Editor's Note: The emergence of targeted therapy has ushered in an era of precision medicine for non-small cell lung cancer (NSCLC), leveraging specific targets on tumor cells to block growth signaling pathways, thereby inhibiting tumor progression and extending patient survival. Recent years have seen continuous iteration and optimization of targeted therapies, improving both their clinical efficacy and safety while enhancing the quality of life for NSCLC patients. As the year draws to a close, Oncology Frontier invited Dr. Yi-Long Wu from Guangdong Provincial People's Hospital to review the 2024 advances in NSCLC targeted therapy, including new drug development, combination strategies, efficacy prediction, and prospects for the future.Innovations in Drug Development
ROS1
For patients with ROS1-positive advanced NSCLC, crizotinib was previously the standard treatment. However, its efficacy, particularly in terms of progression-free survival (PFS), was limited to less than a year.
The TRIDENT-1 study, a global phase I/II clinical trial, evaluated the efficacy of repotrectinib (a ROS1-targeted TKI) in ROS1-positive or NTRK-positive advanced or metastatic solid tumors. The phase II portion included four cohorts of ROS1-positive advanced or metastatic NSCLC patients based on treatment history. Among the TKI-naïve cohort (71 patients) with a median follow-up of 33.9 months, the confirmed overall response rate (cORR) was 79%, with a median duration of response (DoR) of 34.1 months and a median PFS of 35.7 months, showcasing sustained clinical activity in this population.
In addition, a phase II trial assessing lorlatinib as a later-line therapy for ROS1-positive NSCLC demonstrated robust tumor and intracranial responses, with an ORR of 44.6%, intracranial ORR of 62.5%, and a median PFS of 17.9 months.
The TRUST-I study, a multicenter, single-arm, open-label phase II clinical trial conducted in China, evaluated taletrectinib for locally advanced or metastatic ROS1-positive NSCLC. For TKI-naïve patients, taletrectinib achieved an impressive median PFS of 45.6 months, significantly extending survival. Taletrectinib and lorlatinib’s efficacy in second- and later-line settings further establishes a robust treatment strategy for ROS1-positive NSCLC, providing longer survival and greater clinical benefit for patients.
KRAS G12C
In 2024, two KRAS G12C inhibitors were approved in China: fuzeritinib and geseritinib.
Fuzeritinib’s approval was based on a single-arm phase II registration trial conducted in China. The study evaluated fuzeritinib monotherapy in patients with advanced NSCLC harboring KRAS G12C mutations who had failed standard treatments or were intolerant to them. With a median follow-up of 15.1 months, the ORR was 49.1%, the disease control rate (DCR) was 90.5%, and the median DoR had not yet been reached, with a 12-month DoR rate of 53.7%. The median PFS was 9.7 months, with a 12-month PFS rate of 37.9%, and the median OS was not yet reached, with a 12-month OS rate of 54.4%. Subgroup analyses showed consistent benefits across all groups, including patients with brain metastases, who often have a poorer prognosis.
Geseritinib’s approval was based on the phase II D1553-102 study, which included adult NSCLC patients with KRAS G12C mutations across 43 hospitals in China. At a median follow-up of 12.3 months, the ORR was 52.0%, DCR was 88.6%, median PFS was 9.1 months, and median OS was 14.1 months.
The approval of these two drugs marks a significant milestone, addressing the long-standing lack of treatment options for KRAS G12C-mutated NSCLC patients in China.
HER2 Mutations
Two promising low-toxicity small-molecule drugs for HER2-mutated NSCLC, Zongertinib and BAY2927088, are currently under clinical investigation. At the 2024 ESMO Asia Congress, the BEAMION LUNG-1 trial released results from its phase Ib cohort 1 study, evaluating the efficacy of Zongertinib (BI 1810631) in pre-treated advanced NSCLC patients with HER2 mutations. Confirmed by central review, Zongertinib demonstrated an ORR of 71% and a DCR of 93%. Preliminary survival data highlighted durable responses, with 6-month PFS and DoR rates of 69% and 73%, respectively. At the data cutoff, 55% of patients remained on treatment.
As an investigational drug, Zongertinib’s remarkable efficacy and favorable safety profile position it as a strong competitor to existing ADCs. If a small-molecule drug can surpass current monoclonal antibodies and ADCs in effectiveness and safety, it could significantly enhance patient adherence. Further clinical data are eagerly awaited to accelerate its transition to clinical application.
c-MET Gene Amplification
The phase II INSIGHT-2 study assessed the efficacy and safety of combining MET-TKI tepotinib with third-generation EGFR-TKI osimertinib in EGFR-mutant NSCLC patients with MET amplification-induced osimertinib resistance. Results showed a confirmed ORR of 50.0%, a median PFS of 5.6 months, and a median OS of 17.8 months. These findings suggest that this combination offers a therapeutic advantage for MET amplification-mediated resistance in EGFR-mutant NSCLC.
Other ongoing studies, such as SAFFRON and SACHI, are further evaluating the role of EGFR and MET combination therapies.
In first-line treatment for EGFR-mutant NSCLC with MET amplification, the FLOWERS study compared osimertinib plus savolitinib to osimertinib monotherapy. Investigator-assessed ORR was 90.5% in the combination group versus 60.9% in the monotherapy group. Median PFS was 19.6 months versus 9.3 months, with an HR of 0.59 (95% CI 0.19–1.81).
The SANOVA study, which investigates the combination of savolitinib and osimertinib for first-line treatment of EGFR-mutant NSCLC with MET overexpression in Chinese patients, has not yet published its results but holds significant promise.
The phase II LUMINOSITY study evaluated telisotuzumab vedotin in non-squamous, EGFR wild-type NSCLC patients with c-MET protein overexpression. Results indicated an ORR of 35.4%, with ORR of 34.6% in c-MET high-expressing patients and 22.9% in moderately expressing patients. Median DoR, PFS, and OS were favorable, leading to savolitinib’s designation as a breakthrough therapy by China’s NMPA on December 12, 2024, for use in combination with osimertinib in MET-amplified advanced NSCLC following EGFR-TKI failure.
The convergence of research on MET amplification and EGFR-TKI resistance underscores the potential for precise targeted therapies to revolutionize the treatment landscape in 2025.
First-Line Resistance Strategies for NSCLC
The mechanisms of resistance in driver gene-positive NSCLC have been extensively studied and can be classified into five categories:
- On-pathway resistance, involving additional mutations in the original signaling pathway, such as EGFR T790M mutations or EGFR amplifications.
- Off-pathway resistance, driven by activation of bypass or downstream pathways, such as BRAF, HER2, or MET amplification.
- Co-mutations, where other mutations coexist with the primary driver mutation.
- Histological transformation, such as adenocarcinoma transitioning to small-cell lung cancer.
- Unidentified mechanisms, accounting for approximately 40% of cases.
Tailoring treatments based on identified resistance mechanisms allows for more precise therapy. The HARMONi-A study, a randomized phase III trial, compared chemotherapy plus ivonescimab (a PD-1/VEGF bispecific antibody) to chemotherapy alone in EGFR-TKI-resistant NSCLC. Results showed significantly prolonged PFS with a trend toward improved OS, establishing a new treatment option for EGFR-TKI-resistant NSCLC treatment that does not require identifying specific resistance mechanisms. ADC therapies and dual-targeted approaches combining EGFR and MET inhibitors also show promising efficacy in this setting. For driver gene-negative NSCLC, first-line immunotherapy resistance remains poorly understood. Further exploration is necessary to identify effective strategies to overcome resistance.
The Role of Biomarkers in NSCLC Targeted Therapy
Biomarkers play an increasingly vital role in predicting the efficacy of targeted therapies, enabling optimized treatment strategies for specific patient populations. Established biomarkers, such as EGFR, ALK, ROS1, and KRAS, continue to guide clinical decisions, while new targets are under exploration. For example, the role of primary MET amplification as a driver mutation remains under investigation. In immunotherapy, STK11, KEAP1, and EGFR mutations have been confirmed as markers of resistance, with ongoing research into counteracting these mechanisms. Emerging targets such as SMARCA4 are also being actively pursued.
Technologies like artificial intelligence (AI) are accelerating the discovery of new biomarkers, offering fresh momentum for solving complex medical challenges.
Future Prospects for Precision NSCLC Treatment
The rapid advancement of precision medicine and innovative therapies has improved clinical outcomes for lung cancer patients. Professor Wu highlighted key areas of future development:
Adaptive Therapy: This approach tailors treatments based on dynamic changes in biomarkers, allowing for optimized interventions that balance efficacy, quality of life, and cost-effectiveness. Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) monitoring is a pivotal biomarker in adaptive therapy. Efforts to improve its predictive accuracy to over 95% could significantly guide treatment decisions, such as de-escalation strategies after surgery or chemoradiotherapy in early- and advanced-stage NSCLC.
Drug : The CTONG-1602 trial introduced the concept of “drug holidays” for patients with EGFR/ALK/ROS1 mutations who achieved CR following targeted therapy combined with surgery or radiotherapy. ctDNA monitoring provided a basis for de-escalating therapy while maintaining survival benefits, reducing treatment burdens, and paving the way for broader adoption of adaptive treatment models.
Dr. Yi-Long Wu
- Professor of Oncology, Guangdong Provincial People’s Hospital
- Recipient of the IASLC Distinguished Scientist Award
- Vice President of the Chinese Medical Doctor Association
- President of the Guangdong Medical Doctor Association (GDMDA)
- Chief Expert at Guangdong Provincial People’s Hospital (GDPH)
- Honorary Director of Guangdong Lung Cancer Institute (GLCI)
- Chair of the Chinese Thoracic Oncology Group (CTONG)
- Highly Cited Scientist in Clinical Medicine (2018–2024)
- Honorary President and Founding Chair of the Chinese Society of Clinical Oncology (CSCO)
