined in the table. Results of extension cohort will be reported later, upon completion of analysis, at which point arms A2 and C2 details will be reported.
Participants by arm
| Arm | Count |
|---|---|
| Main Study: Arm A: Lazertinib + Amivantamab + Carboplatin + Pemetrexed (LACP/ACP-L) LACP dosing (study start until 6 November 2022): Participants received Lazertinib 240 milligrams (mg) orally on Day 1 of each subsequent cycle, starting with Cycle 3, along with Amivantamab 1400 mg (1750 mg if body weight greater than or equal to \[\>=80\] kilograms \[kg\]) on Cycle 1 Days 1, 2, 8, and 15, and Cycle 2 Day 1 and 1750 mg (2100 mg if body weight \>=80 kg). Participant also received Pemetrexed 500 mg per square meter (mg/m\^2) on Day 1 21-day cycle, in combination with carboplatin 750 mg as IV infusion starting on Cycle 1 Day 1 for 4 cycles. From cycle 5 onwards, participants received Amivantamab, Pemetrexed and Lazertinib IV infusions at same dose, as maintenance until disease progression. ACP-L dosing (from 7 November 2022 until study completion): Participants received Amivantamab 1400 mg (1750 mg if body weight \>=80\] kg) on Cycle 1 Days 1,2, 8, and 15, and Cycle 2 Day 1 and 1750 mg (2100 mg if body weight \>=80 kg). Participant also received Pemetrexed 500 mg/m\^2 on Day 1 of each 21-day cycle, in combination with carboplatin 750 mg as IV infusion starting on Cycle 1 Day 1 for 4 cycles. Lazertinib 240 mg in ACP-L started on Cycle 5 Day 1 or sooner if carboplatin is discontinued before cycle 4. From cycle 5 onwards, participants received Amivantamab, Pemetrexed and Lazertinib IV infusions at same dose, as maintenance until disease progression. Each cycle consists of 21 days. | 263 |
| Main Study: Arm B: Carboplatin + Pemetrexed (CP) Participants received Pemetrexed 500 mg/m\^2 IV infusion and carboplatin 750 mg IV infusion from Day 1 of Cycle 1 to 4. From cycle 5 onwards, participants received Pemetrexed 500 mg/m\^2 IV infusion, as maintenance until disease progression. Each cycle consists of 21 days. | 263 |
| Main Study: Arm C: Amivantamab + Carboplatin + Pemetrexed (ACP) Participants received Amivantamab 1400 mg (1750 mg if body weight \>=80 kg) on Cycle 1 Days 1,2, 8, and 15, and Cycle 2 Day 1 and 1750 mg (2100 mg if body weight \>=80 kg) on Day 1 of each cycle, starting with Cycle 3. Participants also received Pemetrexed 500 mg/m\^2 on Day 1 of each 21-day cycle, in combination with carboplatin 750 mg as IV infusion starting on Cycle 1 Day 1 for 4 cycles. From cycle 5 onwards, participants received Amivantamab and Pemetrexed IV infusions at same dose, as maintenance until disease progression. Each cycle consists of 21 days. | 131 |
| Extension Cohort: All Participants (Arm A2 [ACP-L] + C2 [ACP]) In Arm A2, participants received amivantamab 1400 mg (1750 mg if body weight\>=80 kg) IV infusion once weekly from Cycle 1 Days 1/2, 8, and 15, and Cycle 2 Day 1, and then 1750 mg (2100 mg if body weight \>=80 kg) on Day 1 of each 21-day cycle, starting at cycle 3. Participants also received chemotherapy: pemetrexed 500 mg/m\^2 IV infusion on Day 1 of each 21-day cycle, in combination with carboplatin area under concentration-time curve of 5 mg/mL per minute (AUC 5) IV infusion administered on Day 1 for up to 4 cycles. Lazertinib was administered 240 mg orally, once daily starting Cycle 5 Day 1 or sooner if carboplatin was discontinued earlier. Amivantamab, pemetrexed and lazertinib were to be continued until disease progression (DP), participant withdrawal, adverse event (AE), investigator's decision or initiation of new systemic anti-cancer treatment. In Arm C2, participants received amivantamab 1400 mg (1750 mg if body weight \>=80 kg) IV infusion once weekly from Cycle 1 Days 1/2, 8, and 15, and Cycle 2 Day 1, then 1750 mg (2100 mg if body weight is \>=80 kg) on Day 1 of each 21-day cycle, starting with Cycle 3. Participants also received chemotherapy: pemetrexed 500 mg/m\^2 IV infusion on Day 1 of each 21-day cycle, in combination with carboplatin AUC 5 IV infusion was administered on Day 1, for up to 4 cycles. Amivantamab and pemetrexed were to be continued until DP, participant withdrawal, AE, investigator's decision or initiation of new systemic anti-cancer treatment. | 0 |
| Total | 657 |
Baseline characteristics
| Characteristic | Main Study: Arm A: Lazertinib + Amivantamab + Carboplatin + Pemetrexed (LACP/ACP-L) | Main Study: Arm B: Carboplatin + Pemetrexed (CP) | Main Study: Arm C: Amivantamab + Carboplatin + Pemetrexed (ACP) | Total |
|---|---|---|---|---|
| Age, Continuous | 60.3 years STANDARD_DEVIATION 10.96 | 60.6 years STANDARD_DEVIATION 10.13 | 61.2 years STANDARD_DEVIATION 10.06 | 60.6 years STANDARD_DEVIATION 10.44 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants | 23 Participants | 9 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 234 Participants | 234 Participants | 118 Participants | 586 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 6 Participants | 4 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 125 Participants | 127 Participants | 63 Participants | 315 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 7 Participants | 4 Participants | 16 Participants |
| Race (NIH/OMB) White | 129 Participants | 123 Participants | 60 Participants | 312 Participants |
| Region of Enrollment ARGENTINA | 5 Participants | 6 Participants | 0 Participants | 11 Participants |
| Region of Enrollment BELGIUM | 10 Participants | 3 Participants | 3 Participants | 16 Participants |
| Region of Enrollment BRAZIL | 10 Participants | 13 Participants | 6 Participants | 29 Participants |
| Region of Enrollment BULGARIA | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment CANADA | 7 Participants | 11 Participants | 4 Participants | 22 Participants |
| Region of Enrollment CHINA | 45 Participants | 40 Participants | 15 Participants | 100 Participants |
| Region of Enrollment CZECH REPUBLIC | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Region of Enrollment FRANCE | 14 Participants | 18 Participants | 7 Participants | 39 Participants |
| Region of Enrollment GERMANY | 3 Participants | 4 Participants | 0 Participants | 7 Participants |
| Region of Enrollment HONG KONG | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment INDIA | 14 Participants | 8 Participants | 4 Participants | 26 Participants |
| Region of Enrollment ISRAEL | 6 Participants | 4 Participants | 3 Participants | 13 Participants |
| Region of Enrollment ITALY | 20 Participants | 19 Participants | 11 Participants | 50 Participants |
| Region of Enrollment JAPAN | 17 Participants | 24 Participants | 9 Participants | 50 Participants |
| Region of Enrollment MALAYSIA | 4 Participants | 5 Participants | 8 Participants | 17 Participants |
| Region of Enrollment MEXICO | 5 Participants | 4 Participants | 2 Participants | 11 Participants |
| Region of Enrollment NETHERLANDS | 1 Participants | 4 Participants | 2 Participants | 7 Participants |
| Region of Enrollment POLAND | 1 Participants | 9 Participants | 4 Participants | 14 Participants |
| Region of Enrollment PORTUGAL | 4 Participants | 2 Participants | 1 Participants | 7 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment SOUTH KOREA | 25 Participants | 21 Participants | 17 Participants | 63 Participants |
| Region of Enrollment SPAIN | 30 Participants | 24 Participants | 13 Participants | 67 Participants |
| Region of Enrollment SWEDEN | 3 Participants | 1 Participants | 0 Participants | 4 Participants |
| Region of Enrollment TAIWAN | 10 Participants | 17 Participants | 7 Participants | 34 Participants |
| Region of Enrollment TURKEY | 10 Participants | 5 Participants | 4 Participants | 19 Participants |
| Region of Enrollment UNITED KINGDOM | 8 Participants | 10 Participants | 2 Participants | 20 Participants |
| Region of Enrollment UNITED STATES | 9 Participants | 7 Participants | 7 Participants | 23 Participants |
| Sex: Female, Male Female | 168 Participants | 157 Participants | 81 Participants | 406 Participants |
| Sex: Female, Male Male | 95 Participants | 106 Participants | 50 Participants | 251 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 69 / 263 | 65 / 263 | 27 / 131 |
| other Total, other adverse events | 261 / 263 | 222 / 243 | 129 / 130 |
| serious Total, serious adverse events | 137 / 263 | 49 / 243 | 42 / 130 |
Outcome results
Primary
Main Study + Extension Cohort: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Follow-up for the extension cohort is still ongoing and thus results from the analysis that includes the extension cohort will be reported up on study completion.
Time frame: up to 4 years 10 months
Primary
Main Study + Extension Cohort: Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review
Time frame: Up to 4 years 10 months
Primary
Main Study: 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 is defined as the time from randomization until the date of objective disease progression or death, whichever came first, as assessed by BICR according to RECIST version 1.1. Progressed disease: Sum of diameters increased by greater than or equal to (\>=)20 percent (%) and \>=5 millimeter (mm) from nadir (including baseline if it was smallest sum).
Time frame: From randomization to either disease progression or death, whichever occurred first (up to 1 year 7 months)
Population: Full analysis set (FAS) as defined in the protocol included all randomized participants, classified according to their assigned treatment arm regardless of the actual treatment received. The outcomes reported here are for main study participants. For Arm A participants, data were planned to be analyzed as a single arm collectively for the LACP and ACP-L dosing regimens.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Main Study: Arm A: Lazertinib + Amivantamab + Carboplatin + Pemetrexed (LACP/ACP-L) | Main Study: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Blinded Independent Central Review (BICR) | 8.31 months |
| Main Study: Arm B: Carboplatin + Pemetrexed (CP) | Main Study: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Blinded Independent Central Review (BICR) | 4.17 months |
| Main Study: Arm C: Amivantamab + Carboplatin + Pemetrexed (ACP) | Main Study: Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Blinded Independent Central Review (BICR) | 6.28 months |
p-value: <0.000195% CI: [0.35, 0.56]Log Rank
p-value: <0.000195% CI: [0.36, 0.64]Log Rank
Secondary
Main Study+ Extension Cohort: Change From Baseline With European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Change From Baseline With Non-Small Cell Lung Cancer - Symptom Assessment Questionnaire (NSCLC-SAQ)
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Change From Baseline With Patient-Reported Outcomes Measurement Information System -Physical Function (PROMIS-PF)
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Duration of Response as Assessed by Blinded Independent Central Review
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Intracranial Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Number of Participants With Adverse Events (AEs) by Severity
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Number of Participants With Clinical Laboratory Abnormalities
Time frame: Up to 4 years 10 months
Secondary
Main Study + Extension Cohort: Number of Participants With Serum Anti-amivantamab Antibodies
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Objective Response Rate as Assessed by Blinded Independent Central Review
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Overall Survival
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Plasma Concentration of Lazertinib
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Progression-free Survival (PFS) After First Subsequent Therapy (PFS2)
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Serum Concentration of Amivantamab
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Time to Subsequent Therapy
Time frame: Up to 4 years 10 months
Secondary
Main Study+ Extension Cohort: Time to Symptomatic Progression
Time frame: Up to 4 years 10 months
Secondary
Main Study: Number of Participants With Adverse Events (AEs)
Time frame: Up to 4 years 10 months