This study investigated the efficacy and safety of Tunlametinib Combination Therapy in KRAS-Mutated Unresectable Locally Advanced or Metastatic Non-Small Cell Lung Cancer.
Informed consent, all participants will provide written informed consent.
Participants older than 18 years of age signed their own informed consent form.
The TNM staging was classified according to the 8th edition of the AJCC Cancer Staging Manual of the American Joint Committee on Cancer (AJCC). Eligible patients had histologically or cytologically confirmed unresectable, locally advanced, or metastatic NSCLC9(IIIB、IIIC、IV).
Eligible patients had failed, were intolerant to first-line standard treatment after diagnosis.
Subjects had received anticancer drugs or investigational drugs within the following time window: 1) Any KRAS G12C mutation inhibitor within 3 years prior to the first dose in this study, including but not limited to Sotorasib (AMG510), Adagrasib (MRTX849), IBI351 (GFH925), Glecirasib (JAB-21822), JDQ443, LY3537982, and GDC-6036; 2) Cituximab or its analogues within 3 years prior to the first dose of this study; 3) Prior MEK inhibitor therapy; 4) Any anticancer therapy (including chemotherapy, targeted therapy, immunotherapy, etc.) or any other investigational drug within 28 days prior to the first dose of this study; 5) Received traditional Chinese patent medicines with explicit antitumor indications in NMPA-approved drug labels within 2 weeks prior to the first dose of this study (including Compound Mylabris Capsules, Kang'ai Injection, Kanglaite Capsules/Injection, Aidi Injection, Yadanzi Oil Injection/ capsules, Xiaoaiping tablets/injection, Huachansu capsules, etc.) within 28 days prior to receiving any anticancer therapy (including chemotherapy, targeted therapy, immunotherapy, etc.) or any other investigational drug therapy in this study; and 6) Received known CYP2D6, CYP3A4, P-gp, and BCRP sensitive substrates with narrow therapeutic windows within 14 days prior to study dosing or within 5 drug half-lives (whichever is longer), unless the participants are approved for inclusion by the researchers and all parties involved..
NSCLC with other driver gene mutations that have standard treatment drugs (such as EGFR, ALK, BRAF(V600E), HER-2, MET(exon14), ROS1, RET or NTRK1/2/3, etc.) in the past.
Concurrent primary malignancies are permitted, except in the following circumstances: Other malignancies treated with a single surgical procedure, with complete remission for at least 3 years prior to enrollment; or Untreated basal cell carcinoma or carcinoma in situ (e.g., carcinoma in situ of the skin, breast carcinoma in situ, cervical carcinoma in situ); Prostate cancer requiring only clinical monitoring without treatment.
Symptomatic or progressively worsening CNS metastases or carcinomatous meningitis. Subjects with a history of brain metastases may be considered for inclusion if clinically stable, provided they meet all of the following criteria: 1) Absence of neurological symptoms, no requirement for corticosteroid therapy, and no indication for radiotherapy; the largest lesion on the most recent pre-enrollment imaging study must have a maximum diameter ≤1.5 cm. 2) Active CNS metastases (e.g., brain or meningeal metastases) are not eligible for enrollment. For subjects with brain metastases who have undergone radiotherapy or local treatment: - If no corticosteroids or antiepileptic drugs were used, asymptomatic status must be maintained for at least 7 days after radiotherapy completion. - If corticosteroids or antiepileptic drugs were used, symptomatic status must be maintained for at least 7 days after discontinuation, and the investigator must assess brain metastases as stable and controlled. 3) For subjects asymptomatic after CNS radiotherapy, corticosteroids must have been discontinued for at least 2 weeks prior to the first study dose.
Parallel
Tunlametinib + Cetuximab β
DrugStudy Population: Previously treated subjects with KRAS (non-G12C) mutation-positive, unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC) (n=6). Treatment Regimen: Tunlametinib + Cetuximab β Injection Starting Dose Cohort: Tunlametinib: 9 mg per dose, administered orally twice daily (BID). Cetuximab β Injection: 500 mg/m² per dose (calculated based on body surface area), administered intravenously once every two weeks. Cycle Definition: Every 4 weeks constitutes one treatment cycle. Second Dose Cohort: Tunlametinib: 12 mg or 6 mg per dose, administered orally twice daily (BID). Rationale: This cohort aims to identify the optimal dose. From the perspective of maximizing subject benefit, the dose may be either reduced or increased. Therefore, the dose is subject to dynamic adjustment based on ongoing clinical trial observations, rather than following a traditional dose-escalation design. Investigators will continuously review safety data from subjects a
Tunlametinib + Fulzerasib
DrugStudy Population: Previously treated subjects with KRAS G12C mutation-positive, unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC) (n=6). Treatment Regimen: Tunlametinib + Fluorescein Starting Dose Cohort: Tunlametinib: 9 mg per dose, administered orally twice daily (BID). Fluorescein: 600 mg per dose, administered orally twice daily (BID). Cycle Definition: Every 4 weeks constitutes one treatment cycle. Second Dose Cohort: Tunlametinib: 12 mg or 6 mg per dose, administered orally twice daily (BID). Fluorescein: 600 mg per dose, administered orally twice daily (BID). Cycle Definition: Every 4 weeks constitutes one treatment cycle.
Objective Response Rate (ORR)
Defined as the percentage of subjects achieving complete response (CR) or partial response (PR) as assessed by RECIST 1.1.
Progression Free Survival (PFS)
Defined as the time from randomization to the date of first documentation of from date of randomization until the date of first documented progression or date of death from any cause, whichever came first
Disease Control Rate (DCR)
DCR was defined as the proportion of CR+PR+SD subjects to total subjects
Duration of Response (DoR)
DoR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death
Incidence and severity of adverse events (AEs)
Overall incidence of AEs; the incidence of grade 3 or above AEs; the incidence of severe adverse events (SAE); the incidence of drug-related AEs; the incidence of AEs resulting in permanent withdrawal of drugs; the incidence of AEs leading to dose adjustment.
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