Bicheng Zhang: Post-Resistance Strategies for Third-Generation EGFR-TKIs in NSCLC

Mediamedic shared a post on LinkedIn:

“Editor’s Note: EGFR mutations are among the most common genetic abnormalities in non-squamous non-small cell lung cancer (NSCLC), and EGFR-TKIs have become the standard first-line treatment for advanced EGFR-mutant NSCLC. Despite significant advancements across three generations of EGFR-TKIs, resistance remains unavoidable. Post-resistance treatment options for EGFR-TKI patients, particularly those facing complex third-generation resistance mechanisms, are limited.

• At the 2024 Chinese Congress on Holistic Integrative Oncology (CCHIO) on November 17, Dr. Bicheng Zhang from Wuhan University People’s Hospital delivered a keynote presentation titled “Post-Resistance Strategies for Third-Generation EGFR-TKIs in NSCLC.” His talk explored resistance mechanisms and advancements in treatment strategies. Below is a summary of the key points shared.

Part 1: Resistance Mechanisms and Progression Patterns of Third-Generation EGFR-TKIs

1. Resistance Mechanisms

Third-generation EGFR-TKIs, such as osimertinib, have revolutionized treatment by overcoming resistance to earlier generations and effectively controlling brain metastases. However, resistance mechanisms still include:

• EGFR-Dependent Resistance: Mutations blocking TKI suppression of EGFR tyrosine kinase activity.
• Bypass or Downstream Activation: Alternate signaling pathways drive cell survival and proliferation despite TKI binding.
• Histological or Phenotypic Transformation: Includes transitions from adenocarcinoma to squamous or small-cell lung cancer (SCLC) and epithelial-mesenchymal transformation (EMT).

Off-target resistance is more prevalent than on-target resistance.

2. Progression Patterns

Post-resistance progression patterns include:

• Oligoprogression: Limited to ≤5 lesions in ≤3 organs.
• CNS Progression: Brain metastases or leptomeningeal involvement.
• Widespread Progression: Requires mechanism-specific treatment adjustments.

Part 2: Strategies for Oligoprogression and CNS Progression

1. Oligoprogression

For patients showing limited progression while on EGFR-TKI therapy, combining local therapies (radiotherapy, surgery, or ablation) with continued EGFR-TKI has demonstrated benefits.

• Studies: In a retrospective analysis, patients receiving SBRT consolidation post-osimertinib showed improved progression-free survival (PFS) (17.2 vs. 11.3 months). A Phase II trial (NCT02759835) involving local therapies in osimertinib-treated patients reported encouraging PFS2 outcomes.

2. CNS Progression

Approximately 40% of EGFR-mutant NSCLC patients experience CNS progression. Treatment strategies include:

• Dose Escalation: For patients with stable extracranial disease, escalating osimertinib from 80 mg to 160 mg may benefit leptomeningeal disease.
• Local Therapy: Radiotherapy or surgical interventions remain pivotal in managing CNS metastases.

Part 3: Strategies for Widespread Progression Based on Resistance Mechanisms

1. C797S Mutation

The C797S mutation is a common EGFR-dependent resistance mechanism post-osimertinib.

• Treatment: Combining first-generation TKIs with osimertinib shows modest benefit but limited durability. Brigatinib with cetuximab offers a potential option for cis-oriented C797S mutations.

2. MET Amplification

MET amplification rates post-osimertinib are 7%-30%.

• Treatment: MET-TKIs (e.g., capmatinib) combined with osimertinib demonstrate efficacy. MET-targeted antibody-drug conjugates (ADCs) and bispecific antibodies like amivantamab hold promise.

3. HER2 Aberrations

HER2 mutations, amplifications, and overexpression are observed in NSCLC.

• Treatment: Trastuzumab deruxtecan (T-DXd) has shown significant efficacy, with FDA approval for HER2-mutant metastatic NSCLC.

4. Histological Transformation to SCLC

Histological transformation occurs in 5%-14% of EGFR-TKI-resistant adenocarcinomas.

• Challenges: Patients often exhibit rapid progression with poor prognoses (median survival: 6-10.9 months).

Part 4: Strategies for Widespread Progression Without Identifiable Resistance Mechanisms

1. Immune Therapy Combinations

• Studies: The TATTON trial reported significant immune-related adverse events (22% ILD incidence) with osimertinib + durvalumab. Immune checkpoint inhibitors (ICIs) combined with TKIs are not recommended due to safety concerns.

2. Immune Therapy + Chemotherapy

• KEYNOTE-789 and CheckMate722: Both trials failed to show significant PFS or OS improvements for ICIs combined with chemotherapy post-EGFR-TKI failure.

3. Immune Therapy + Anti-Angiogenesis + Chemotherapy

• IMpower150: Demonstrated significant OS and PFS benefits for the ABCP regimen (atezolizumab + bevacizumab + carboplatin + paclitaxel) in EGFR-mutant NSCLC post-TKI failure.
• ORIENT-31: Showed significant PFS benefits with sintilimab + chemotherapy + anti-angiogenesis agents, leading to its NMPA approval for EGFR-TKI-resistant NSCLC.

Part 5: Emerging Bispecific Antibodies and ADCs

1. Bispecific Antibodies

• Amivantamab: Shows intracranial efficacy and survival benefits in combination with chemotherapy post-osimertinib resistance.
• AK112 (envafolimab): Improves PFS and shows promise as a new standard for resistant EGFR-mutant NSCLC.

2. ADCs

• HER3-DXd: Demonstrates promising efficacy in HER3-positive NSCLC with ORR at 29.8% and PFS improvement in ongoing trials.
• TROP2 ADCs: Trop-2-targeted agents like Dato-DXd and SKB264 show significant efficacy in TKI-resistant NSCLC, with ongoing trials.

Conclusion:

Professor Zhang highlighted that while resistance to third-generation EGFR-TKIs remains a significant hurdle, tailored strategies based on resistance mechanisms can improve survival. Key takeaways include:

• Local therapies combined with TKIs are effective for oligoprogression and CNS metastases.
• Bispecific antibodies and ADCs represent the future of treatment, with ongoing trials poised to redefine post-resistance strategies.
• Despite advancements, larger Phase III trials are needed to validate current findings and optimize treatment protocols.

Dr. Bicheng Zhang

• MD, PhD, Chief Physician, Associate Professor, Doctoral Supervisor
• Director, Oncology Department, Wuhan University People’s Hospital Shouyi Campus
• Vice Chair, Expert Committee on Oncology, National Health Commission
• Standing Committee Member, CSCO Immunotherapy and Patient Education Committees
• Member, Chinese Anti-Cancer Association (CACA) Tumor Biomarkers Committee