In a retrospective analysis of 3,054 advanced NSCLC patients, 41 with EGFR exon 19 deletion-insertions (19delins) received first-generation EGFR TKIs, achieving median PFS of 10.4 months; those with L747_T751delinsP had notably longer PFS of 18.7 months. Another study of 2,467 treatment-naïve patients found 93 with 19delins treated with first-generation TKIs had median PFS of 19 months, exceeding the 13 months for common 19del mutations. For third-generation TKIs, a study of 215 19delins patients (57 first-line) showed median PFS of 12.9 months, inferior to 23.2 months for common 19del. Our center's retrospective study of 4,666 NSCLC patients in Fujian (2017-2020) included 69 with 19delins: median PFS was 16.7 months with first-generation TKIs versus 7.2 months with third-generation. Evidence suggests specific EGFR deletion locations may affect TKI efficacy; first-generation TKIs may be superior in some 19delins subtypes, while third-generation appear limited. Large prospective data are lacking. This project aims to compare first- versus third-generation EGFR TKIs in 19delins patients via a randomized controlled trial, stratify sensitivity by subtype, and improve survival.

In a retrospective analysis of 3,054 patients with advanced non-small cell lung cancer (NSCLC), a total of 41 patients with EGFR exon 19 deletion-insertion mutations (19delins) were enrolled, all of whom received first-generation EGFR TKIs. The results showed a median progression-free survival (PFS) of 10.4 months, among which patients with L747_T751delinsP had a median PFS of 18.7 months, which appeared superior to that of patients with other 19delins mutations.

Another retrospective study analyzed 2,467 treatment-naïve patients with locally advanced NSCLC, among whom 93 patients with EGFR exon 19delins mutations were treated with first-generation EGFR TKIs (gefitinib, erlotinib). The median PFS was 19 months in patients with EGFR 19delins mutations, which was longer than that (13 months) in patients with common EGFR 19del mutations treated with first-generation EGFR TKIs during the same period.

However, regarding third-generation EGFR TKIs, a retrospective study enrolled 215 patients with EGFR 19delins mutations, including 57 patients treated with third-generation EGFR TKIs (osimertinib, furmonertinib, aumolertinib) as first-line therapy. The median PFS reached 12.9 months, which was lower than that (23.2 months) in patients with common EGFR 19del mutations.

This result is consistent with our center's previously published findings. A retrospective study of 4,666 NSCLC patients with EGFR mutations in Fujian Province from January 2017 to December 2020 included 69 patients with the EGFR exon 19delins subtype. The median PFS was 16.653 months in patients receiving first-generation EGFR TKIs and 7.179 months in those receiving third-generation EGFR TKIs.

Collectively, available evidence suggests that the specific location and structural variation type of EGFR deletions may affect the efficacy of different generations of TKIs. Especially for rare mutations such as 19delins, first-generation TKIs may show better efficacy in certain subtypes, while the efficacy of third-generation TKIs is relatively limited.

At present, large-scale prospective clinical data are still lacking for this type of mutation, and the optimal targeted therapeutic strategy remains to be further explored.

This project aims to clarify the efficacy and safety of first-generation versus third-generation EGFR TKIs in patients with EGFR exon 19delins mutations through a prospective, randomized controlled trial, further stratify the sensitivity of EGFR TKIs in patients with different EGFR mutation subtypes, and achieve longer survival benefits.

Inclusion Criteria:

• Age ≥ 18 years;
• Histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer (NSCLC) (AJCC Cancer Staging Manual, 9th edition, Stage IIIB, IIIC or IV) that is not amenable or suitable for surgical resection or other radical therapies, as assessed by the investigator;
• Epidermal growth factor receptor (EGFR) exon 19 deletion-insertion mutation (19delins) documented by testing of tumor tissue or plasma samples using methods including IHC, NGS, ARMS, etc.;
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1;
• No prior systemic anti-tumor therapy for locally advanced or metastatic NSCLC;
• Life expectancy ≥ 12 months;
• At least one measurable lesion by imaging in the screening period according to RECIST v1.1;
• Ability to swallow and retain oral medication;
• Adequate organ system function;
• Female subjects of childbearing potential must have a negative serum pregnancy test within 7 days prior to initiation of study treatment, and agree to use a medically accepted highly effective method of contraception during the study and for 3 months after the last dose of study drug;
• Voluntary and able to comply with study and follow-up procedures; Ability to understand the nature of the trial and provide written informed consent.

Exclusion Criteria:

• Advanced and/or symptomatic brain metastases (measurable or non-measurable) and/or leptomeningeal metastases;
• Active hepatitis B, positive for hepatitis C virus antibody, positive for human immunodeficiency virus (HIV) antibody, or positive for Treponema pallidum antibody;
• Women of childbearing potential with a positive serum pregnancy test within 7 days prior to initiation of treatment, pregnant or lactating women, or male and female subjects who are not using effective contraception or plan to conceive during the entire treatment period and for 3 months after the end of treatment;
• Patients who have used any of the following medications within 14 days prior to the first dose or require concomitant use of such medications during treatment: drugs with a risk of causing QTc prolongation and/or torsade de pointes; strong inhibitors or strong inducers of CYP3A;
• Underwent major surgery or immunotherapy within 4 weeks prior to the first dose; received radiation therapy within 2 weeks prior to the first dose;
• Patients with imaging evidence of tumor invasion of major blood vessels, or those judged to have a very high likelihood of tumor invasion of critical blood vessels leading to fatal massive hemorrhage during the subsequent study period;
• History of interstitial lung disease, drug-induced interstitial disease, or any clinically evident active interstitial lung disease; presence of idiopathic pulmonary fibrosis on baseline CT scan;
• Other severe, acute, or chronic medical conditions that, in the investigator's opinion, may increase the risk associated with study participation or may interfere with the interpretation of study results, including uncontrolled diabetes mellitus, medical or psychiatric illnesses, or laboratory abnormalities;
• Any other conditions deemed by the investigator to make the subject unsuitable for participation in this trial.