Participants are eligible to be enrolled in the study only if all of the following criteria apply:
1. Have signed the informed consent form
2. Are aged ≥18 years at time of signing the informed consent form
3. Are able to comply with the study protocol, in the investigator’s judgment
4. Have measurable disease per RECIST v1.1
5. Note: A 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 radiological examination should be performed for this lesion at least 7 days after biopsy.
6. Have histologically or cytologically documented locally advanced or metastatic NSCLC not amenable to curative surgery or radiotherapy; diagnosis must be stated in a pathology report.
7. Have documented results of the presence of an EGFR PACC mutation in tumor tissue or blood from local testing via a validated NGS or validated PCR assay performed at a Clinical Laboratory Improvement Amendments (CLIA)– or equivalently certified laboratory, or at a laboratory certified by a nationally recognized entity. The results must be accompanied by an EGFR test report. Refer to Appendix 11 for more details.
8. Consent to provide an archival tumor tissue specimen (formalin-fixed, paraffin-embedded [FFPE] tissue block [preferred] or at least 15 unstained, serially cut sections on slides from an FFPE tumor specimen). The specimens must be provided during screening or no later than within 30 days of Cycle 1 Day 1 and must be accompanied by a pathology report. Refer to Section 8.5 for more details.
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
10. Have a life expectancy of greater than 12 weeks
11. Have adequate hematological and organ function within 14 days prior to Cycle 1 Day 1, defined by the following:
• Absolute neutrophil count (ANC) ≥ 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 (ALP) ≤2.5× ULN, with the following exceptions:
− Patients with documented liver metastases may have AST, ALT, and/or
ALP ≤ 3.0 × ULN.
− Patients with documented bone metastases may have ALP ≤ 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. Participants receiving therapeutic anticoagulation should be taking a stable dose for at least 1 week prior to Cycle 1 Day 1.
12. Have completed prior adjuvant, neo-adjuvant, or chemoradiation therapies (eg, chemotherapy, radiotherapy, immunotherapy, biologic therapy, investigational agents) at least 12 months prior to the first dose of study treatment
13. For women of childbearing potential (WOCBPs): A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state of ≥12 continuous months of amenorrhea with no identified cause other than menopause, and is not permanently infertile due to surgery (ie, removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (eg, Müllerian
agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. WOCBPs must adhere to the following guidance:
• Must agree to remain abstinent (refrain from heterosexual intercourse) or use contraception, which includes 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 60 days after discontinuation of study treatment.
Note: 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 participant. Periodic abstinence (eg, 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 on the local informed consent form.
• Must refrain from donating eggs during the treatment period and for 60 days after discontinuation of study treatment must not breastfeed and must have a negative serum pregnancy test result within 2 weeks prior to first dose of study treatment. Note: Includes those who have had tubal ligation.
14. Men who are not surgically sterile must adhere to the following guidance:
• When with a female partner of childbearing potential, during the treatment period, and for at least 6 months after discontinuation of study treatment, must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year
• Note: 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 participant.
Periodic abstinence (eg, 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 on the local
informed consent form.
• Must agree to refrain from donating sperm from the start of dosing until 6 months after discontinuing study treatment
15. For participants with CNS metastases, the following criteria must be met:
• Have measurable disease outside the CNS
• Have no ongoing symptoms attributed to CNS metastases
• Have no ongoing requirement for corticosteroids as therapy for CNS metastases, and corticosteroids must be discontinued for ≥ 2 weeks prior to first dose of study treatment
• Have no spinal cord compression or CNS metastases requiring anticonvulsants or corticosteroids for symptomatic control
• Have no known or suspected leptomeningeal disease
• For participants with previously treated brain metastases:
− Have no evidence of interim CNS disease progression between the completion of previous CNS-directed therapy and the screening radiographic CNS imaging
− May receive local therapy provided that the participant meets the washout criteria below for whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), or surgical resection
• Participants 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 they meet the following:
− Time since WBRT is ≥ 3 weeks prior to randomization of study treatment, time since SRS is ≥ 7 days prior to randomization of study treatment, or time since surgical resection is ≥ 4 weeks prior to first dose of study treatment

Participants are excluded from the study if any of the following criteria apply:
1. Are unable or unwilling to swallow pills
2. Are unable to comply with study and follow-up procedures
3. Have NSCLC with any of the following EGFR mutations: exon 19 deletion, L858R, or C797S
4. Have had prior treatment with EGFR-targeted agents (eg, EGFR-TKIs, EGFR-targeted proteolysis-targeting chimeras [PROTACs], monoclonal antibodies, or bispecific antibodies)
5. Have had prior treatment with any systemic anti-cancer therapy for locally advanced or metastatic NSCLC not amenable to curative surgery or radiation, including chemotherapy, biologic therapy, immunotherapy, or any investigational drug
6. Have malabsorption syndrome or other conditions that would interfere with enteral absorption
7. Have pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures biweekly or more frequently
Note: Indwelling pleural or abdominal catheters may be allowed, provided that the participant has adequately recovered from the procedure, is hemodynamically stable, and has symptomatically improved.
8. Have severe acute or chronic infections, including the following:
• Uncontrolled acute infection or active infection that necessitates systemic treatment within 2 weeks prior to the first dose of study treatment
• Uncontrolled HIV infection (defined as cluster of differentiation [CD] 4+ T-cell count <350 cells/µL).
Note: Participants must have been taking established antiretroviral therapy (ART) for at least 4 weeks and have an HIV viral load <400 copies/mL prior to enrollment. If the lower limit of detection (LLoD) of HIV viral load assay at the site is higher than 400 copies/mL or the site uses units other than copies/mL, participants with an HIV viral load result lower than the LLoD at the site are considered eligible.
• For hepatitis B: Hepatitis B surface antigen (HBsAg)–positive participants are excluded.
− HBsAg-negative participants must be tested for hepatitis B core antibody (HBcAb). If the HBcAb test is negative, then the participant is eligible.
− HBcAb-positive participants must be tested for quantitative hepatitis B virus (HBV) DNA:
 Carriers of HBV who have stable HBV infection (eg, HBV DNA quantitative test shows DNA ≤2500 copies/mL or 500 IU/mL) after medical treatment are eligible.
 If the LLoD of the HBV DNA assay at the site is higher than 2500 copies/mL or 500 IU/mL, participants with results lower than the site’s LLoD are considered eligible.
Note: If a single HBcAb test cannot be completed, both immunoglobulin (Ig) M and IgG HBcAb tests must be performed; if the IgM and IgG HBcAb tests arepositive, then a quantitative HBV DNA test must be performed (see above).
• For hepatitis C: Participants with a positive hepatitis C virus (HCV) antibody must be tested for quantitative HCV RNA.
− If the participant’s HCV RNA quantitative test is negative (eg, ≤LLoD), then the participant is eligible.
• 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 (eg, American Society of Clinical Oncology, European Society for Medical Oncology, or Chinese Society of Clinical Oncology).
9. Have had previous interstitial lung disease (ILD), including drug-induced ILD, or active ILD/active radiation pneumonitis
10. Have a history of or active clinically significant cardiovascular dysfunction, including the following:
• Stroke or transient ischemic attack within 6 months prior to first dose of study treatment
• Myocardial infarction within 6 months prior to first dose of study treatment
• 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
11. Have a mean resting corrected QT interval (QTc) >470 ms, obtained from triplicate electrocardiograms (ECGs) with QT interval corrected by Fridericia’s method (QTcF)
12. Have clinically significant prolonged QT interval or other arrhythmia or clinical status that, in the opinion of investigators, may increase the risk of prolonged QT interval (eg, complete left bundle branch block, third-degree atrioventricular block, second-degree heart block, PR interval >250 ms, 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). For a list of drugs that may cause QT interval prolongation/torsades de pointes (TdP), refer to Appendix 4.
13. Have symptomatic hypercalcemia requiring the continued use of bisphosphonate therapy or denosumab
14. Have had a significant traumatic injury or major surgical procedure within 4 weeks prior to first dose of study treatment
15. Have chronic diarrhea; short bowel syndrome or significant upper GI surgery, including gastric resection; active inflammatory bowel disease (eg, Crohn’s disease or ulcerative colitis); or any active bowel inflammation (including diverticulitis)
16. Have 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, may affect the interpretation of the results, or renders participants at high risk from treatment
complications (eg, uncontrolled hypertension, active bleeding)
17. Have had radiation therapy (other than palliative radiation for bone metastases as described below, or radiation for CNS metastases as described in inclusion criterion no. 14) as cancer therapy within 4 weeks prior to first dose of study treatment
18. Have had palliative radiation to bone metastases within 2 weeks prior to initiation of study drug
19. Have any unresolved toxicities from prior therapy (eg, adjuvant chemotherapy) of Grade >1 at initiation of study drug, with the exceptions of alopecia and prior chemotherapy-related Grade 2 neuropathy
20. Have a history of other malignancy within 3 years prior to screening, with the exception of participants 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)
21. Are pregnant or breastfeeding or are intending to become pregnant during the study or within 60 days after the final dose of study treatment
22. Have used a strong cytochrome P450 (CYP) 3A4 inhibitor within 7 days prior to the first dose of study treatment or a strong CYP3A4 inducer within 3 weeks prior to the first dose of study treatment
23. Have used traditional Chinese medicines/herbal medicines indicated for the treatment of cancer within 14 days prior to the first dose of study treatment
24. Have a history of allergic reactions to any components, including excipients, of the firmonertinib, osimertinib, and afatinib drug products

• Oncology (Adult)

• ArriVent Biopharma, Inc.