ADEPPT is an international, multicentre, single-arm phase II trial. The protocol treatment consists of adagrasib, which is administered at a dose of 600 mg orally, twice daily until progression or unacceptable toxicity.The primary objective of this trial is to assess the clinical efficacy of adagrasib treatment, in terms of objective response, in patients with KRASG12C-mutant NSCLC, including the elderly (≥70 years) or patients with poor performance status (ECOG PS=2).

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 effective contraceptive methods.
9. 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.
10. 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.

Exclusion Criteria:

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

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 of minimum 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 of study treatment or inability to swallow oral medications.

5. 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.

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 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.

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 use an effective contraceptive method during the study.

12. 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.