A Study of Sotorasib in People with Non-Small Cell Lung Cancer

Inclusion Criteria:

• Written informed consent

• Biopsy-proven metastatic or recurrent non-small cell lung cancer

• KRAS G12C mutation on prior tumor biopsy or cell-free DNA (cfDNA) testing

• No prior therapy in the advanced setting

• Measurable disease per RECIST 1.1

• Karnofsky performance status (KPS) ≥ 70%

• Age ≥ 18

• Adequate organ function

• Hemoglobin ≥ 10^9 g/dL

• Platelets ≥ 75 x 10^9/L

• Absolute neutrophil count (ANC) > 1.5 x 10^9/L

• AST < 3 x ULN (if liver metastases are present, < 5 x ULN)

• ALT < 3 x ULN (if liver metastases are present, < 5 x ULN)

• Alkaline phosphatase < 2 x ULN (if liver or bone metastases are present,< 3xULN)

• Total bilirubin ≤1.5 x ULN; subjects with Gilbert's syndrome can enroll ifconjugated bilirubin is within normal limits

• Serum creatinine < 1.5 x ULN or if available, calculated or measured creatinineclearance > 30 mL/min/1.73 m^2

In addition, patients must:

• Be willing to undergo pre-treatment and day 7-21 on-treatment tumor biopsies

• Decline first-line chemotherapy and/or anti-PD-(L)1 therapy, or previously haveexperienced disease progression after adjuvant or consolidation chemotherapy oranti-PD-(L)1 therapy for early stage (I-III) NSCLC

Before enrollment, a woman must be either:

• Not of childbearing potential: premenarchal; postmenopausal (>45 years of age withamenorrhea for at least 12 months); post-hysterectomy, bilateral salpingectomy,bilateral oophorectomy); or otherwise be incapable of pregnancy

• Of childbearing potential and practicing effective method(s) of birth controlconsistent with local regulations regarding the use of birth control methods forsubjects participating in clinical studies, as described below:

• Practicing true abstinence (when this is in line with the preferred and usuallifestyle of the subject), which is defined as refraining from heterosexualintercourse during the entire period of the study, including up to 6 monthsafter the last dose of study drug is given. Periodic abstinence (calendar,symptothermal, post-ovulation methods) is not consider an acceptablecontraceptive method

• Have a sole partner who is vasectomized

• Practicing 2 methods of contraception, including one highly effective method (i.e.,established use of oral, injected or implanted hormonal methods of contraception;placement of intrauterine device [IUD] or intrauterine system [IUS], AND, a secondmethod (e.g., condom with spermicidal foam/gel/film/cream/suppository or collusivecap [diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository) Subjects must agree to continue contraception throughout thestudy and continuing through at least 7 days after the last dose of study drug

• NOTE: If the childbearing potential changes after start of the study (e.g., womanwho is not heterosexually active becomes active, premenarchal woman experiencesmenarche) the woman must begin a highly effective method of birth control, asdescribed above.

• A woman of childbearing potential must have a negative serum (b-human chorionicgonadotropin [b-hCG]) at Screening

• A man who is sexually active with a woman of childbearing potential must agree touse a condom with spermicidal foam/gel/film/cream/suppository and his partner mustalso be practicing a highly effective method of contraception (i.e., established useof oral, injected or implanted hormonal methods of required to use contraception.The subject must also not donate sperm during the study and for at least 7 daysafter receiving the last dose of study drug.

contraception; placement of an intrauterine device [IUD] or intrauterine system [IUS]). If the subject is vasectomized, he must still use a condom (with or without spermicide), but his female partner is not required to use contraception. The subject must also not donate sperm during the study and for at least 7 days after receiving the last dose of study drug.

Exclusion Criteria:

• Symptomatic brain metastases

• Any radiotherapy within 1 week of starting treatment on protocol

• Any major surgery within 1 week of starting treatment on protocol

• Exposure to prior adjuvant or consolidation anti-PD-1 or PD-(L)1 therapy for stageI-III disease within 12 weeks of start of initiation of sotorasib

• Unresolved > grade 1 toxicity from any previous treatment

• Prior history of > grade 1 pneumonitis from any previous treatment

• Congestive heart failure defined as New York Heart Association (NYHA) Class III-IVor hospitalization for congestive heart failure (any NYHA class) within 6 months ofstudy Day 1 Gastrointestinal (GI) tract disease causing the inability to take oralmedication, malabsorption syndrome, requirement for intravenous alimentation,uncontrolled inflammatory GI disease (eg, Crohn's disease, ulcerative colitis)

• Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg) o NOTE:Subjects with a prior history of HBV demonstrated by positive hepatitis B coreantibody are eligible if they have at Screening 1) a negative HBsAg and 2) a HBV DNA (viral load) below the lower limit of quantification, per local testing. Subjectswith a positive HBsAg due to recent vaccination are eligible if HBV DNA (viral load)is below the lower limit of quantification, per local testing.

Positive hepatitis C antibody (anti-HCV)

o NOTE: Subjects with a prior history of HCV, who have completed antiviral treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible.

• Other clinically active or chronic liver disease

• Currently enrolled in another investigational device or drug study, or less than 28days since ending another investigational device or drug study(s), or receivingother investigational agent(s)

• Use of known cytochrome P450 (CYP) 3A4 sensitive substrates (with a narrowtherapeutic window), within 14 days or 5 half-lives (whichever is longer) of thedrug or its major active metabolite, whichever is longer, prior to study day 1 thatwas not reviewed and approved by the principal investigator

• Use of strong inducers of CYP3A4 within 14 days or 5 half-lives (whichever islonger) prior to study day 1 that was not reviewed and approved by the principalinvestigator

• Use of P-gp substrates within 14 days or 5 half-lives (whichever is longer) prior tostudy day 1 that was not reviewed and approved by the principal investigator

• Patients who do not agree to pre-treatment and on-treatment tumor biopsies duringthe informed consent process will be excluded from the study. Patients who agree topre-treatment and on-treatment tumor biopsies, but in whom either biopsy isultimately deemed unsafe by the investigators/treatment team, will be allowed toparticipate in the study and will remain evaluable for the clinical endpoints.