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Advances in NSCLC Treatment – Overcoming Osimertinib Resistance and

In the ever-evolving landscape of cancer treatment, recent breakthroughs in the fight against non-small cell lung cancer (NSCLC) have brought new hope to patients and clinicians alike. At the forefront of these advancements is the remarkable progress in understanding and targeting mutations in the epidermal growth factor receptor (EGFR), which are among the most common drivers of this cancer type. Predominantly, two mutations, exon 19 deletions and exon 21 L858R mutations, account for approximately 85-90% of EGFR mutations in NSCLC. This deepened understanding has paved the way for the development and implementation of EGFR tyrosine kinase inhibitors (TKIs), a class of targeted therapies that have significantly altered the treatment landscape. Demonstrating impressive response rates of 60-80%, these TKIs have been instrumental in improving clinical outcomes for patients.


Leading the charge in this new era of personalized medicine is Osimertinib, a third-generation EGFR TKI. Currently established as the standard of care for NSCLC patients harboring ex19del and L858R mutations, Osimertinib has shown remarkable efficacy, with a median progression-free survival of 18.9 months and overall survival reaching 38.6 months. However, the journey doesn’t end here. Despite the initial effective control of the disease, resistance to Osimertinib inevitably develops in nearly all cases, posing a significant challenge in the ongoing battle against NSCLC. In response, the latest research has shifted focus towards exploring combinations of chemotherapy, immunotherapy, and anti-angiogenic therapy, offering a beacon of hope for patients who experience relapse post-Osimertinib treatment. This pursuit highlights the continuous effort in the medical community to not only extend life but also improve the quality of life for patients battling NSCLC.

Delving deeper into the complexities of osimertinib resistance in non-small cell lung cancer (NSCLC), recent advancements in next-generation sequencing (NGS) have shed light on the underlying mechanisms. Through the analysis of circulating tumor DNA (ctDNA) and tumor samples from patients who have progressed on osimertinib, researchers have been able to categorize the resistance mechanisms into two main types: EGFR-dependent and EGFR-independent. EGFR-dependent resistance involves alterations that prevent osimertinib from effectively inhibiting the EGFR, while EGFR-independent resistance is characterized by the activation of alternative signaling pathways or cellular reprogramming, such as epithelial-mesenchymal transition and histologic transformations.

The most common EGFR-dependent resistance mechanism is the C797S mutation in the EGFR gene, which inhibits osimertinib’s ability to bind to the ATP binding site in the kinase domain. Other identified EGFR-dependent mechanisms include mutations like L792X, G796X, L718Q, and EGFR amplification. On the other hand, the most frequently reported EGFR-independent mechanism is MET amplification. Additional mechanisms include activation of pathways like mitogen-activated protein kinase or phosphatidylinositol 3-kinase, as well as gene fusions and histologic transformations. Notably, in about half of the cases experiencing progression on osimertinib, no clear mechanism of resistance has been pinpointed.

The challenge of overcoming osimertinib resistance is compounded by the heterogeneous nature of these resistance patterns, which can even vary within a single patient. The mechanism of resistance also appears to be influenced by whether the disease progression occurred in a first-line or second-line treatment setting (after initial EGFR TKI therapy, particularly in T790M mutation-positive cases). Considering the complexity of these resistance patterns, coupled with the limited response of this patient population to immuno-oncology (IO) monotherapy and the absence of approved targeted therapies post-osimertinib, current treatment guidelines predominantly recommend platinum-based chemotherapy regimens for patients following osimertinib progression. This recommendation underscores the ongoing need for innovative and effective treatment strategies in the management of NSCLC.

In the quest to enhance treatment options for non-small cell lung cancer (NSCLC), amivantamab, a novel bispecific antibody, has emerged as a significant player. This groundbreaking therapy targets two key receptors, EGFR and MET, by binding to them and inhibiting ligand binding. This process leads to a decrease in cell surface receptors and triggers both trogocytosis and antibody-dependent cellular cytotoxicity, making amivantamab a multifaceted weapon against cancer. Its effectiveness spans a range of EGFR-driven and MET-driven NSCLC cases, displaying anti-tumor activity with a safety profile that is generally well tolerated by patients. Amivantamab has gained approval for treating NSCLC patients with specific EGFR exon 20 insertion mutations who have seen disease progression after platinum-based chemotherapy.

Amivantamab’s unique mode of action, binding to the extracellular parts of receptors, complements EGFR tyrosine kinase inhibitors (TKIs) by targeting both the external and internal domains of EGFR. This dual approach has shown promising results in preclinical studies, notably in the H1975-HGF murine xenograft model. In these studies, combining amivantamab with lazertinib, a potent, brain-penetrating third-generation EGFR TKI, led to greater tumor reduction and more sustained disease control compared to using either treatment alone. This synergy is particularly notable as lazertinib is effective against both activating EGFR mutations and the resistant T790M mutation.

Building on these encouraging results, the CHRYSALIS study is currently underway, investigating the combined use of amivantamab and lazertinib. This trial focuses on patients with metastatic NSCLC exhibiting EGFR ex19del or L858R mutations who have progressed following treatment with osimertinib or another third-generation EGFR TKI, but have not yet received cytotoxic chemotherapy in the metastatic setting.