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
