Phase II trial of amivantamab plus monochemotherapy in platinum unfit NSCLC patients with EGFR exon20 insertion mutations

Prior treatment

• Concomitant radiotherapy
• Symptomatic or immediately requiring therapy for brain metastases or carcinomatous meningitis. Subjects with asymptomatic and stable or treated brain metastases may participate
• Participant had major surgery excluding placement of vascular access or tumor biopsy, or had significant traumatic injury within 4 weeks before randomization, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study
• Participant has active cardiovascular disease including, but not limited to: A medical history of deep vein thrombosis or pulmonary embolism within 1 month prior to randomization or any of the following within 6 months prior to randomization: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non-obstructive catheter-associated thrombus, incidental or asymptomatic pulmonary embolism, are not exclusionary
• Participant has an uncontrolled illness, including but not limited to: • Uncontrolled diabetes • Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics 1 week prior to starting study treatment] or diagnosed or suspected viral infection. • Active bleeding diathesis • Impaired oxygenation requiring continuous oxygen supplementation • Psychiatric illness, social situation, or any other circumstances that would limit compliance with study requirements • Any ophthalmologic condition that is clinically unstable

Other illness

• Uncontrolled infectious liver disease
• Participant has concurrent or prior malignancy other than the disease under study. The following exceptions require consultation with the Medical Monitor: a. Non-muscle invasive bladder cancer (NMIBC) treated within the last 24 months that is considered completely cured. b. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured. c. Non-invasive cervical cancer treated within the last 24 months that is considered completely cured.
• History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV)
• Other serious illness or medical condition potentially interfering with the study
• Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg)
• Positive hepatitis C antibody (anti-HCV)
• Uncontrolled (persistent) hypertension: systolic blood pressure >160 mm Hg; diastolic blood pressure >100 mm Hg
• Congestive heart failure (CHF), defined as New York Heart Association (NYHA) class III-IV or hospitalization for CHF (any NYHA class; refer to Appendix 6: New York Heart Association Criteria) within 6 months of randomization

Lab values

• Previous treatment with any EGFR Exon20ins–targeted TKIs
• Participant is positive for human immunodeficiency virus (HIV), with 1 or more of the following: • 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 • Not agreeing 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)

Other

• Pregnancy or lactating female
• Absence of measurable lesions

• Written informed consent
• Adequate bone marrow function (ANC ≥ 1.5x109/L, platelets ≥75x109/L, haemoglobin >9 g/dl); Adequate liver function (Total bilirubin ≤1.5 x ULN; subjects with Gilbert’s syndrome can enroll if conjugated bilirubin is within normal limits, transaminases no more than 3xULN/<5xULN in presence of liver metastases)
• Normal level of alkaline phosphatase and Serum creatinine <1.5 x ULN and creatinine clearance >45 mL/min as measured or calculated; refer to Appendix 5: Cockcroft-Gault Formula for Estimated creatinine clearance
• Patients should be using adequate contraceptive measures, should not be breastfeeding, until 7 months after the last dose, and must have a negative pregnancy test (serum or urine) prior to first dose of study drug (within 72 hours) and must agree to further serum or urine pregnancy tests during the study; or female patients must have an evidence of non-childbearing potential by fulfilling one of the following criteria at screening:  Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments;  Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution.
• Male or female patient aged ≥18 years
• Histologically or cytologically confirmed stage IV or recurrent non-squamous NSCLC harboring EGFR exon20 insertion mutation
• No prior systemic treatment
• Unfit for platinum-based chemotherapy; Unfit for platinum is defined by a glomerular filtration rate (GFR) value less than 50 ml/min/BSA (body surface area) 1.73 m2 (or a CCR value of <50 ml/min) or age 80 years, presence of neurological disorders or hypersensitivity to platinum
• At least one radiological measurable disease according to RECIST criteria version 1.1
• Patients with brain metastases are eligible if they are asymptomatic and stable (i.e. without evidence of progression by imaging for at least two weeks prior to the first dose of trial treatment and without deterioration of any neurologic symptoms)
• Performance status 0-2 (ECOG PS)
• Patient compliance to trial procedures