Sequential Chemotherapy With Befotertinib in Non-Small Cell Lung Cancer (NSCLC) Patients With Resistance to Third-Generation EGFR-TKI

Official title

A Study Evaluating the Efficacy and Safety of Pemetrexed Combined With Platinum-Based Chemotherapy Followed by Befotertinib in Patients With Non-Small Cell Lung Cancer After Third-Generation EGFR TKI Resistance

Overview

Non-small cell lung cancer (NSCLC) accounts for over 85% of lung cancers. Approximately 30-40% of East Asian adenocarcinoma patients harbor EGFR mutations. Third-generation EGFR-TKIs achieve a median PFS of about 20 months as first-line therapy, but resistance eventually develops. Studies like MARIPOSA-2 confirm that amivantamab combined with chemotherapy ± lazertinib or immunotherapy regimens (ivucitinib/sintilimab + bevacizumab + chemotherapy) can extend median PFS post-resistance from approximately 4 months to 6-8 months. As a third-generation TKI, befitinib has demonstrated PFS of 16-22 months in both first-line and post-T790M mutation settings. This study aims to further evaluate the feasibility and safety of "pemetrexed + carboplatin followed by befotertinib" for patients resistant to third-generation TKIs.

Interventions

• Drug Befotertinib
  Befotertinib was administered orally at a starting dose of 75 mg per day for 21 days, which could be increased to 100 mg per day if grade 2 or higher thrombocytopenia or headache did not occur within 21 days, or maintained at the original dose (75 mg per day) if grade 2 or higher thrombocytopenia or headache occurred within 21 days.
• Drug Pemetrexed + Carboplatin
  pemetrexed (500 mg/m²) and carboplatin (AUC 5), administered every 3 weeks, for a total of 2\~4 cycles.

Primary outcome measures

• progression free survival [Time frame: From enrollment to the end of treatment at 12 months]

Secondary outcome measures (4)

• objective remission rate [Time frame: From enrollment to the end of treatment at 12 month]
• Disease control rate [Time frame: From enrollment to the end of treatment at 12 months]
• overall survival [Time frame: From enrollment to the end of treatment at 36 months]
• adverse event [Time frame: From enrollment to the end of treatment at 12 months]

Eligibility criteria

Inclusion criteria

• Age ≥18 years;
• Histologically or cytologically confirmed advanced or metastatic non-squamous NSCLC; and prior resistance to third-generation EGFR TKIs, with EGFR-sensitive mutations confirmed via tissue or blood samples (defined as: 19 Del or 21 L858R);
• Exclusion of small cell lung cancer (SCLC) or squamous cell carcinoma (SqCC) transformation, and known NSCLC with clear targetable mutations for targeted therapy, such as HER2, MET amplification (GCN ≥ 5), KRAS G12C mutation, BRAF V600E mutation, RET fusion mutation, ALK fusion mutation, NTRK fusion mutation, etc.;
• ECOG performance status (PS) score of 0-2;
• Life expectancy of at least 12 weeks;
• Ability to swallow oral medications;
• Adequate organ system function, defined as follows and determined based on investigator judgment:

• Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L
• Platelets ≥ 100 x 10⁹/L;
• Hemoglobin ≥ 9 g/dL (≥ 90 g/L). Note: Blood transfusions are permitted to achieve the required hemoglobin level;
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN);
• If no liver metastases: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; if liver metastases present: ≤ 5 × ULN;
• Creatinine ≤1.5 × ULN. If ≥1.5 × ULN, patients remain eligible if the Cockcroft-Gault-calculated creatinine clearance ≥50 mL/min (0.83 mL/s);
• Female subjects of childbearing potential must have a negative serum pregnancy test within 3 days prior to study drug initiation and agree to use a medically approved highly effective contraceptive method (e.g., intrauterine device, oral contraceptives, or condoms) during the study and for 3 months after the last study drug administration; Male subjects with female partners of childbearing potential must be surgically sterilized or agree to use an effective method of contraception during the study period and for 3 months after the last study dose.
• Voluntarily agree and be capable of adhering to the trial and follow-up procedures.
• Be able to understand the nature of the trial and complete the written informed consent form.

Exclusion criteria

• Rare EGFR mutations;
• Prior treatment with pemetrexed and platinum-based chemotherapy regimens;
• Advanced and/or symptomatic brain metastases (measurable or non-measurable) and/or leptomeningeal metastases;
• Active hepatitis B (serum HBV DNA ≥10⁴ copies/mL \[i.e., 20,000 IU/mL\]), hepatitis C virus antibody positive, HIV antibody positive, or treponema pallidum antibody positive;
• Women of childbearing potential with a positive serum pregnancy test within 7 days prior to treatment initiation, pregnant or lactating women, or male and female subjects not using effective contraception or planning pregnancy during treatment and for 3 months post-treatment;
• Patients who used or require concomitant use of the following drugs within 14 days prior to the first dose or during treatment: drugs associated with QTc prolongation and/or risk of torsades de pointes ventricular tachycardia; strong CYP3A inhibitors or inducers;
• Patients who underwent major surgery or immunotherapy within 4 weeks prior to the first dose; patients who received radiotherapy within 2 weeks prior to the first dose.
• Imaging (CT or MRI) demonstrating tumor invasion of major vessels, or a high likelihood of tumor invasion into critical vessels causing fatal hemorrhage during the study period;
• History of interstitial lung disease, drug-induced interstitial disease, or any clinically evident active interstitial lung disease; presence of idiopathic pulmonary fibrosis identified on baseline CT scan;
• Other severe acute or chronic medical conditions, including uncontrolled diabetes, medical or psychiatric disorders, or laboratory abnormalities, that in the investigator's judgment may increase study-related risks or interfere with interpretation of study results;
• Other conditions deemed by the investigator to be unsuitable for participation in this trial.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 2 centers

• Sun Yat-sen University Cancer Center — Guangzhou
• The Cancer Center of The Fifth Affiliated Hospital of Sun Yat-sen University — Zhuhai

Identifiers

NCT: NCT07181499 · BD-BF-IV028

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗