Adagrasib in Patients With KRASG12C-mutant NSCLC Who Are Elderly or Have Poor Performance Status

Prior treatment

• Prior investigational therapy within 28 days or at least 5 half-lives before enrolment.
• Prior treatment with an agent targeting KRASG12C.
• Leptomeningeal disease or untreated brain metastases.
  • Patient should be neurologically stable for at least 2 weeks before enrolment, without the need for corticosteroids, except for prednisone (or its equivalent) at a dose of ≤10 mg daily.
  • For patients with definitively treated brain metastases, a time period of minimum of 2 weeks must have elapsed from the last day of radiotherapy.
• History of stroke or transient ischemic attack within 6 months prior to enrolment.
• Ongoing need for treatment with concomitant medication with any of the following characteristics: known risk of Torsades de Pointes; substrate of CYP3A with narrow therapeutic index; strong inducer of CYP3A and/or P-gp; strong inhibitor of BCRP; and proton pump inhibitors that cannot be switched to alternative treatment prior to enrolment.

Other illness

• History of intestinal disease or major gastric surgery likely to alter absorption of study treatment or inability to swallow oral medications.
• Known human immunodeficiency virus (HIV) infection.
• Acute or chronic hepatitis B or C infection.

Lab values

• Any of the following cardiac abnormalities:
  • Unstable angina pectoris or myocardial infarction within 6 months prior to enrolment.
  • Symptomatic or uncontrolled atrial fibrillation within 6 months prior to enrolment.
  • Congestive heart failure ≥NYHA Class 3 within 6 months prior to enrolment.
  • Prolonged QTc interval \>480 ms or family or medical history of congenital Long QT Syndrome.

Other

• Women who are pregnant or in the period of lactation.
• Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study.
• Judgement 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.

• Histologically or cytologically confirmed stage IV NSCLC.
• KRASG12C-mutation by local testing (by tissue or ctDNA).
• Prior treatment with at least one line of systemic therapy for NSCLC (e.g., platinum-based doublet chemotherapy and/or immune-checkpoint inhibition or both).
• Life expectancy ≥12 weeks.
• Measurable disease according to RECIST v1.1.
• Age ≥18 years with ECOG PS 2 (cohort 1), or age ≥70 years with ECOG PS 0-1 (cohort 2).
• Adequate haematological, renal and liver function
• Men and women of childbearing potential must agree to use use highly effective contraceptive methods.
• Women of childbearing potential, including women who had their last menstruation in the last 2 years, must have a negative urinary or serum beta HCG pregnancy test within 5 weeks before enrolment. Pregnancy test must be repeated within 7 days before the first dose of adagrasib treatment.Ability to comply with the trial protocol, in the investigator's judgment.
• Written IC for study participation must be signed and dated by the patient and the investigator prior to any study-related intervention, including the submission of mandatory biomaterial.