Amivantamab, Lazertinib, and Pemetrexed for First-line Treatment of Recurrent/Metastatic Non-small Cell Lung Cancers With Epidermal Growth Factor Receptor Mutations

NCT ID: NCT05299125

Last Updated: 2025-10-01

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 54 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-05-24
• Study Completion Date: 2027-07-31

Brief Summary

This is a phase II, single-arm, multicenter trial, conducted through Latin American Coorperative Oncology Group (LACOG). Treatment-naïve patients with recurrent/metastatic NSCLCs harboring EGFR exon 19 deletions or exon 21 L858R point mutations will be enrolled. At baseline, an archival or (optional) new tissue sample will be obtained for biomarker evaluation, as well as liquid biopsies. Treatment will continue until disease progression or unacceptable toxicity.

Detailed Description

This study aims to test the hypothesis that delivery of maximum therapy consisting of lazertinib plus amivantamab plus chemotherapy as frontline treatment in patients with recurrent/metastatic NSCLC with EGFR exon 19 or exon 21 mutations will be feasible, safe, and will improve PFS compared to historical controls. If successful, this study may allow for the estimation of efficacy and toxicity of a three drug regimen of amivantamab, lazertinib, and pemetrexed and may support further evaluation of maximum therapy against osimertinib single agent, lazertinib single agent, osimertinib plus chemotherapy, and/or lazertinib plus amivantamab.

Conditions

Metastatic Non-small Cell Lung Cancers

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Single Arm: Therapy consisting of lazertinib plus amivantamab plus chemotherapy

CYCLE 1 (21-day cycle) Amivantamab 1400 mg (1750 mg if body weight is >80 kg) IV once weekly + Lazertinib 240 mg po daily + Pemetrexed 500 mg/m² IV on day 1

CYCLE 2 (21-day cycle) Amivantamab 1400 mg (1750 mg if body weight is >80 kg) IV on day 1 + Lazertinib 240 mg po daily + Pemetrexed 500 mg/m² IV on day 1

MAINTENANCE CYCLES 3 - 8 (21-day cycle) Amivantamab 1750 mg (2100 mg if body weight is >80 kg) IV on day 1 + Lazertinib 240 mg po daily + Pemetrexed 500 mg/m² IV on day 1

MAINTENANCE CYCLES 9 + (21-day cycle) Amivantamab 1750 mg (2100 mg if body weight is >80 kg) IV on day 1 + Lazertinib 240 mg po daily

Group Type: EXPERIMENTAL

Amivantamab

Intervention Type: DRUG

Low fucose, fully human immunoglobulin gamma-1-based bispecific antibody directed against EGFR and MET tyrosine kinase receptors. It shows clinical activity against tumors with the primary activating EGFR mutations Exon 19del or Exon 21 L858R substitution, EGFR Exon 20ins mutations, the EGFR resistance mutations Threonine790Methionine (T790M) or Cysteine797Serine (C797S), and activation of the Mesenchymal Epithelial Transition (MET) pathway.

Lazertinib

Intervention Type: DRUG

It selectively inhibits both primary activating EGFR mutations (Exon 19del, Exon 21 L858R substitution) and the EGFR T790M resistance mutation, while having less activity versus wild-type EGFR.

Pemetrexed 500 mg

Intervention Type: DRUG

Inhibits enzymes involved in folate-dependent metabolism, thereby disrupting cellular replication.

Interventions

Amivantamab

Low fucose, fully human immunoglobulin gamma-1-based bispecific antibody directed against EGFR and MET tyrosine kinase receptors. It shows clinical activity against tumors with the primary activating EGFR mutations Exon 19del or Exon 21 L858R substitution, EGFR Exon 20ins mutations, the EGFR resistance mutations Threonine790Methionine (T790M) or Cysteine797Serine (C797S), and activation of the Mesenchymal Epithelial Transition (MET) pathway.

Intervention Type: DRUG

Lazertinib

It selectively inhibits both primary activating EGFR mutations (Exon 19del, Exon 21 L858R substitution) and the EGFR T790M resistance mutation, while having less activity versus wild-type EGFR.

Intervention Type: DRUG

Pemetrexed 500 mg

Inhibits enzymes involved in folate-dependent metabolism, thereby disrupting cellular replication.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Participant must be ≥18 years of age;

2. Participant must have histologically or cytologically confirmed locally advanced or metastatic NSCLC not amenable to curative therapy. Participants must be treatment-naïve for metastatic NSCLC. Prior adjuvant and neo-adjuvant therapy for early-stage disease is permitted, prior systemic therapy for potentially curable locally advanced disease is also permitted;

3. Participant must have a tumor that was previously determined to have Exon 19del or Exon 21 L858R substitution, as detected by a validated test in accordance with site standard of care. Note: A copy of the test report documenting the EGFR mutation must be included in the participant records and must also be submitted to the sponsor prior to enrollment;

4. Unstained tumor tissue and blood (for ctDNA, biomarker), both collected prior to treatment initiation, must be provided. Unstained FFPE tumor tissue blocks must be provided whenever possible. Alternatively, re-cut unstained sections from FFPE tumor tissue block, presented on slides must be provided (recommended 10-15 slides);

5. Subject must have specific organ and bone marrow function;

6. Participant must have ECOG status of 0 to 2;

7. Any toxicities from prior anticancer therapy must have resolved to CTCAE Grade 1 or baseline level;

8. Participant must have at least 1 measurable lesion, according to RECIST v1.1 that has not been previously irradiated. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

Exclusion Criteria

1. Participant has received any prior systemic treatment for metastatic disease (prior systemic therapy for potentially curable locally advanced disease, adjuvant or neoadjuvant therapy are allowed, if administered more than 12 months prior to the development of the recurrent disease);

2. Participant has symptomatic brain metastases. A participant with asymptomatic or previously treated and stable brain metastases may participate in this study. Participants who have received definitive radiation or surgical treatment for symptomatic or unstable brain metastases and have been clinically stable and asymptomatic for at least 2 weeks before Screening are eligible, provided they have been either off corticosteroid treatment or are receiving low-dose corticosteroid treatment (≤10 mg/day prednisone or equivalent) for at least 2 weeks prior to enrollment;

3. Participant has severe co-morbidities that in the opinion of the investigator pose the patient at undue risk from participating in the study;

4. Participant has an active or past medical history of leptomeningeal disease;

5. Participant has spinal cord compression that has not been definitively treated with surgery or radiation or requires steroid treatment within 2 weeks prior to enrollment. Low-dose corticosteroid treatment ≤10mg/day prednisone or equivalent is allowed;

6. Participant has an active or past medical history of Interstitial lung disease (ILD)/pneumonitis, including drug-induced or radiation ILD/pneumonitis;

7. Immune-mediated rash from checkpoint inhibitors that has not resolved prior to enrollment;

8. Subject has uncontrolled inter-current illness;

9. Participant has active cardiovascular disease;

10. Participant is currently receiving medications or herbal supplements known to be potent CYP3A4/5 inhibitors or inducers and is unable to stop use for an appropriate washout period prior to enrollment (see Appendix 8: Prohibited and Restricted Medications and Therapies That Induce, Inhibit, or Are Substrates of CYP3A4/5);

11. Participant has received any prior treatment with an EGFR TKI;

12. Known positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg);

13. Known positive hepatitis C antibody (anti-HCV). Note: Subjects with a prior history of HCV, who have completed antiviral treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible;

14. Other clinically active or chronic liver disease;

15. Known active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), Patients positive for human immunodeficiency virus (HIV) can be eligible if receiving highly active antiretroviral therapy (ART) and CD4 count >350 within 6 months of the start of treatment (consultation of Medical Monitor is required in this case). Screening for tuberculosis, hepatitis B, hepatitis C, and/or HIV infections is not required, unless there is clinical suspicion of these infections;

16. Participant had major surgery (e.g., requiring general anesthesia), excluding placement of vascular access or tumor biopsy, or had significant traumatic injury within 2 weeks before signing the ICF, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen, LP

INDUSTRY

Sponsor Role: collaborator

Latin American Cooperative Oncology Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

William Nassib William Junior

Role: PRINCIPAL_INVESTIGATOR

Latin American Cooperative Oncology Group

Locations

Pronutrir - Oncologia e Nutrição

Fortaleza, Ceará, Brazil

Hospital Evangélico de Cachoeiro de Itapemirim

Cachoeiro de Itapemirim, Espírito Santo, Brazil

Hospital Erasto Gaertner

Curitiba, Paraná, Brazil

Liga Norte Riograndense Contra o Câncer

Natal, Rio Grande do Norte, Brazil

Irmandade da Santa Casa de Misericórdia de Porto Alegre

Porto Alegre, Rio Grande do Sul, Brazil

Centro de Pesquisa em Oncologia do Hospital São Lucas da PUCRS

Porto Alegre, Rio Grande do Sul, Brazil

Hospital de Amor de Barretos

Barretos, São Paulo, Brazil

Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP

Ribeirão Preto, São Paulo, Brazil

Hospital de Base de São José do Rio Preto

São José do Rio Preto, São Paulo, Brazil

INCA - Instituto Nacional de Câncer

Rio de Janeiro, , Brazil

Centro de Tratamento de Tumores Botafogo (Oncoclínicas)

Rio de Janeiro, , Brazil

ICESP - Instituto do Câncer do Estado de São Paulo

São Paulo, , Brazil

BP - A Beneficência Portuguesa de São Paulo

São Paulo, , Brazil

São Camilo Oncologia

São Paulo, , Brazil

Countries

Brazil

Other Identifiers

73841937LUC2002

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

LACOG 0821

Identifier Type: -

Identifier Source: org_study_id