Lazertinib and Osimertinib are medications for a specific type of lung cancer, targeting a particular genetic alteration in cancer cells. This article compares Lazertinib and Osimertinib, discussing their mechanisms, effectiveness, side effects, and role in cancer care.
Understanding EGFR-Mutated Lung Cancer
Non-small cell lung cancer (NSCLC) is a common form of lung cancer, accounting for about 85% of all lung cancer cases. A subset of NSCLC patients harbor mutations within the Epidermal Growth Factor Receptor (EGFR) gene. The EGFR protein normally helps cells grow and divide. However, when a mutation occurs in the EGFR gene, it can cause the receptor to remain constantly active, leading to uncontrolled cell growth, which is characteristic of cancer.
These EGFR mutations act as “drivers” of cancer growth, making them targets for specialized treatments. Approximately 10-15% of lung cancers in the United States have these sensitizing EGFR mutations, with a higher incidence observed in Asian populations. The most common EGFR mutations are exon 19 deletions and L858R point mutations in exon 21. Understanding these mutations is important for determining therapeutic strategies for patients.
Targeting the Epidermal Growth Factor Receptor
Both Lazertinib and Osimertinib belong to a class of medications called tyrosine kinase inhibitors (TKIs). These drugs work by specifically blocking the activity of the mutated EGFR pathway, inhibiting cancer cell proliferation. They achieve this by binding to the ATP-binding site within the EGFR tyrosine kinase domain. This binding prevents the phosphorylation of the receptor, which is necessary for activating downstream signaling pathways involved in tumor growth and metastasis.
Lazertinib and Osimertinib are classified as “third-generation” EGFR TKIs. They are designed to overcome a common resistance mechanism that can develop with earlier generations of EGFR TKIs: the T790M mutation in exon 20. Third-generation TKIs, like Osimertinib, are potent inhibitors of T790M-mutant EGFR while showing minimal activity against the normal, or “wild-type,” EGFR. This selectivity helps reduce side effects from inhibiting healthy cells.
Comparative Efficacy and Key Trials
The efficacy of Osimertinib was established through the FLAURA trial, a double-blind, randomized Phase 3 study. This trial compared first-line Osimertinib with older EGFR TKIs (gefitinib or erlotinib) in patients with advanced EGFR-mutated NSCLC. Osimertinib demonstrated superior progression-free survival (PFS), with a median PFS of 18.9 months compared to 10.2 months for the comparator group. The FLAURA trial also showed a longer median overall survival (OS) for Osimertinib at 38.6 months, versus 31.8 months for the older TKIs.
Lazertinib’s efficacy has been evaluated in several trials, including the LASER301 study and an exploratory analysis within the MARIPOSA trial. The global Phase 3 LASER301 study compared Lazertinib to gefitinib in treatment-naïve EGFR-mutated advanced NSCLC. Lazertinib showed a longer median PFS of 20.6 months compared to 9.7 months for gefitinib, representing a 55% lower risk of disease progression or death. The objective response rate (ORR) was similar for both drugs at 76%.
The Phase 3 MARIPOSA study directly compared Lazertinib monotherapy with Osimertinib monotherapy in previously untreated EGFR-mutant advanced NSCLC. At a median follow-up of 22.0 months, the median PFS was 18.5 months for Lazertinib and 16.6 months for Osimertinib, showing comparable efficacy between the two. The objective response rate was 83% for Lazertinib and 85% for Osimertinib, with similar median durations of response. Median overall survival was not reached for either arm at the interim analysis. The MARIPOSA trial also investigated a combination of amivantamab plus lazertinib, which showed an improvement in PFS (23.7 months vs 16.6 months for osimertinib) and overall survival compared to Osimertinib alone.
Differences in Side Effect Profiles
Both Lazertinib and Osimertinib, as EGFR TKIs, share common side effects related to their mechanism of inhibiting EGFR, a protein also found in healthy cells. These commonly include skin-related issues like rash and gastrointestinal issues such as diarrhea. In the MARIPOSA study, the safety profiles of Lazertinib and Osimertinib were generally comparable, with most adverse events being mild to moderate (Grade 1-2).
However, some differences in their side effect profiles have been observed. Osimertinib has been associated with higher rates of diarrhea compared to Lazertinib. Conversely, Lazertinib was associated with lower rates of QT interval prolongation, a heart-related side effect, and cardiomyopathy compared to Osimertinib. Lazertinib also showed lower rates of thrombocytopenia and neutropenia, which are reductions in platelet and neutrophil counts, respectively. In contrast, Lazertinib had higher rates of rash, muscle spasms, and paresthesia (a tingling or prickling sensation) compared to Osimertinib.
Role in Lung Cancer Treatment
Osimertinib is an accepted first-line treatment for EGFR-mutated locally advanced or metastatic NSCLC, and it is the only globally approved third-generation TKI for this indication as a monotherapy. Its use is based on its demonstrated ability to improve progression-free and overall survival compared to earlier generation TKIs. Osimertinib can also be used in combination with platinum-based chemotherapy as a first-line treatment, which has shown improvement in overall survival compared to Osimertinib monotherapy in the FLAURA2 trial.
Lazertinib is approved for use in Korea and has been investigated in combination with amivantamab, which has received FDA approval for first-line treatment of EGFR-mutant advanced NSCLC. While Lazertinib monotherapy showed comparable efficacy to Osimertinib in the MARIPOSA trial, its primary role in the MARIPOSA study was as part of a combination regimen with amivantamab. This combination demonstrated superior progression-free and overall survival over Osimertinib monotherapy, suggesting a new potential first-line standard of care. The choice between these treatments is individualized, considering factors like disease burden, patient comorbidities, and potential side effect profiles.