Phase 3 Study to Investigate the Efficacy and Safety of Furmonertinib Compared to Platinum-Based Chemotherapy as First-Line Treatment for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer.

JRCT ID: jRCT2011230009

Registered date:03/06/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Locally advanced or metastatic non-squamous non-small cell lung cancer
• Date of first enrollment: 14/08/2023
• Target sample size: 42
• Countries of recruitment: Australia,Japan,France,Japan,Taiwan,Japan,Netherlands,Japan,Spain,Japan,South Korea,Japan,Thailand,Japan,Philippines,Japan,Singapore,Japan,Brazil,Japan,Malaysia,Japan,Israel,Japan,Mexico,Japan,UK,Japan,Canada,Japan,Belgium,Japan,Hungary,Japan,China,Japan
• Study type: Interventional

Intervention(s)

Patients will be randomized in a 1:1:1 ratio to treatment with furmonertinib 240 mg QD, furmonertinib 160 mg QD, or platinum-based chemotherapy.
During the Treatment Period, study drug will be administered in 21-day cycles. Patients assigned to furmonertinib will take the assigned dose daily. Patients assigned to chemotherapy will receive platinum-based chemotherapy (carboplatin or cisplatin based on investigator's choice) + pemetrexed intravenously (IV) on Day 1 of each 21-day cycle for 4 cycles, followed by maintenance therapy with pemetrexed as per local standard of care.

Outcome(s)

• Primary Outcome: PFS, where PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Patients must meet the following criteria for study entry:
1. Signed Informed Consent Form
2. Age >= 18 years at time of signing Informed Consent Form
3. Ability to comply with the study protocol, in the investigator's judgment
4. Measurable disease per RECIST v1.1
5. Histologically or cytologically documented, locally advanced or metastatic non-squamous NSCLC not amenable to curative surgery or radiotherapy
6. Documented results of the presence of an EGFR exon 20 insertion mutation (i.e., addition of 1 or more amino acids) in tumor tissue or blood from local or central testing via a validated next-generation sequencing (NGS) or a validated polymerase chain reaction (PCR) assay performed at a Clinical Laboratory Improvement Amendments (CLIA) or equivalently certified laboratory or in a laboratory certified by a nationally recognized entity.
7. Consent to provide archival tumor tissue specimen (formalin-fixed, paraffin-embedded [FFPE] tissue block [preferred] or at least 15 unstained, serially cut sections on slides from FFPE tumor specimen). The specimens should be provided during screening or no later than within 30 days of Cycle 1, Day 1 and must be accompanied by a pathology report.
8. No prior systemic anticancer therapy regimens received for locally advanced or metastatic NSCLC including prior treatment with any EGFR-targeting agents (e.g., previous EGFR tyrosine kinase inhibitors (EGFR-TKIs), monoclonal antibodies, or bispecific antibodies)
9. Patients who have received prior neo-adjuvant and/or adjuvant chemotherapy, immunotherapy, or chemoradiotherapy for non-metastatic disease must have experienced a treatment-free interval of at least 12 months.
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
11. Life expectancy of >= 12 weeks
12. Adequate hematologic and organ function within 14 days prior to initiation of study treatment, defined by the following:
- Absolute neutrophil count >= 1500/microL
- Hemoglobin >= 9 g/dL
- Platelet count >= 100,000/microL
- Total bilirubin <= 1.5 x upper limit of normal (ULN) or <= 3 x ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia)
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (AP) <= 2.5 x ULN, with the following exceptions:
-- Patients with documented liver metastases may have AST, ALT, and/or AP <= 5.0 x ULN.
-- Patients with documented bone metastases may have AP <= 5.0 x ULN.
- Creatinine clearance >= 45 mL/min on the basis of the Cockcroft-Gault estimation
- International normalized ratio (INR) <= 1.5 x ULN and activated partial thromboplastin time (aPTT) <= 1.5 x ULN
13. For women of childbearing potential (WOCBP): Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined below:
- A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state >= 12 continuous months of amenorrhea with no identified cause other than menopause, and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Mullerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.
- WOCBP must remain abstinent or utilize a barrier method such as a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and at least 6 months after discontinuation of furmonertinib treatment. WOCBP must refrain from donating eggs during the Treatment Period and 6 months after discontinuation of furmonertinib treatment.
- Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
- The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
- WOCBP (including those who have had a tubal ligation) should not be breastfeeding and must have a negative serum pregnancy test result within 14 days prior to initiation of study drug.
- WOCBP enrolled in the chemotherapy arm should refer to the local labeling and/or standard local practice for contraception requirements.
14. For men who are not surgically sterile: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm, as defined below:
- With a female partner of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the Treatment Period and for at least 6 months after discontinuation of furmonertinib treatment. Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing furmonertinib treatment.
- The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
15. Patients with CNS metastases are eligible, provided they meet all of the following criteria:
- Measurable disease outside the CNS
- No ongoing requirement for corticosteroids as therapy for CNS metastases, with corticosteroids discontinued for >= 2 weeks prior to enrollment
- No ongoing symptoms attributed to CNS metastases
- No active CNS metastases or spinal cord compression (i.e., progressing or requiring anticonvulsants or corticosteroids for symptomatic control)
- No known or suspected leptomeningeal disease
- Patients with previously treated brain metastases:
-- No evidence of interim CNS disease progression between the completion of previous CNS directed therapy and the screening radiographic CNS imaging
-- Patients may receive local therapy provided that they meet the washout criteria below for WBRT, SRS, or surgical resection.
- Patients treated with CNS local therapy for newly identified lesions found on contrast brain magnetic resonance imaging (MRI) performed during screening may be eligible to enroll if:
-- Time since whole brain radiation therapy (WBRT) is >= 21 days prior to randomization of study treatment, time since stereotactic radiosurgery (SRS) is >= 7 days prior to randomization of study treatment, or time since surgical resection is >= 28 days.

Exclude criteria

Patients who meet any of the following criteria will be excluded from study entry:
1. Inability or unwillingness to swallow pills
2. Inability to comply with study and follow-up procedures
3. Malabsorption syndrome or other conditions that would interfere with enteral absorption
4. Pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures biweekly or more frequently
- Indwelling pleural or abdominal catheters may be allowed, provided the patient has adequately recovered from the procedure, is hemodynamically stable, and has symptomatically improved.
5. Severe acute or chronic infections, including:
- Uncontrolled acute infection, active infection that necessitates systemic treatment, or systemic antibiotic treatment within 2 weeks prior to the first dose of investigational product.
- Patients with uncontrolled human immunodeficiency virus (HIV) infection (defined as CD4+ T cell count < 350 cells/microL).
- Patients with active chronic hepatitis B or with active hepatitis C infection, which includes patients who are hepatitis B surface antigen (HBsAg)-positive, or HbsAg-negative but HbcAb-positive, or hepatitis C virus (HCV) antibody-positive at screening, are not eligible until further definite quantitative testing of hepatitis B virus (HBV) DNA (e.g., <= 2500 copies/mL or 500 IU/mL) and HCV ribonucleic acid (RNA) tests (e.g., <= lower limit of detection) can conclusively rule out presence of active hepatitis B or C infection that requires treatment.
6. In the setting of a pandemic or epidemic, screening for active infections should be considered according to local or institutional guidelines or those of applicable professional societies (e.g., American Society of Clinical Oncology or European Society for Medical Oncology).
7. Previous interstitial lung disease (ILD) (including drug-induced ILD) or active ILD/radiation pneumonitis
8. History of or active clinically significant cardiovascular dysfunction, including the following:
- History of stroke or transient ischemic attack within 6 months prior to first dose of study drug
- History of myocardial infarction within 6 months prior to first dose of study drug
- New York Heart Association (NYHA) Class III or IV cardiac disease or congestive heart failure requiring medication
- Uncontrolled arrhythmias, or history of or active ventricular arrhythmia requiring medication
- Coronary heart disease that is symptomatic or unstable angina
9. Mean resting corrected QT interval (QTc) > 470 msec, obtained from triplicate electrocardiograms (ECGs) based on Fridericia's formula (QTcF)
10. Clinically significant prolonged QT interval or other arrhythmia or clinical status considered by investigators that may increase the risk of prolonged QT interval (e.g., complete left bundle branch block, third-degree atrioventricular block, second degree heart block, PR interval > 250 msec, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives, serious hypokalemia, heart failure) or current use of the drugs that may lead to prolonged QT interval/torsades de pointes.
11. Symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
12. Significant traumatic injury or major surgical procedure within 4 weeks prior to Day 1 of Cycle 1
13. Patients with chronic diarrhea, short bowel syndrome or significant upper GI surgery including gastric resection, a history of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), or any active bowel inflammation (including diverticulitis)
14. Any other diseases, pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or renders the patients at high risk from treatment complications (e.g., uncontrolled hypertension, active bleeding)
15. Radiation therapy (other than palliative radiation to bone metastases and radiation to CNS metastases as described above) as cancer therapy within 4 weeks prior to initiation of study treatment
16. Palliative radiation to bone metastases within 2 weeks prior to initiation of study drug
17. Any unresolved toxicities from prior therapy (e.g., adjuvant chemotherapy) > Grade 1 at initiation of study drug, with the exceptions of alopecia and prior platinum therapy-related Grade 2 neuropathy
18. History of other malignancy within 3 years prior to screening, with the exception of patients with a negligible risk of metastases or death and/or treated with expected curative outcome (such as appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, or ductal carcinoma in situ)
19. Pregnant or breastfeeding or intending to become pregnant during the study or within 6 months after the final dose of furmonertinib
20. Use of a strong cytochrome P450 3A4 (CYP3A4) inhibitor within 7 days prior to the first dose of investigational product or a strong CYP3A4 inducer within 21 days prior to the first dose of investigational product
21. Use of traditional Chinese medicines/herbal medicines indicated for the treatment of cancer within 2 weeks prior to the first dose of investigational product
22. History of allergic reactions to any components, including excipients, of the furmonertinib drug product
23. History of allergic reactions to pemetrexed, cisplatin, carboplatin, other platinum-containing compounds, or other components of their preparation

Related Information

• Primary Sponsor: Imanishi Naoki
• Secondary ID(s): 2022-002006-24,NCT05607550