The FDA has approved lazertinib (Lazcluze) in combination with amivantamab-vmjw (Rybrevant) for the first-line treatment of non-small cell lung cancer with specific genetic mutations.
In a significant advancement for the treatment of non-small cell lung cancer (NSCLC), the U.S. Food and Drug Administration (FDA) has granted approval to lazertinib (Lazcluze) when used in combination with amivantamab-vmjw (Rybrevant). This combination therapy is indicated for patients with locally advanced or metastatic NSCLC that harbor specific mutations.
The approval is based on data from the MARIPOSA clinical trial, which demonstrated a significant improvement in progression-free survival (PFS) for patients receiving the combination therapy compared to those treated with osimertinib alone.
What is NSCLC?
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all lung cancer cases. It is characterized by abnormal cell growth in the lung tissues. NSCLC is classified into three main subtypes- squamous cell carcinoma (25% of lung cancers), adenocarcinoma (40% of lung cancers), and large cell carcinoma (10% of lung cancers).
NSCLC arises from the epithelial cells of the lung and its histological type correlates with its location. Squamous cell carcinoma typically originates near the central bronchi. Whereas, adenocarcinoma and bronchioloalveolar carcinoma usually start in the peripheral lung tissue. While NSCLC generally progresses more slowly than small cell lung cancer, it often spreads to other parts of the body by the time it is diagnosed, making early detection crucial for effective treatment.
Current treatments
The treatment for NSCLC is multifaceted and depends on various factors, including the stage of the disease and the patient’s overall health. While surgery remains the most promising option for early-stage disease, advanced-stage NSCLC requires a combination of treatments.
Chemotherapy, often administered in conjunction with radiation therapy, can provide palliative benefits and improve overall survival in some cases. Molecularly targeted therapies have revolutionized the treatment landscape, offering targeted approaches for patients with specific genetic mutations. For instance, EGFR inhibitors have shown efficacy in patients with EGFR mutations, and ALK inhibitors have been successful in treating ALK-positive NSCLC.
While these treatments offer hope for patients with NSCLC, it’s essential to note that the disease remains challenging to treat.
How does Lazertinib work?
Lazertinib is a potent, irreversible tyrosine kinase inhibitor (TKI) designed to target the epidermal growth factor receptor (EGFR) tyrosine kinase domain. Its primary mechanism of action involves binding to the EGFR kinase domain, preventing the phosphorylation of downstream signaling proteins. This inhibition disrupts the EGFR signaling pathway, which is crucial for the growth and survival of non-small cell lung cancer (NSCLC) cells with specific EGFR mutations.
Lazertinib exhibits high selectivity for EGFR, minimizing off-target effects on other kinases. This selectivity is essential for reducing potential side effects associated with broad-spectrum TKIs. By effectively targeting EGFR, lazertinib can inhibit the proliferation, migration, and invasion of NSCLC cells, leading to tumor growth inhibition and potential regression.
In combination with amivantamab-vmjw, a monoclonal antibody that targets EGFR and HER2, lazertinib demonstrates enhanced efficacy in NSCLC patients with EGFR exon 19 deletions or exon 21 L858R mutations. This combination therapy leverages the complementary mechanisms of action of the two agents, potentially resulting in improved outcomes compared to either drug alone.
Clinical Studies, Efficacy and and Side Effects
Mariposa is a clinical trial comparing the effectiveness of amivantamab and lazertinib combination therapy, against osimertinib, or lazertinib alone in treating patients with EGFR-mutated NSCLC. It is a Phase 3 randomized study designed to assess the efficacy and safety of these treatments as a first-line option for patients with EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer.
This phase 3 trial was done in 267 areas with 1074 patients with EGFR exon 19 deletion or exon 21 L858R substitution mutations. Patients were randomly assigned to receive lazertinib in combination with amivantamab, osimertinib monotherapy, or lazertinib monotherapy. Progression-free survival (PFS) as assessed by blinded independent central review (BICR) were the primary endpoint of the study.
Lazertinib with amivantamab demonstrated a statistically significant improvement in PFS compared to osimertinib. The median PFS was 23.7 months in the lazertinib with amivantamab arm and 16.6 months in the osimertinib arm. While overall survival data was immature at the time of the analysis, there was no indication of a detrimental effect. The most common adverse events were rash, nail toxicity, infusion-related reactions, musculoskeletal pain, and edema. A serious safety signal of venous thromboembolic events (VTE) was observed with the combination therapy.
The MARIPOSA trial provided compelling evidence for the efficacy of lazertinib in combination with amivantamab as a first-line treatment option for EGFR-mutated NSCLC. The combination therapy demonstrated superior PFS compared to osimertinib, with a favorable safety profile. While the long-term survival benefits remain to be fully assessed, the results from MARIPOSA offer hope for patients with this challenging disease.
Dr. Avraneel Paul, Ph.D.
Sources
- https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq#_514
- https://www.prnewswire.com/news-releases/rybrevant-amivantamab-vmjw-plus-lazcluze-lazertinib-approved-in-the-us-as-a-first-line-chemotherapy-free-treatment-for-patients-with-egfr-mutated-advanced-lung-cancer-302226047.html
- https://www.clinicaltrials.gov/study/NCT04487080
- https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer
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