MARIPOSA-2

Key outcome parameters

Primary endpoints:

• PFS using RECIST v1.1 guidelines (LACP vs CP and ACP vs CP

Secondary endpoints:

• Objective response (by BICR)
• Overall survival
• Duration of response (by BICR)
• Time to subsequent therapy
• PFS after first subsequent therapy (PFS2)
• Time to symptomatic progression
• Incidence and severity of adverse events and clinical laboratory abnormalities
• Serum amivantamab and plasma lazertinib concentrations, and serum anti-amivantamab antibodies
• NSCLC-SAQ
• EORTC-QLQ-C30
• PROMIS-PF
• Intracranial PFS (by BICR)
• Objective response (by BICR)
• Duration of response (by BICR)
• PFS (by BICR

Exploratory endpoints:

• Disease control rate
• Time to treatment discontinuation
• EQ-5D-5L
• PRO CTCAE
• Characterization of tumor genetics by NGS of ctDNA at baseline, and changes at progression

Intervention

Arm A (LACP):

• Lazertinib 240 mg orally, once daily
• Amivantamab by intravenous (IV) infusion in 21-day cycles
• Carboplatin and pemetrexed as in Arm B

Arm B (CP):

• Carboplatin AUC 5 on Day 1 of each 21-day cycle, for up to 4 cycles
• Pemetrexed 500 mg/m2 on Day 1 of each 21-day cycle, with carboplatin for up to 4 cycles, and then as maintenance until disease progression

Arm C (ACP):

• Amivantamab as in Arm A
• Carboplatin and pemetrexed as in Arm B

Key inclusion criteria

Inclusion criteria

• At least 18 years of age
• Participant must have histologically or cytologically confirmed, locally advanced or metastatic, non-squamous NSCLC, characterized at or after the time of locally advanced or metastatic disease diagnosis by either EGFR Exon 19del or Exon 21 L858R mutation
• Participant must have progressed on or after osimertinib monotherapy as the most recent line of treatment. Osimertinib must have been administered as either the first-line treatment for locally advanced or metastatic disease or in the second-line setting after prior treatment with first- or second-generation EGFR TKI as a monotherapy. Participants who received either neoadjuvant and/or adjuvant treatment of any type are eligible if progression to locally advanced or metastatic disease occurred at least 12 months after the last dose of such therapy and then the participant progressed on or after osimertinib in the locally advanced or metastatic setting
• Participant must have at least 1 measurable lesion, according to RECIST v1.1, that has not been previously irradiated
• Participant with a history of brain metastases must have had all lesions treated as clinically indicated
• Participant must have Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
• Participant must have adequate organ and bone marrow function
• Any toxicities from prior systemic anticancer therapy must have resolved to CTCAE v5.0
• Participant must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study
• Woman of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study
• Woman must be either of the following: not of childbearing potential; or of childbearing potential and practicing true abstinence during the entire period of the study, including up to 7 months after the last dose of study treatment is given or have a sole partner who is vasectomized or practicing at least 1 highly effective user independent method of contraception
• Woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 7 months after receiving the last dose of study treatment
• Man must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for 6 months after receiving the last dose of study treatment. A man who is sexually active with a woman of childbearing potential must agree to use a condom and his partner must also be practicing a highly effective method of contraception
• Male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 6 months after receiving the last dose of study treatment
• Participant must be willing and able to adhere to the lifestyle restrictions specified in this protocol.

Key exclusion criteria

Exclusion criteria

• Participant has an uncontrolled illness
• Participant received prior systemic anticancer therapy in the locally advanced or metastatic setting, or in the adjuvant setting, for the same nonsquamous NSCLC intended for treatment now, except as allowed by Inclusion Criterion 3
• Participant received radiotherapy for palliative treatment of NSCLC less than 14 days prior to randomization
• Participant with symptomatic or progressive brain metastases
• Participant previously enrolled in the Sponsor’s study 73841937NSC3003 (NCT04487080)
• Participant has history of or current evidence of leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation
• Participant has known small cell transformation
• Participant has uncontrolled tumor-related pain. Symptomatic lesions amenable to palliative radiotherapy (eg, bone metastases, or metastases causing nerve impingement) should be treated at least 14 days prior to randomization
• Participant has a medical history of ILD, including drug-induced ILD or radiation pneumonitis
• Participant has a history of hypersensitivity to carboplatin or pemetrexed, or to any excipient of carboplatin, pemetrexed, amivantamab, or lazertinib
• Participant has an active malignancy (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study
• Participant has any contraindication to treatment with pemetrexed or carboplatin or participant has a history of hypersensitivity to, or cannot take, vitamin B12 or folic acid
• Participant has a history of clinically significant cardiovascular disease
• Participant had major surgery or had significant traumatic injury within 4 weeks before randomization, or will not have fully recovered from surgery, or has surgery planned during study participation that will require general anesthesia
• Participant has at screening positive hepatitis B surface antigen, positive hepatitis C, or other clinically active infectious liver disease
• Participant has received a live or live attenuated vaccine within 4 weeks before randomization
• Participant is known to be positive for human immunodeficiency virus (HIV) with 1 or more of the following:
  • Not receiving highly active antiretroviral therapy (ART)
  • Had a change in ART within 6 months of the start of screening
  • Receiving ART that may interfere with study treatment (consult Sponsor for review of medication prior to enrollment)
  • CD4 count <350 at screening
  • AIDS-defining opportunistic infection within 6 months of start of screening
  • Does not agree to start ART and be on ART>4 weeks plus having HIV viral load <400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV controlled)
• Participant is currently receiving a medication or herbal supplement known to be a strong cytochrome P450 (CYP) 3A4/5 inducer and is not able to stop use for an appropriate washout period prior to randomization
• Participant has received an investigational agent within 12 months before randomization or is currently enrolled in an investigational study
• Participant is pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 7 months after the last dose of study treatment
• Participant plans to father a child while enrolled in this study or within 6 months after the last dose of study treatment
• Participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments