AMG510 (sotorasib) Plus Lenvatinib As Second-line Treatment in Patients with KRASG12C Mutant, Metastatic NSCLC

A Multicentre, Single-arm Phase II Trial of Sotorasib Plus Lenvatinib, As Second-line Treatment in Patients with KRASG12C-mutant, Metastatic NSCLC

AMBER is a multicentre, single-arm phase II trial. The protocol treatment consists of of sotorasib plus lenvatinib, as a second-line treatment. The primary objective of the trial is to evaluate the clinical efficacy of sotorasib plus lenvatinib, in terms of objective response rate, for patients with KRASG12C-mutant, metastatic NSCLC.

Inclusion Criteria:

• Pathologically documented metastatic NSCLC.
• Documented disease progression on prior treatment. Prior treatment must have included platinum-based doublet chemotherapy and immune-checkpoint inhibition.
• KRASG12C-mutation (identified through local molecular testing, using a validated test).
• Measurable disease per RECIST v1.1 criteria.
• Age ≥18 years.
• ECOG Performance Status of 0-1.
• Life expectancy of >3 months.
• Ability to swallow oral medications and willing to complete a treatment diary.
• Adequate haematological function.
• Adequate renal function.
• Adequate liver function.
• Men and women of childbearing potential must use highly effective contraception.
• Women of childbearing potential, including women who had their last menstruation in the last 2 years, must have a negative urinary or serum pregnancy test within 5 weeks before enrolment. Pregnancy test must be repeated within 3 days before the first dose of protocol treatment.
• Written IC for study participation must be signed and dated by the patient and the investigator prior to any study-related intervention.

Exclusion Criteria:

• Active brain metastases E.g., untreated brain lesions (new or progressing) and/or symptomatic brain lesions (symptoms as determined by the investigator).

Patients who have had brain metastases resected or have received whole brain radiation therapy ending at least 4 weeks (or stereotactic radiosurgery ending at least 2 weeks) prior to enrolment are eligible if they meet all of the following criteria:

• Residual neurological symptoms are only of grade ≤2
• On stable doses of dexamethasone or equivalent for at least 2 weeks, if applicable.
• History or presence of haematological malignancies. Exception: curatively treated haematological malignancies with no disease evidence in the last 2 years.
• History of (non-infectious) pneumonitis that required steroids or evidence of ILD/pneumonitis.
• Active hepatitis B and C and uncontrolled HIV.
• Uncontrolled blood pressure (systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg) in spite of an optimised regimen of antihypertensive medication.
• Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, long QT syndrome (LQTS), unstable angina, myocardial infarction or stroke within 6 months before enrolment, or cardiac arrhythmia requiring medical treatment at screening
• Bleeding or thrombotic disorders or patients at risk for severe haemorrhage. The degree of tumour invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe haemorrhage associated with tumour shrinkage/necrosis following lenvatinib therapy.
• Current or recent (within 10 days of enrolment) use of aspirin (>325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, or clostazol.
• Electrolyte abnormalities that have not been corrected.
• Proteinuria on urine dipstick testing >1+, unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is <2 g/24 hours.
• History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 months prior to inclusion.
• Unresolved toxicities from previous lines of anti-cancer treatment regimens and/or (with the exception of alopecia) complications from major surgery prior to enrolment.
• Previous treatment with KRAS- and/or VEGF/R inhibitors.
• Hypersensitivity to sotorasib or lenvatinib.
• Women who are pregnant or breastfeeding or who are planning to become pregnant or breastfeed.
• Sexually active men and women of childbearing potential who are not willing to use a highly effective contraceptive method during the trial and for 7 days after the last dose of sotorasib and until 30 days after the last dose of lenvatinib.
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.