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

Inclusion Criteria:

1. Histologically or cytologically confirmed stage IV NSCLC.

2. KRASG12C-mutation by local testing (by tissue or ctDNA).

3. 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).

4. Life expectancy ≥12 weeks.

5. Measurable disease according to RECIST v1.1.

6. Age ≥18 years with ECOG PS 2 (cohort 1), or age ≥70 years with ECOG PS 0-1 (cohort 2).

7. Adequate haematological, renal and liver function

8. Men and women of childbearing potential must agree to use use highly effectivecontraceptive methods.

9. Women of childbearing potential, including women who had their last menstruation inthe last 2 years, must have a negative urinary or serum beta HCG pregnancy testwithin 5 weeks before enrolment. Pregnancy test must be repeated within 7 daysbefore the first dose of adagrasib treatment.Ability to comply with the trialprotocol, in the investigator's judgment.

10. Written IC for study participation must be signed and dated by the patient and theinvestigator prior to any study-related intervention, including the submission ofmandatory biomaterial.

Exclusion Criteria:

1. Prior investigational therapy within 28 days or at least 5 half-lives beforeenrolment.

2. Prior treatment with an agent targeting KRASG12C.

3. 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 ofminimum of 2 weeks must have elapsed from the last day of radiotherapy.

4. History of intestinal disease or major gastric surgery likely to alter absorption ofstudy treatment or inability to swallow oral medications.

5. Any of the following cardiac abnormalities:

• Unstable angina pectoris or myocardial infarction within 6 months prior toenrolment.

• Symptomatic or uncontrolled atrial fibrillation within 6 months prior toenrolment.

• Congestive heart failure ≥NYHA Class 3 within 6 months prior to enrolment.

• Prolonged QTc interval >480 ms or family or medical history of congenital LongQT Syndrome.

6. History of stroke or transient ischemic attack within 6 months prior to enrolment.

7. Ongoing need for treatment with concomitant medication with any of the followingcharacteristics: known risk of Torsades de Pointes; substrate of CYP3A with narrowtherapeutic 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 toenrolment.

8. Known human immunodeficiency virus (HIV) infection.

9. Acute or chronic hepatitis B or C infection.

10. Women who are pregnant or in the period of lactation.

11. Sexually active men and women of childbearing potential who are not willing to usean effective contraceptive method during the study.

12. Judgement by the investigator that the patient should not participate in the studyif the patient is unlikely to comply with study procedures, restrictions andrequirements.