A Global, Phase 3, Randomized, Multicenter, Open-Label 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 with Epidermal Growth Factor Receptor Exon 20 Insertion Mutations

atients 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
Note: Measurable lesion can neither be subject to local therapy such as
radiotherapy nor used for biopsy in the Screening Period; if there is only 1
measurable lesion, this lesion will be permitted to be biopsied. However, the
baseline radiologic examination should be performed for this lesion at least 14
days after biopsy.
5. Histologically or cytologically documented, locally advanced or metastatic
non-squamous NSCLC not amenable to curative surgery or radiotherapy
6. Documented validated results confirming 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) assay or a validated polymerase
chain reaction (PCR) test with confirmation by Sanger sequencing performed at a
Clinical Laboratory Improvement Amendments (CLIA) or equivalently certified
laboratory.
* If local testing does not meet the above criteria, then a central test
designated by the Sponsor or a commercially available NGS assay should be
performed as specified in the laboratory manual.
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.
• It is preferred that the specimen is prepared from the most recently
collected and available tumor tissue. See the laboratory manual for
instructions.
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/µL
• Hemoglobin >= 9 g/dL
• Platelet count >= 100,000/µL
• Total bilirubin <= 1.5 × upper limit of normal (ULN) or <= 3 × ULN in the
presence of documented Gilbert*s Syndrome (unconjugated hyperbilirubinemia)
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and
alkaline phosphatase (AP) <= 2.5 × ULN, with the following exceptions:
* Patients with documented liver metastases may have AST, ALT, and/or AP <= 5.0
× ULN.
* Patients with documented bone metastases may have AP <= 5.0 × ULN.
• Creatinine clearance >= 45 mL/min on the basis of the Cockcroft-Gault
estimation:
(140 - age) × (weight in kg) × (0.85 if female)
72 × (serum creatinine in mg/dL)
• International normalized ratio (INR) <= 1.5 × ULN and activated partial
thromboplastin time (aPTT) <= 1.5 × ULN
Note: This applies only to patients who are not receiving therapeutic
anticoagulation. Patients receiving therapeutic anticoagulation should be on a
stable dose for at least 1 week prior to Cycle 1, Day 1.
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.,
Müllerian 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 study treatment. WOCBP must refrain from donating eggs during the
Treatment Period and 6 months after discontinuation of study 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.
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 who is not pregnant, 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 study treatment. Patients should
refrain from donating sperm from the start of dosing until 6 months after
discontinuing study treatment.
• With pregnant female partners, men must remain abstinent or use a condom to
avoid exposing the embryo during the Treatment Period and for at least 60 days
after discontinuation of study 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

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/µL).
Note: Patients must have been on established antiretroviral therapy (ART) for at
least four weeks and have an HIV viral load < 400 copies/mL prior to
enrollment). If the lower limit of detection of HIV viral load assay at the
site is
higher than 400 copies/mL or with units other than copies/mL, patients with an
HIV viral load result lower than the lower limit of detection in the site are
considered eligible. Patients with unknown HIV infection status who do not
agree to take HIV test are not eligible.
• Patients with active chronic hepatitis B or with active hepatitis C infection,
which includes patients who are hepatitis B surface antigen (HBsAg)-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.
Note: If a patient has a negative HBsAg test and a positive total HbcAb test at
screening, an HBV DNA test must also be performed to determine if the patient
has an HBV infection. Patients who are carriers of HBV, with stable HBV
infection (e.g., HBV DNA quantitative test showed DNA <= 2500 copies/mL or
500 IU/mL) after medical treatment or with cured hepatitis C are permitted to
enroll. If the lower limit of detection of HBV DNA assay in the site is higher
than 2500 cps/mL or 500 IU/mL, patients with HBV DNA quantitative test result
lower than the lower limit of detection in the site are considered eligible.
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), drug-induced ILD, radiation
pneumonitis, or active ILD
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), using the screening clinic ECG machine-
derived Fridericia*s formula (QTcF) value
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
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 60 days after the final dose of study drug
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 an herbal medicine (e.g., Chinese medicine or traditional Chinese
medicine preparation indicated for cancer, or a traditional Chinese medicine or
traditional Chinese medicine preparation with adjuvant anticancer effects)
within 2 weeks prior to the first dose of investigational product or is
expected to be used during the study
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