This study aims to provide a comprehensive understanding of sotorasib's mechanisms of action and resistance in NSCLC patients.

Inclusion Criteria:

• Age higher than 18 years;
• ECOG less or equal to 1 at the time of screening;
• Pathologically documented, previously treated, locally-advanced and unresectable or metastatic NSCLC with KRAS p.G12C mutation confirmed through molecular testing (results of both tissue and liquid biopsy are accepted);
• Subjects will have progressed or experienced disease recurrence on or after receiving at least 1 prior systemic therapy for locally advanced and unresectable or metastatic disease.
• Life expectancy of longer than 3 months from the time of screening, in the opinion of the investigator;
• Patients must have lesions easily accessible to biopsy and must have accepted to perform pre-treatment, on-treatment and end-of-treatment biopsies;
• Have adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to registration
• Patients must understand, sign and date the written informed consent from prior to any protocol-specific procedures performed.
• Patients should be able and willing to comply with study visits and procedures as per protocol.
• Patients must be affiliated to a Social Security System or beneficiary of the same.

Exclusion Criteria:

• Patient unwilling to participate to the biological investigations and to perform biopsies and blood sample collection as required in the protocol;

• Use of known cytochrome P450 (CYP) 3A4 or P-gp sensitive substrates (with a narrow therapeutic window), within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to registration, that was not reviewed and approved by the principal investigator.

• Use of strong inducers of CYP3A4 (including herbal supplements such as St. John's wort) within 14 days or 5 half-lives (whichever is longer) prior to registration, that was not reviewed and approved by the principal investigator.

• Inadequate washout period prior to registration, defined as: Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s) from a previous cancer treatment regimen or clinical study shorter than 14 days or 5 half-lives;

• Prior treatment with a KRAS inhibitor.

• Major surgery within 28 days of registration.

• Significant gastrointestinal disorder that results in significant malabsorption, requirement for intravenous alimentation, or inability to take oral medication.

• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 6 months prior to registration, unstable arrhythmias or unstable angina.

• Severe infections within 2 weeks prior to registration, but not limited to hospitalization for complications of infection, bacteremia or severe pneumonia. Prophylactic antibiotics are allowed.

• Baseline or unresolved pneumonitis from prior treatment;

• Current CTCAE version 5.0 grade higher or equal to 2 peripheral neuropathy.

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures at a frequency greater than monthly. Subjects with PleurX catheters in place may be considered for the study with Principal Investigator approval.

• Known history of Human Immunodeficiency Virus (HIV) infection

• Exclusion of hepatitis infection based on the following results and/or criteria:

  1. Positive hepatitis B surface antigen (HepBsAg) (indicative of chronic Hepatitis B or recent acute hepatitis B)

  2. Negative HepBsAg with a positive for hepatitis B core antibody (Hepatitis B core antibody testing is not required for screening, however if this is done and is positive, then hepatitis B surface antibody [Anti-HBs] testing is necessary.

     Undetectable anti-HBs in this setting would suggest unclear and possible infection, and needs exclusion).

  3. Positive Hepatitis C virus antibody: Hepatitis C virus RNA by polymerase chain reaction is necessary. Detectable Hepatitis C virus RNA renders the subject ineligible.

• Leptomeningeal disease and active brain metastases. Subjects who have had brain metastases resected or have received whole brain radiation therapy or stereotactic radiosurgery ending at least 2 weeks prior to registration are eligible if they meet all of the following criteria:

  1. residual neurological symptoms grade less or equal to 2;
  2. on stable doses of dexamethasone or equivalent for at least 2 weeks, if applicable; and
  3. follow-up brain imaging performed within 30 days of enrollment shows no progression or new lesions appearing.

• Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 7 days after the last dose of sotorasib or during treatment if planning to become pregnant.

• Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 7 days after the last dose of sotorasib

• Female subjects of childbearing potential with a positive pregnancy test assessed at Screening or day 1 by a serum pregnancy test and/or urine pregnancy test.

• Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 7 days after the last dose of sotorasib

• Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 7 days after the last dose of sotorasib

• Male subjects unwilling to abstain from donating sperm during treatment and for an additional 7 days after the last dose of investigational product.

• Any evidence of primary malignancy other than locally advanced or metastatic lung cancer at within 3 years of registration, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated;

• Participation in another clinical trial evaluating an experimental drug (except non-interventional research).

• Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.

• Hypersensitivity to the active substance or to any excipient

• Patients with hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption