Sotorasib in Previously Treated Locally Advanced or Metastatic NSCLC Subjects With Mutated KRAS p.G12C

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 ormetastatic 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 afterreceiving at least 1 prior systemic therapy for locally advanced and unresectable ormetastatic disease.

• Life expectancy of longer than 3 months from the time of screening, in the opinionof the investigator;

• Patients must have lesions easily accessible to biopsy and must have accepted toperform pre-treatment, on-treatment and end-of-treatment biopsies;

• Have adequate bone marrow reserve and organ function, based on local laboratory datawithin 14 days prior to registration

• Patients must understand, sign and date the written informed consent from prior toany protocol-specific procedures performed.

• Patients should be able and willing to comply with study visits and procedures asper 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 performbiopsies and blood sample collection as required in the protocol;

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

• Use of strong inducers of CYP3A4 (including herbal supplements such as St. John'swort) 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 cytotoxicchemotherapy, investigational agents or other anticancer drug(s) from a previouscancer 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 cardiacdisease (Class II or greater), myocardial infarction within 6 months prior toregistration, unstable arrhythmias or unstable angina.

• Severe infections within 2 weeks prior to registration, but not limited tohospitalization 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 recurrentdrainage procedures at a frequency greater than monthly. Subjects with PleurXcatheters in place may be considered for the study with Principal Investigatorapproval.

• 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 HepatitisB or recent acute hepatitis B)

2. Negative HepBsAg with a positive for hepatitis B core antibody (Hepatitis Bcore antibody testing is not required for screening, however if this is doneand is positive, then hepatitis B surface antibody [Anti-HBs] testing isnecessary.Undetectable anti-HBs in this setting would suggest unclear and possibleinfection, and needs exclusion).

3. Positive Hepatitis C virus antibody: Hepatitis C virus RNA by polymerase chainreaction is necessary. Detectable Hepatitis C virus RNA renders the subjectineligible.

• Leptomeningeal disease and active brain metastases. Subjects who have had brainmetastases resected or have received whole brain radiation therapy or stereotacticradiosurgery ending at least 2 weeks prior to registration are eligible if they meetall 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, ifapplicable; and

3. follow-up brain imaging performed within 30 days of enrollment shows noprogression or new lesions appearing.

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

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

• Female subjects of childbearing potential with a positive pregnancy test assessed atScreening 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 topractice sexual abstinence (refrain from heterosexual intercourse) or usecontraception during treatment and for an additional 7 days after the last dose ofsotorasib

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

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

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

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

• Patient under guardianship or deprived of his liberty by a judicial oradministrative 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 deficiencyor glucose-galactose malabsorption