Lazcluze (lazertinib)

Our study concluded that combination regimens based on third-generation TKIs (osimertinib plus ramucirumab, osimertinib plus chemotherapy, osimertinib plus bevacizumab, amivantamab plus lazertinib and aumolertinib plus apatinib) could be the new and clinically preferable first-line, standard of care for EGFR-mutated advanced non-small cell lung cancer.

In NSCLC, therapies such as osimertinib have improved efficacy in treating EGFR-mutant BM, with emerging combinations such as amivantamab and lazertinib offering promising alternatives for patients resistant to frontline therapies. In HER2-positive breast cancer, significant advancements with tucatinib and trastuzumab deruxtecan (T-DXd) have transformed the treatment landscape, achieving improved survival and intracranial control in patients with BM. Similarly, in triple-negative breast cancer (TNBC), novel therapies such as sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) offer new hope for managing BM. For melanoma, the combination of immune checkpoint inhibitors such as nivolumab and ipilimumab has proven effective in enhancing survival for patients with BM, both in BRAF-mutant and wild-type cases...Future research should optimise combination therapies, overcome resistance, and refine treatment sequencing. Continued emphasis on personalized, biomarker-driven approaches offers the potential to further improve outcomes, even for complex cases.

P2, N=365, Recruiting, Janssen Research & Development, LLC | Not yet recruiting --> Recruiting

P2, N=365, Not yet recruiting, Janssen Research & Development, LLC

P2, N=150, Active, not recruiting, Myung-Ju Ahn | Recruiting --> Active, not recruiting

P2, N=200, Recruiting, Janssen Research & Development, LLC | N=300 --> 200

P1, N=701, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting | N=460 --> 701

P3, N=418, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Jan 2025 --> Dec 2025

Lazertinib is a promising treatment option for patients with EGFR T790M-positive NSCLC following disease progression on prior EGFR-directed TKIs. Patients in LASER201 experienced prolonged OS, regardless of their EGFR mutation, brain metastases, or prior brain radiation status. Clearance of plasma EGFR mutations after lazertinib was associated with patient outcomes.

These results suggest that using lazertinib instead of brain local treatment could be a potential strategy in patients with EGFR-variant NSCLC whose CNS metastases progressed after prior EGFR TKI treatment. ClinicalTrials.gov Identifier: NCT05326425.

No abstract available

P1, N=460, Recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2026 --> Jun 2026

P3, N=776, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2025 --> Jun 2026

P2, N=74, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Aug 2026 --> Oct 2025

P3, N=393, Active, not recruiting, Yuhan Corporation | Trial completion date: Jun 2024 --> Jun 2026

Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib)...HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020...This study suggests that erlotinib may be more suitable than 4G TKIs to overcome secondary mutations after front-line osimertinib. We found that off-target mechanisms that cause resistance to earlier-generation TKIs will also cause resistance to 4G TKIs.

Triple therapy with an MCL-1 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP/MCL-1 signals contribute to adaptive lazertinib resistance in EGFR-mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be a highly effective strategy in eliminating lazertinib-resistant cells.

P3, N=1074, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Apr 2024 --> Aug 2023

Ami+laz had significantly lower rates of EGFR and MET resistance alterations with trends for lower rates of TP53 resistance mutations and RB1 loss compared with osi. These initial findings suggest that first-line ami+laz is changing the biology of acquired resistance and demonstrate clear proof of mechanism with potent inhibition of resistance via the EGFR and MET pathways.

Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Based on this retrospective, external control study, lazertinib has demonstrated significantly better efficacy compared with platinum-based chemotherapy. The external controls provide important context to evaluate efficacy in single-arm studies.

Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

The median overall survival with lazertinib was not reached and that with osimertinib was 29.8 months (HR 0.44; 95% CI 0.25-0.77, p = 0.005). Our study suggests that lazertinib has an ORR and PFS comparable to those of osimertinib and has the potential for superior survival benefits.

Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced infusion-related reactions, increased convenience, and prolonged survival.

The retrospective subgroup analysis of IMpower150 indicated that the quad regimen (carboplatin, paclitaxel, bevacizumab, atezolizumab) improved PFS and overall survival (OS) in patients with EGFR-mutant NSCLC who progressed on first-generation EGFR-TKIs...MARIPOSA-2 provided the first randomized trial post-osimertinib in EGFR-mutant NSCLC patients with another quad regimen (platinum, pemetrexed, lazertinib, amivantamab)...Here, we discuss how the results of IMpower151 and ATTLAS may rejuvenate interest in a non-EGFR containing quad regimen as a potential post-osimertinib monotherapy treatment. Randomized trials comparing the results of these studies, including the quad regimen of MARIPOSA-2 versus the quad regimen of IMpower151/Impower150/ATTLAS in post-osimertinib (or other 3G EGFR-TKI) progression, are urgently needed.

P2, N=390, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: May 2024 --> Oct 2025

P1, N=160, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting

P3 | "Clinical Trial Registration Number: NCT05388669"

P3 | "Clinical Trial Registration Number: NCT04487080"

P2, N=300, Recruiting, Janssen Research & Development, LLC | N=180 --> 300

P2, N=74, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting

The MARIPOSA trial was designed to study if the combination of amivantamab plus lazertinib in untreated epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients would provide improved progression-free survival. Here, we discuss the rationale for the study and the early results of MARIPOSA.

Our data support the use of osimertinib in real-word settings and highlight the need for designing registration trials that are more inclusive of patient/disease characteristics seen in routine clinical practice. It is yet to be determined if the use of evolving first-line EGFR inhibitor combination strategies (either platinum-doublet chemotherapy plus osimertinib or amivantamab plus lazertinib) will similarly translate from clinical trials to real-word settings.

P1, N=166, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Jan 2024 --> Oct 2024

P1, N=751, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2024 --> Jun 2025

This analysis demonstrated long-term clinical benefit with lazertinib 240 mg in patients with EGFR-mutated NSCLC who had not previously received EGFR TKIs. The safety profile for lazertinib was tolerable and consistent with that previously reported.

P2, N=67, Recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2025 --> Aug 2026

P2, N=180, Recruiting, Janssen Research & Development, LLC | Not yet recruiting --> Recruiting

P2, N=160, Not yet recruiting, Yonsei University

P1, N=166, Recruiting, Janssen Research & Development, LLC | Trial completion date: Feb 2025 --> Oct 2025

Passaro et al.1 demonstrated in EGFR+ NSCLC post-1L osimertinib both "quad" (lazertinib [L] + amivantamab [A] + chemotherapy [CP]) and "triplet" (ACP) regimens achieved improved median progression-free survival over CP. Nonetheless, a high incidence of adverse events requiring dose modifications may limit adaptation of the triplet and quad MARIPOSA-2 regimens.