Lazertinib + Amivantamab for Non-Small Cell Lung Cancer

(Chrysalis-2 Trial)

Not currently recruiting at 122 trial locations

Overseen By Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Janssen Research & Development, LLC

Must be taking: Direct oral anticoagulant

Must not be taking: PD-1, PD-L1 antibodies

Disqualifiers: Uncontrolled illness, Untreated CNS metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 7

Duration: Up to 2.5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of combining Lazertinib and Amivantamab (Rybrevant) for individuals with advanced non-small cell lung cancer (NSCLC) that has a specific mutation. Researchers aim to determine if this combination can shrink tumors and improve outcomes for patients who have previously tried other therapies. It is suitable for those with NSCLC with EGFR mutations who have experienced progression after treatments like osimertinib or chemotherapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you should discuss your current medications with the study team to ensure they don't interfere with the trial treatments.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining Lazertinib and Amivantamab is generally safe. Patients who received this combination usually tolerated it well, with manageable side effects. One study found that this combination was more effective than Lazertinib alone for certain lung cancers, and adding Amivantamab did not significantly increase serious side effects.

The FDA has already approved Amivantamab for some lung cancers, supporting its safety. Common side effects include skin reactions and infusion-related reactions, which are usually mild and manageable.

Earlier studies have also shown Lazertinib alone to be safe. The most common side effects were mild, such as rash and changes in liver enzyme levels, and could be managed with supportive care.

Overall, both treatments appear well-tolerated according to available data. Participating in clinical trials can further clarify their safety when used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for non-small cell lung cancer (NSCLC) because they offer a fresh approach compared to standard therapies like chemotherapy and first- or second-generation EGFR inhibitors. Amivantamab and Lazertinib, used individually or in combination, target specific mutations in the EGFR gene, which are often responsible for cancer growth. This targeted mechanism of action is different from traditional treatments, which don't specifically target these mutations. Moreover, the combination therapy aims to address resistance issues seen with current treatments, potentially offering more effective and longer-lasting results for patients with specific genetic profiles.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Research has shown that using Lazertinib and Amivantamab together, as studied in several arms of this trial, may help treat non-small cell lung cancer (NSCLC) with specific genetic changes known as EGFR mutations. Studies have found that this combination can extend patient survival compared to the current standard treatment, osimertinib. It also helps prevent the cancer from developing resistance, a common issue with other therapies. Additionally, Amivantamab alone, studied in a separate arm of this trial, has proven effective for certain EGFR mutations, suggesting it could be beneficial on its own. Overall, this combination treatment offers hope for patients with specific genetic types of NSCLC. ^{2 5 6 7 8}

Who Is on the Research Team?

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Are You a Good Fit for This Trial?

This trial is for adults with advanced non-small cell lung cancer (NSCLC) that has specific EGFR mutations. Participants may have had previous treatments like chemotherapy or EGFR inhibitors, but must not have uncontrolled illnesses, active infections, severe gastrointestinal issues, or untreated brain metastases. They should be able to swallow pills and comply with study requirements.

Inclusion Criteria

A woman of childbearing potential: Must have a negative serum beta human chorionic gonadotropin at screening; Must agree not to breast-feed during the study and for 6 months after the last dose of study intervention. (Enrollment is not allowed even if a woman who is breast-feeding stops breast-feeding); 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 intervention

I am fully active or restricted in physically strenuous activity but can do light work.

I have NSCLC with an EGFR mutation, it's spread, and I've tried all treatment options.

Exclusion Criteria

I do not have any uncontrolled illnesses or conditions that would interfere with the study.

I have brain or CNS metastases that haven't been treated, but I might be stable after therapy.

Side effects from my previous cancer treatment have mostly gone away.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Lazertinib and Amivantamab in various combinations, with some cohorts also receiving platinum-doublet chemotherapy.

Up to 2.5 years

Every 7 days for the first 28 days, then every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2.5 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Amivantamab
• Carboplatin
• Lazertinib
• Pemetrexed

Trial Overview

The trial is testing Lazertinib alone or combined with Amivantamab in NSCLC patients. It aims to find the safest dose when used together and assess how well they work against tumors with certain EGFR mutations. Some will also receive standard chemotherapy drugs Carboplatin and Pemetrexed.

How Is the Trial Designed?

Group I: Phase 1b (expansion) Cohort F: Amivantamab Monotherapy Experimental Treatment 1 Intervention

Participants will receive Amivantamab monotherapy once weekly (QW) for 4 weeks, then every 2 weeks thereafter. Cohort F will seek to validate the IHC-based biomarker strategy, previously identified in Cohort D, by characterizing the activity of JNJ-61186372 monotherapy (Cohort F) in biomarker-positive participants with osimertinib-relapsed, but chemotherapy-naïve, EGFR Exon19del or L858R mutated NSCLC.

Group II: Phase 1b (expansion) Cohort E: Lazertinib and Amivantamab Experimental Treatment 2 Interventions

Participants will receive at the RP2CD of Lazertinib orally QD and Amivantamab, every 7 days for the first 28 days cycle and every 2 weeks thereafter. Cohort E will seek to validate the immunohistochemical (IHC)-based biomarker strategy, by characterizing the activity of Amivantamab and Lazertinib combination in biomarker-positive participants with osimertinib-relapsed, but chemotherapy-naïve, EGFR Exon19del or L858R mutated NSCLC. In addition, Cohort E will seek to collect prospective data to confirm that prophylactic anticoagulation safely and effectively decreases the incidence of VTE events for patients treated with the combination of Amivantamab and Lazertinib, using Cohort F as reference.

Group III: Phase 1b (expansion) Cohort D: Lazertinib and Amivantamab Experimental Treatment 2 Interventions

Cohort D will seek to validate one or both potential biomarker strategies (next generation sequencing \[NGS\] and Immunohistochemical \[IHC\]), previously identified in Cohort E of Study 61186372EDI1001, in participants with osimertinib-relapsed, but chemotherapy-naive, EGFR Exon19del or L858R mutated NSCLC. Participants will receive at the RP2CD of Lazertinib orally QD and Amivantamab, every 7 days for the first 28 days cycle and every 2 weeks thereafter.

Group IV: Phase 1b (expansion) Cohort C: Lazertinib and Amivantamab Experimental Treatment 2 Interventions

This Cohort C will further characterize the safety, tolerability and preliminary antitumor activity of Lazertinib and JNJ-61186372 combination in participants with uncommon EGFR mutations. Participants will receive at the RP2CD of Lazertinib orally QD and Amivantamab, every 7 days for the first 28 days cycle and every 2 weeks thereafter.

Group V: Phase 1b (expansion) Cohort B: Lazertinib and Amivantamab Experimental Treatment 2 Interventions

This Cohort B will further characterize the safety, tolerability and preliminary antitumor activity of Lazertinib and JNJ-61186372 combination in participants previously treated with advanced or metastatic NSCLC with documented primary EGFR Exon 20ins activating mutation. Participants will receive at the RP2CD of Lazertinib orally QD and Amivantamab, every 7 days for the first 28 days cycle and every 2 weeks thereafter.

Group VI: Phase 1b (expansion) Cohort A: Lazertinib and Amivantamab Experimental Treatment 2 Interventions

This cohort A will further characterize the safety, tolerability, and preliminary antitumor activity of Lazertinib and Amivantamab based combinations within specific NSCLC population "who have progressed after osimertinib and subsequent platinum-based chemotherapy, and platinum-based chemotherapy regimen as the last line of therapy prior to study enrollment. Prior use of first or second generation EGFR TKI is allowed if administered prior to osimertinib. Participants will receive at the RP2CD of Lazertinib orally QD and Amivantamab, every 7 days for the first 28 days cycle and every 2 weeks thereafter.

Group VII: Phase 1b (combination): Lazertinib, Amivantamab and Platinum-doublet Chemotherapy (LACP) Experimental Treatment 4 Interventions

Participants will receive Lazertinib starting dose administered orally once daily (QD) in combination with Amivantamab, and doses of platinum-based chemotherapy (carboplatin and pemetrexed) per standard of care according to local guidance in a 21-day cycle for 4 cycles followed by maintenance with Lazertinib, Amivantamab and pemetrexed until disease progression or unacceptable toxicities.

Group VIII: Phase 1b (combination): Lazertinib and Amivantamab Experimental Treatment 2 Interventions

Participants will receive Lazertinib and Amivantamab, after the safety of RP2D of Lazertinib is confirmed in the Phase 1, in 28-day cycles until documented evidence of disease progression, unacceptable toxicity, noncompliance, or withdrawal of consent, or the investigator decides to discontinue treatment, whichever comes first. This phase will start enrolling participants after the safety of Amivantamab is confirmed in Japanese participants in Study 61186372EDI1001 (NCT02609776).

Group IX: Phase 1 (monotherapy dose escalation): Lazertinib Experimental Treatment 1 Intervention

Participants will receive Lazertinib monotherapy orally once daily (QD) in 21-day cycles until documented evidence of disease progression, unacceptable toxicity, noncompliance, or withdrawal of consent, or the investigator decides to discontinue treatment, whichever comes first. The subsequent doses of Lazertinib will be assigned by the Study Evaluation Team (SET) according to the dose escalation strategy by Bayesian logistic regression model (BLRM).

Amivantamab is already approved in United States, European Union for the following indications:

Approved in United States as Rybrevant for:

• Locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations
• Locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations

Approved in European Union as Rybrevant for:

• Locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations
• Locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations

Who Is Running the Clinical Trial?

Janssen Research & Development, LLC

Lead Sponsor

Trials

1,022

Recruited

6,408,000+

Joaquin Duato

Janssen Research & Development, LLC

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Research & Development, LLC

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Published Research Related to This Trial

In a phase III trial involving 657 patients with advanced EGFR-mutated non-small-cell lung cancer, both amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy significantly improved progression-free survival (PFS) compared to standard chemotherapy, with median PFS of 6.3 and 8.3 months versus 4.2 months, respectively.

The combination therapies also showed a higher objective response rate (64% and 63% for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively) compared to chemotherapy (36%), although the amivantamab-lazertinib-chemotherapy regimen had more hematologic adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Passaro, A., Wang, J., Wang, Y., et al.[2023]

The combination of amivantamab and lazertinib showed a 36% overall response rate in patients with EGFR-mutant non-small cell lung cancer who had progressed on previous treatments, indicating potential efficacy in a challenging treatment setting.

The safety profile of the combination therapy was consistent with previous studies, with only 4% of patients experiencing severe side effects, suggesting that this treatment may be safe for patients who are chemotherapy naive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial. Cho, BC., Kim, DW., Spira, AI., et al.[2023]

Amivantamab, a bispecific antibody targeting EGFR and MET, received accelerated FDA approval for treating non-small cell lung cancer (NSCLC) patients with specific EGFR mutations, showing a 40% objective response rate in a Phase I/IB trial with a median response duration of 11.1 months.

In patients with other EGFR mutations, amivantamab alone had a 19% response rate, while combining it with lazertinib improved the response to 36%, indicating potential benefits of combination therapy in NSCLC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amivantamab in the Treatment of Metastatic NSCLC: Patient Selection and Special Considerations. Petrini, I., Giaccone, G.[2022]

Amivantamab is a bispecific monoclonal antibody that targets both EGFR and MET, specifically developed for treating non-small cell lung cancer (NSCLC) with EGFR Exon 20 insertion mutations.

It received its first approval in the USA on May 21, 2021, for adult patients with advanced NSCLC who have progressed after platinum-based chemotherapy, and is currently in preregistration in multiple countries including the EU and Japan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amivantamab: First Approval. Syed, YY.[2021]

The ongoing CHRYSALIS study shows that the combination of amivantamab, an EGFR-MET bispecific antibody, and lazertinib, a third-generation EGFR TKI, is effective in treating both treatment-naive patients and those who have relapsed after osimertinib.

The MARIPOSA study is a phase 3 trial designed to compare the safety and efficacy of the amivantamab and lazertinib combination therapy against single-agent osimertinib, aiming to improve first-line treatment outcomes for patients with EGFR-mutant non-small-cell lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer. Cho, BC., Felip, E., Hayashi, H., et al.[2022]

Amivantamab, approved for treating non-small cell lung cancer with specific genetic mutations, works by targeting two pathways: the epithelial growth factor receptor and mesenchymal epithelial transition factor, enhancing the immune response against cancer cells.

Preclinical studies indicate that Amivantamab effectively inhibits cancer cell growth in models with exon20 insertions of the epithelial growth factor receptor, suggesting its potential as a targeted therapy for this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amivantamab: A New Hope in Targeting Non-small Cell Lung Cancer. Billowria, K., Das Gupta, G., Chawla, PA.[2023]

Citations

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RYBREVANT® (amivantamab-vmjw) plus LAZCLUZE™ ...

Median overall survival not yet reached with projected improvement of more than one year versus osimertinib.

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The use of amivantamab–chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC ...

3.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38205202/

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The efficacy of amivantamab was confirmed for the real-world population for EGFR E20I-mutated NSCLC. PD-L1 status could be a poor predictive factor.

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ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e20529

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Download article citation data for: Real-world effectiveness and safety of amivantamab for exon 20 EGFR-mutant non-small cell lung cancer (NSCLC) ...

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sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0169500225006580

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rybrevanthcp.com/

RYBREVANT® (amivantamab-vmjw) HCP

The official healthcare provider website for RYBREVANT® (amivantamab-vmjw), a treatment for EGFR+ mNSCLC. See Full Prescribing & Safety Info.

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investor.jnj.com/investor-news/news-details/2025/Data-published-in-The-New-England-Journal-of-Medicine-demonstrate-RYBREVANT-amivantamab-vmjw-plus-LAZCLUZE-lazertinib-is-re-setting-survival-expectations-in-first-line-EGFR-mutated-lung-cancer/default.aspx

News Details - JNJ Investor Relations

Data published in The New England Journal of Medicine demonstrate RYBREVANT® (amivantamab ... Non-Small Cell Lung Cancer (NSCLC) (COPERNICUS).

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RYBREVANT® (amivantamab-vmjw)

RYBREVANT ® is approved to treat advanced non–small cell lung cancer (NSCLC) ... It is not known if RYBREVANT® or LAZCLUZE™ is safe and effective in children.