Sequential pemetrexed + carboplatin followed by befotertinib for EGFR‑mutant NSCLC after resistance to third‑generation EGFR inhibitors

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

This treatment plan will see if giving pemetrexed plus carboplatin followed by the oral drug befotertinib helps people with EGFR‑mutant non‑small cell lung cancer who have stopped responding to third‑generation EGFR inhibitors.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 28 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Betta Pharmaceuticals Co., Ltd. (industry)
• Drugs / interventions: chemotherapy, immunotherapy, amivantamab, sintilimab, bevacizumab, lazertinib, ivucitinib, befitinib, befotertinib
• Locations: 2 sites (Guangzhou, Guangdong and 1 other locations)
• Trial ID: NCT07181499 on ClinicalTrials.gov

What this trial studies

This Phase 2 study enrolls patients with advanced or metastatic non‑squamous NSCLC harboring EGFR sensitizing mutations (exon 19 deletion or L858R) who have developed resistance to third‑generation EGFR TKIs. Participants receive a course of pemetrexed plus carboplatin chemotherapy followed by oral befotertinib, with safety and feasibility as primary concerns. Patients with histologic transformation to small cell or squamous carcinoma or with other clear actionable driver alterations are excluded. The trial is being run at two Sun Yat‑sen University affiliated cancer centers in Guangdong, China.

Who should consider this trial

Good fit: Ideal candidates are adults with advanced or metastatic non‑squamous NSCLC carrying EGFR sensitizing mutations (19del or L858R), documented resistance to third‑generation EGFR TKIs, ECOG 0–2, adequate organ function, and ability to take oral medication.

Not a fit: Patients with small cell or squamous transformation, or with other targetable driver mutations such as HER2, MET amplification, KRAS G12C, BRAF V600E, RET, ALK, or NTRK fusions are unlikely to benefit from this regimen.

Why it matters

Potential benefit: If successful, this approach could extend the time without disease progression after resistance to third‑generation EGFR inhibitors and offer an additional treatment option.

How similar studies have performed: Related approaches combining chemotherapy with targeted or antibody agents have modestly improved post‑TKI progression‑free survival in prior studies (e.g., MARIPOSA‑2), and befotertinib has shown promising PFS in earlier settings, but the specific sequential chemo‑then‑befotertinib strategy is relatively novel.

Eligibility criteria

Inclusion Criteria:

1. Age ≥18 years;
2. 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);
3. 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.;
4. ECOG performance status (PS) score of 0-2;
5. Life expectancy of at least 12 weeks;
6. Ability to swallow oral medications;
7. Adequate organ system function, defined as follows and determined based on investigator judgment:

   1. Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L
   2. Platelets ≥ 100 x 10⁹/L;
   3. Hemoglobin ≥ 9 g/dL (≥ 90 g/L). Note: Blood transfusions are permitted to achieve the required hemoglobin level;
   4. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN);
   5. If no liver metastases: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; if liver metastases present: ≤ 5 × ULN;
   6. 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);
8. 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.
9. Voluntarily agree and be capable of adhering to the trial and follow-up procedures.
10. Be able to understand the nature of the trial and complete the written informed consent form.

Exclusion Criteria:

1. Rare EGFR mutations;
2. Prior treatment with pemetrexed and platinum-based chemotherapy regimens;
3. Advanced and/or symptomatic brain metastases (measurable or non-measurable) and/or leptomeningeal metastases;
4. 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;
5. 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;
6. 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;
7. 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.
8. 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;
9. 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;
10. 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;
11. Other conditions deemed by the investigator to be unsuitable for participation in this trial.

Where this trial is running

Guangzhou, Guangdong and 1 other locations

• Sun Yat-sen University Cancer Center — Guangzhou, Guangdong, China (RECRUITING)
• The Cancer Center of The Fifth Affiliated Hospital of Sun Yat-sen University — Zhuhai, Guangdong, China (RECRUITING)

Study contacts

• Principal investigator: YingNi Lian — First People's Hospital of Zhaoqing
• Study coordinator: Shaodong Hong

Conditions: NSCLC, Adjuvant Drug Therapy, EGFR