Phase 3 Randomized Study of Amivantamab, Lazertinib, and Platinum-Based Chemotherapy in EGFR-Mutated Advanced NSCLC Post-Osimertinib Failure
- Trial ID
- 2023-506518-33-00
- Protocol
- 61186372NSC3002
- Sponsor
- Janssen Cilag International
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, open-label, randomized study is to assess the **efficacy** of a combination therapy consisting of **lazertinib**, **amivantamab**, **carboplatin**, and **pemetrexed** (LACP/ACP-L) compared to carboplatin and pemetrexed (CP) alone in patients with locally advanced or metastatic **Non-Small Cell Lung Cancer** (NSCLC) harboring **EGFR** Exon 19del or Exon 21 L858R substitution mutations. This evaluation is crucial as it aims to determine the potential benefits of the combination therapy in improving clinical outcomes for patients who have experienced failure with **osimertinib** treatment. The study also aims to compare the efficacy of ACP against CP in the same patient population, providing insights into alternative therapeutic strategies for this challenging clinical scenario.
Participants
The clinical trial involves a total of **517 participants** diagnosed with **locally advanced or metastatic non-small cell lung cancer** (NSCLC), specifically those with epidermal growth factor receptor (EGFR) Exon 19del or Exon 21 L858R mutations. The study population includes both male and female subjects, aged 18 years and older, who have progressed on or after osimertinib monotherapy. Participants were selected based on their confirmed diagnosis of non-squamous NSCLC and adequate organ and bone marrow function. The trial includes individuals with a history of brain metastases, provided all lesions have been treated and there is no current indication for further local therapy. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Lifestyle considerations include adherence to specified protocol restrictions, and participants must agree to use effective contraception methods during and after the study. The trial population is inclusive of vulnerable groups, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographics.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of a combination therapy involving **amivantamab**, **lazertinib**, **carboplatin**, and **pemetrexed** compared to a standard platinum-based chemotherapy regimen in patients with **locally advanced or metastatic non-small cell lung cancer** (NSCLC) characterized by specific **EGFR** mutations. The trial aims to assess progression-free survival as the primary endpoint, with the study duration estimated to conclude by June 2026. Participants will be involved in the study for a maximum treatment period of 53 to 84 weeks, depending on the specific treatment arm they are assigned to.
The trial will commence with a screening visit to confirm eligibility, which includes verifying the presence of EGFR mutations and ensuring adequate organ function. Following successful screening, participants will be randomized into one of the treatment arms. The study involves multiple follow-up visits to monitor the efficacy and safety of the treatment, with assessments conducted according to **RECIST v1.1** guidelines. These visits will include physical examinations, laboratory tests, and imaging studies to evaluate disease progression and treatment response. The end-of-study visit will occur after the completion of the treatment period or upon early termination due to disease progression or unacceptable toxicity.
Participants are expected to adhere to specific lifestyle restrictions and contraceptive measures throughout the study and for a defined period after the last dose of study treatment. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols. The trial is structured to ensure rigorous monitoring and data collection to achieve its primary and secondary objectives, contributing valuable insights into the treatment of EGFR-mutated NSCLC.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Pemetrexed Seacross** is provided as a 500 mg powder for concentrate for solution for infusion. It is administered intravenously with a maximum dose of 500 mg/m² per day. The treatment period for this medication is up to 53 weeks. The vials are labeled with a clinical label booklet, repackaged in the original commercial carton with another clinical label booklet, and released for use in the clinical trial.
**Lazertinib**, identified by the sponsor product code JNJ-73841937, is administered in tablet form. The route of administration is oral, and the treatment period is up to 53 weeks. The maximum daily and total dose amounts are not specified in the data provided.
**Carboplatin** is used in multiple formulations within the trial. One formulation is a solution for infusion, provided as CARBO-cell® 10 mg/ml, and another is a 10 mg/ml intravenous infusion. Both are administered intravenously with a maximum daily dose of 750 mg. The treatment period for carboplatin is up to 84 weeks. The vials are labeled with a clinical label booklet, repackaged in the original commercial carton with another clinical label booklet, and released for use in the clinical trial.
**Amivantamab**, identified by the sponsor product code JNJ-61186372, is provided as a solution for infusion. It is administered intravenously, and the treatment period is up to 53 weeks. The maximum daily and total dose amounts are not specified in the data provided.
**Pemetrexed Disodium** is another formulation used in the trial, provided as a PHF00200MIG pharmaceutical form. It is administered intravenously with a maximum dose of 500 mg/m² per day. The treatment period for this medication is up to 53 weeks.
Participant compliance with the dosing schedule is monitored throughout the trial. The trial aims to assess the efficacy of the combination of lazertinib, amivantamab, carboplatin, and pemetrexed compared to carboplatin and pemetrexed alone in patients with locally advanced or metastatic non-small cell lung cancer with specific EGFR mutations.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**, utilizing the RECIST v1.1 guidelines. This assessment will be conducted by a blinded independent central review (BICR) to ensure objectivity and accuracy. The trial aims to evaluate the efficacy of a combination therapy involving lazertinib, amivantamab, carboplatin, and pemetrexed (LACP/ACP-L) compared to carboplatin and pemetrexed (CP) in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) characterized by EGFR Exon 19del or Exon 21 L858R mutations.
Inclusion and Exclusion Criteria
Inclusion Criteria
- At least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place).
- 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.
- A participant must be either of the following: a. Not of childbearing potential; or b. Of childbearing potential and • practicing true abstinence during the entire period of the study, including up to 7 months after the last dose of study treatment is given; or • have a sole partner who is vasectomized; or • practicing at least 1 highly effective user independent method of contraception. Participant must agree to continue contraception throughout the study and through 6 months after the last dose of study treatment.
- A participant must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study treatment.
- Participant must have histologically or cytologically confirmed, locally advanced or metastatic, non-squamous NSCLC, characterized at or after the time of locally advanced metastatic disease diagnosis by either EGFR Exon 19del or Exon 21 L858R mutation, by an FDA-approved or other validated test of either ctDNA or tumor tissue in a CLIA certified laboratory (sites in the US) or an accredited local laboratory (sites outside of the US). A de-identified copy of the initial test report documenting the EGFR mutation must be included in the participant records and must be submitted to the sponsor during the Screening Phase. If provision of this report is not permitted by the site or local policies, then sponsor-approved equivalent documentation must be provided.
- 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 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 halflives) prior to randomization (ie, last dose no later than Day -8).
- Participant must have at least 1 measurable lesion, according to RECIST v1.1, that has not been previously irradiated. Measurable lesions should not have been biopsied during screening, but if only 1 nonirradiated measurable lesion exists, it may undergo the optional diagnostic biopsy and be acceptable as a target lesion, provided the baseline tumor assessment scans are performed at least 14 days after the biopsy.
- Participants with a history of brain metastases must have had all lesions treated as clinically indicated (ie, 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 than 10 mg rednisone or equivalent daily for the treatment of intracranial disease.
- Participant must have Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
- Participant must have adequate organ and bone marrow function as follows, without history of red blood cell transfusion, platelet transfusion, erythropoietin stimulating agents, or platelet-boosting treatments within 7 days prior to the date of the laboratory test: • Hemoglobin ≥10 g/dL • Absolute neutrophil count ≥1.5×10^9/L, without use of G-CSF within 10 days prior to the date of the test • Platelets ≥100×10^9/L • ALT and AST ≤3×upper limit of normal (ULN) • Total bilirubin ≤1.5×ULN if no liver metastasis, or ≤3×ULN in the presence of liver metastasis (participants with Gilbert's syndrome can enroll if conjugated bilirubin is within normal limits) • Creatinine clearance >50 mL/min as measured or calculated by Cockcroft-Gault formula
- 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).
- Participant must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
- A participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for 6 months after receiving the last dose of study treatment. A participant who is sexually active with a participant of childbearing potential must agree to use a condom and the partner must also be practicing a highly effective method of contraception. A participant who is vasectomized must still use a condom for prevention of passage of exposure through ejaculation, but the participant’s partner is not required to use contraception.
- A participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 6 months after receiving the last dose of study treatment. Participants should be advised to consider preservation of sperm prior to treatment with pemetrexed or carboplatin, as these agents may impair fertility.
- Participant must be willing and able to adhere to the lifestyle restrictions specified in this protocol.
Exclusion Criteria
- Participant has an uncontrolled illness, including but not limited to: • Uncontrolled diabetes • Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics at least 1 week prior to starting study treatment] or diagnosed or suspected viral infection), except as allowed by Exclusion Criterion 17 for HIV • Active bleeding diathesis • Impaired oxygenation requiring continuous oxygen supplementation • Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of study treatment • Psychiatric illness or any other circumstances (including social circumstances) that would limit compliance with study requirements • Any ophthalmologic condition that is clinically unstable
- Participant received prior systemic anticancer therapy in the locally advanced or metastatic setting, or in the adjuvant setting, for the same nonsquamous NSCLC intended for treatment now, except as allowed by Inclusion Criterion 3.
- Participant received radiotherapy for palliative treatment of NSCLC less than 14 days prior to randomization.
- Participants with symptomatic or progressive brain metastases.
- Participant previously enrolled in the Sponsor's study 73841937NSC3003 (NCT04487080).
- 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 uncontrolled tumor-related pain. Symptomatic lesions amenable to palliative radiotherapy (eg, bone metastases, or metastases causing nerve impingement) should be treated at least 14 days prior to randomization.
- Participant has a medical history of ILD, including drug induced ILD or radiation pneumonitis.
- Participant has a history of hypersensitivity to carboplatin or pemetrexed, or to any excipient of carboplatin, pemetrexed, amivantamab, or lazertinib.
- Participant has an active malignancy (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. Exceptions include participants who have undergone curative therapy and have no evidence of disease recurrence since completion of that therapy, and those with local cancers that have been apparently cured such as: a. Non-muscle invasive bladder cancer (NMIBC) treated within the last 24 months that is considered completely cured. b. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured. c. Non-invasive cervical cancer treated within the last 24 months that is considered completely cured. d. Localized prostate cancer (N0M0): • with a Gleason score of 6, treated within the last 24 months or untreated and under surveillance, • with a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence, • or history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence. e. Breast cancer: • lobular carcinoma in situ or ductal carcinoma in situ that is considered completely cured, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence. f. Other malignancy that is considered cured with minimal risk of recurrence.
- Participant has any contraindication to treatment with pemetrexed or carboplatin or participant has a history of hypersensitivity to, or cannot take, vitamin B12 or folic acid.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Nov 2021 | 21 |
 Bulgaria | Not Recruiting | 01 Nov 2021 | 3 |
 Czechia | Not Recruiting | 01 Nov 2021 | 3 |
 Denmark | Not Recruiting | 01 Nov 2021 | 1 |
 France | Not Recruiting | 01 Nov 2021 | 48 |
 Germany | Not Recruiting | 01 Nov 2021 | 10 |
 Italy | Not Recruiting | 01 Nov 2021 | 58 |
 The Netherlands | Not Recruiting | 01 Nov 2021 | — |
 Poland | Not Recruiting | 01 Nov 2021 | 21 |
 Portugal | Not Recruiting | 01 Nov 2021 | 7 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Carboplatin 10 mg/ml Intravenous Infusion | Other | INTRAVENOUS INFUSION | INTRAVENOUS USE | 750 | 84 | PRD1161259 |
PEMETREXED | Other | PHF00200MIG | INTRAVENOUS USE | 500 | 53 | SCP11423984 |
CARBOPLATIN | Other | PHF00230MIG | INTRAVENOUS USE | 750 | 84 | SCP10337134 |
JNJ-73841937 | Test | TABLET | ORAL USE | 0 | 53 | PRD10153788 |
JNJ-61186372 | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 0 | 53 | PRD9813175 |
Pemetrexed Seacross 500 mg powder for concentrate for solution for infusion | Other | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 500 | 53 | PRD8605124 |
CARBO-cell® 10 mg/ml Infusionslösung, Konzentrat zur Herstellung einer Infusionslösung Carboplatin | Other | INFUSIONSLÖSUNG, KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 750 | 84 | PRD1972920 |