CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: December 17, 2024
Expiration: June 16, 2025
Progress of EGFR Research
Helena Yu, MD:
The EGFR mutation was first discovered as a driver mutation in NSCLC in 2004. During the past 20 years, there has been marked progress in how EGFR-mutated NSCLC is understood and treated. Initially, early-generation EGFR TKIs were used and approved and ultimately became the first-line standard of care for patients with metastatic EGFR-mutated NSCLC. EGFR T790M was then identified as the primary mechanism of resistance to these early-generation EGFR inhibitors.1 Subsequently, osimertinib, which targets and inhibits EGFR T790M, was developed. Recently, osimertinib was assessed in the first line setting in the FLAURA study and eventually was approved for first-line use in EGFR-mutated lung cancer. Liquid-based molecular testing on circulating tumor DNA in plasma was developed that can be used in combination with tumor tissue biopsies to help identify EGFR mutations.1 In the past year, first-line combination strategies, including osimertinib plus chemotherapy and mivantamab plus chemotherapy, have been approved. Amitvantamab is also approved in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations.2,3 Alongside the development of these new EGFR TKIs, a novel type of therapy, antibody–drug conjugates (ADCs), was developed for use in EGFR-mutated lung cancer and is the focus of this module.1,4,5
Mechanisms of Osimertinib Resistance in EGFRm NSCLC
Helena Yu, MD:
Now that osimertinib monotherapy is the first-line standard of care for metastatic EGFR-mutated lung cancer, the mechanisms of resistance to osimertinib have begun to be understood.6 Of interest, these mechanisms of resistance differ when osimertinib is given in the later-line setting vs the first-line setting. Later-line osimertinib results in more on-target resistance, including a significant frequency of the EGFR C797S mutation in resistant tumors.6 In contrast, first-line osimertinib is correlated with more diverse mechanisms of resistance, with less on-target EGFR-mediated resistance and more off-target resistance consisting of mutations in bypass signaling pathways as well as histologic transformation. This occurs when an adenocarcinoma of the lung becomes either squamous cell lung cancer or small-cell lung cancer.6
In addition, in approximately one half of cases, the mechanism of resistance to osimertinib is not revealed by next-generation sequencing.6
Mechanisms of Acquired Resistance to Kinase Inhibitors in Lung Cancer
Helena Yu, MD:
This figure illustrates the different mechanisms of resistance to EGFR inhibitors, particularly osimertinib. One type of osimertinib resistance is on-target resistance, meaning that acquired alterations in the EGFR gene prevent the EGFR inhibitor from effectively binding to and inhibiting EGFR.7
The most common acquired mutation resulting in on-target resistance to osimertinib is EGFR C797S. Fourth-generation EGFR inhibitors that target EGFR C797S are currently in development and being assessed.7
Mutations also occur in bypass signaling pathways. The most common example of this is MET amplification. Combination EGFR and MET inhibitors have been successful in the setting of acquired MET amplification. Other acquired alterations include acquired fusions (eg, ALK or RET fusions) as well as acquired mutations in KRAS and BRAF, among others.7
Histologic transformation is also observed with early-generation EGFR inhibitors and commonly with osimertinib, which might be because osimertinib is a better on-target EGFR inhibitor, allowing more off-target resistance.7
Mechanisms of Osimertinib Resistance
Helena Yu, MD:
This schematic shows various treatment options for the different types of osimertinib resistance identified. With on-target resistance, the combination of osimertinib and early-generation EGFR TKIs can be used, and some fourth-generation EGFR inhibitors are currently being studied. For off-target resistance, MET inhibitors can be used for MET amplification.8,9 Clinical trials and case series have shown that crizotinib, capmatinib, tepotinib, and the novel MET inhibitor savolitinib can be combined with osimertinib. For RET fusions, osimertinib and selpercatinib can be used, with significant efficacy. For ALK fusions, alectinib has shown efficacy. For BRAF mutations, trametinib plus osimertinib with or without dabrafenib has been used.8,9 For HER2 amplification or HER2-acquired mutations, one of the HER2-directed ADCs can be used. For lineage plasticity, appropriate histology-directed chemotherapy should be used. For lung cancers with no identifiable genomic alteration that is driving resistance, the standard second-line therapy is histology-appropriate chemotherapy or participation in a clinical trial.8,9
Treatment Sequencing in EGFRm NSCLC
Helena Yu, MD:
Treatment options for EGFRm NSCLC have become increasingly complex and complicated. Now that there are several options for first-line treatment, there are more options to choose from for every line of treatment.10
First, healthcare professionals should decide what treatment is most appropriate for the first-line setting—whether osimertinib monotherapy or a combination strategy (eg, osimertinib plus chemotherapy or amivantamab plus lazertinib) should be used. One way to help determine treatment options in the first-line setting is to consider risk stratification, followed by risk-adaptive treatment choices. Multiple potential biomarkers that are currently under consideration could help identify the best treatment options for a given patient. Some that could be used for risk stratification include patient factors like disease burden, the presence of comorbidities, the presence of brain metastases, and genomic biomarkers such as EGFR mutation subtype, EGFR circulating tumor DNA presence and clearance, and comutations such as those in TP53 and RB1.11-15
However, what is used in the first-line setting often dictates what treatment options are available in the second-line setting and beyond. For example, if one uses platinum-based chemotherapy in combination with osimertinib in the first-line setting, chemotherappy is not a standard option that would be used in the second-line setting. Healthcare professionals would need to think about amivantamab, ADCs, or other therapies instead.10
Similarly, if amivantamab plus lazertinib is used in the first-line setting, then subsequent regimens that include amivantamab are unlikely to be used in the second-line setting and beyond.10
Proposed Role of HER3 in EGFR TKI Resistance
Helena Yu, MD:
Acquired resistance to EGFR TKIs, including osimertinib, occurs in nearly all cases after treatment. Data suggest that HER3 expression is relevant in resistance to EGFR inhibitors. Preclinical studies demonstrated that inhibition of downstream signaling pathways, including AKT, leads to upregulation and increased HER3 phosphorylation with reactivation of PI3K pathway signaling.16-18
Another way that HER3 can drive EGFR resistance is by increasing MET amplification. Further, HER3 heterodimerizes with EGFR and HER2 and affects downstream signaling to also drive EGFR resistance.16-18
HER3 Expression Increases With Acquired EGFR TKI Resistance
Helena Yu, MD:
HER3 expression is dynamic over time within a tumor, and both temporal and spatial heterogeneity have been seen with HER3 expression, specifically in NSCLC with EGFR mutation. When assessing tumors before and after exposure to an EGFR TKI, there does seem to be increased HER3 expression in tumor samples after EGFR TKI treatment, suggesting that this resistance setting may be an opportunity to use HER3 inhibitors in clinical practice.16
Timeline for Novel Agents in Advanced NSCLC
Helena Yu, MD:
Clinical trials are the only way novel therapies are assessed and ultimately get to patients. During the past 20 years, first-generation EGFR inhibitors like gefitinib and erlotinib were approved. Subsequently, later-generation EGFR inhibitors, including osimertinib, proved effective in the later-line setting and then ultimately found a place in the first-line setting.19,20
In addition to EGFR TKIs, monoclonal antibodies (mAbs) and ADCs have been assessed in this setting. One ADC that is clinically relevant is HER3-DXd, which was assessed in clinical trials beginning in 2017 and has shown efficacy in EGFR-mutated lung cancer.19,20
Current Landscape of NSCLC Therapy
Helena Yu, MD:
Currently, no oral targeted therapies have been approved for use after osimertinib. Chemotherapy and chemotherapy combinations are used in the later-line setting. However, these options are limited, and their efficacy is modest.21,22
Clinical trials allow patients to access novel therapies, and concerted efforts result in accelerated drug development, which allows appropriate patients access to novel drugs sooner. After the completion of clinical trials, expanded access programs allow access to novel therapies prior to regulatory approval.21,22
Preclinical investigations are critical for identifying novel drugs to bring to clinics. One excellent example is when EGFR T790M was discovered in tumors that developed resistance to erlotinib; drugs that might inhibit EGFR T790M were assessed, which ultimately led to the approval of osimertinib.21,22
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