Aumolertinib With Chemotherapy or Alone Compared With Osimertinib in Patients With Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer

A Randomized, Three-Arm, Open-Label Phase 3b Clinical Trial of Aumolertinib, Versus Aumolertinib With Chemotherapy, Versus Osimertinib for Patients With Metastatic NSCLC and an EGFR Mutation (TREBLE)

Aumolertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets EGFR mutations. The reason for this study is to learn whether adding chemotherapy to a new investigational drug called aumolertinib helps to slow or stop cancer growth in people with EGFR mutation-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC). The study will compare this new combination of drugs to osimertinib, given alone. Aumolertinib given alone will also be used in the study, and it will be looked at in comparison with osimertinib given alone.

This is a randomized, open-label study with 3 different groups that are listed below. "Randomized" means the study treatment participants take will be chosen by chance (decided at random by a computer). "Open-label" means that the participant, the study doctor, and the Sponsor will know which study treatment each participant is receiving.

Participants will be randomly assigned to one of the following 3 treatment groups:

• Group 1: Treatment with aumolertinib alone, taken orally (by mouth) as a pill once a day. Around 100 participants will be randomly assigned to this group.
• Group 2: Treatment with aumolertinib taken orally as a pill once a day, in combination with chemotherapy given intravenously (IV; through a needle placed in a vein) on the schedule provided by the study doctor. Around 200 participants will be randomly assigned to this group.
• Group 3: Treatment with osimertinib alone, taken orally as a pill once a day. Around 200 participants will be randomly assigned to this group.

Because there will be twice as many participants in Group 2 and Group 3 as in Group 1, the chance of a participant being randomly assigned to either of those groups is twice as likely as being assigned to Group 1.

Participants can continue to receive study treatment as long as they have not withdrawn consent, as long as they choose to continue to receive study treatment and are judged by their doctor to continue to receive clinical benefit from receiving the study treatment, and as long as no other study treatment and/or study discontinuation criteria are met .

Inclusion Criteria:

1. Is at least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place)
2. Has pathologically confirmed NSCLC that is Stage IIIB, metastatic (Stage IVA or IVB), or recurrent, and which is not amenable to curative intent therapy.
3. Tumor harbors one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity-ex19del or L858R-either alone or in combination with other EGFR mutations (eg, G719X, exon 20 insertions, S7681, L861Q)
4. Has Eastern Cooperative Oncology group performance status of 0, 1, or 2 at the time of enrollment.
5. Has adequate organ function at the time of enrollment.
6. Has QTc interval of ≤ 470 ms
7. Male participants must agree to use a highly effective method of contraception and to refrain from donating sperm while receiving study treatment
8. Female participants are eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies: is not of childbearing potential OR is of childbearing potential and using a highly effective contraceptive method while receiving study treatment AND agrees not to donate eggs (ova, oocytes) during this period
9. All female participants must have a negative serum or urine pregnancy test result within 48 hours prior to initiation of study drug dosing

Exclusion Criteria:

1. Is a candidate for curative intent therapy for the NSCLC diagnosis.
2. Tumor has mixed small-cell and non-small-cell pathology.
3. Has received prior systemic treatment for metastatic NSCLC. Prior chemotherapy or immunotherapy is permitted, provided that it was used for treatment of locoregional NSCLC as a component of curative intent therapy and administration was completed more than 6 months ago.
4. Has refractory nausea and vomiting, chronic gastrointestinal disease(s), inability to swallow the formulated product (percutaneous endoscopic gastrostomy tube administration may be allowed if tablets are not crushed), or a history of previous significant bowel resection-any of which would preclude adequate absorption of aumolertinib or osimertinib.
5. Has active or past medical history of interstitial lung disease, drug-induced interstitial lung disease or radiation pneumonitis that required steroid treatment
6. Has evidence of active bacterial, viral, or fungal infection which would preclude safe enrollment, as assessed by the treating Investigator.
7. Has significant concomitant condition, that in the Investigator's judgment would prevent the participant from receiving study treatment or being followed in this study, or which otherwise renders the participant inappropriate for the study.
8. For participants in the aumolertinib monotherapy and aumolertinib with chemotherapy arms, use of strong CYP3A4 inhibitors/inducers within 14 days before initial study drug dosing and use of grapefruit-containing products within 72 hours before initial study drug dosing is prohibited.
9. Has a history of prolonged QT syndrome or Torsades de Pointes
10. Has any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, including evidence of QT prolongation (QTc >470 ms for males and >480 ms for females) or has any factor, including any current medication(s), known to increase the risk of QTc prolongation or the risk of arrhythmic events
11. Hypersensitivity or allergy to aumolertinib or osimertinib or their excipients