LUMAKRAS

1 INDICATIONS AND USAGE LUMAKRAS is an inhibitor of the RAS GTPase family indicated for: KRAS G12C-mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) As a single agent, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. ( 1.1 ) This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1.1 ) KRAS G12C-mutated Metastatic Colorectal Cancer (mCRC) In combination with panitumumab, for the treatment of adult patients with KRAS G12C-mutated mCRC as determined by an FDA approved-test, who have received prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy. ( 1.2 ) 1.1 KRAS G12C-mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) LUMAKRAS as a single agent is indicated for the treatment of adult patients with KRAS G12C -mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test [see Dosage and Administration (2.1) ] , who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR) [see Clinical Studies (14.1) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 1.2 KRAS G12C-mutated Metastatic Colorectal Cancer (mCRC) LUMAKRAS, in combination with panitumumab, is indicated for the treatment of adult patients with KRAS G12C -mutated metastatic colorectal cancer (mCRC), as determined by an FDA-approved test, who have received prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy [see Dosage and Administration (2.1) and Clinical Studies (14.2) ] .

2 DOSAGE AND ADMINISTRATION Recommended dosage as a single agent for NSCLC and in combination with panitumumab for mCRC: 960 mg orally once daily. ( 2.2 ) Swallow tablets whole with or without food. ( 2.2 ) 2.1 Patient Selection KRAS G12C-mutated Locally Advanced or Metastatic NSCLC Select patients for treatment of locally advanced or metastatic NSCLC with LUMAKRAS based on the presence of KRAS G12C mutation in tumor or plasma specimens. If no mutation is detected in a plasma specimen, test tumor tissue [see Clinical Studies (14.1) ]. KRAS G12C-mutated mCRC Select patients for treatment of mCRC based on the presence of KRAS G12C mutation in tumor specimens [see Clinical Studies (14.2) ]. Information on FDA-approved tests for the detection of KRAS G12C mutations is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage and Administration LUMAKRAS as a Single Agent for KRAS G12C-mutated Locally Advanced or Metastatic NSCLC The recommended dosage of LUMAKRAS is 960 mg (three 320 mg tablets or four 240 mg tablets or eight 120 mg tablets) orally once daily until disease progression or unacceptable toxicity. LUMAKRAS in Combination with Panitumumab for KRAS G12C-mutated mCRC The recommended dosage of LUMAKRAS is 960 mg (three 320 mg tablets or four 240 mg tablets or eight 120 mg tablets) orally once daily in combination with panitumumab until disease progression or unacceptable toxicity. Administer the first dose of LUMAKRAS prior to first panitumumab infusion. Refer to the panitumumab full prescribing information for recommended panitumumab dosage information. Take the daily dose of LUMAKRAS at the same time each day with or without food [see Clinical Pharmacology (12.3) ] . Swallow tablets whole. Do not chew, crush or split tablets . If a dose of LUMAKRAS is missed by more than 6 hours, take the next dose as prescribed the next day. Do not take 2 doses at the same time to make up for the missed dose. If vomiting occurs after taking LUMAKRAS, do not take an additional dose. Take the next dose as prescribed the next day. Administration to Patients Who Have Difficulty Swallowing Solids Disperse tablets in 120 mL (4 ounces) of non-carbonated, room-temperature water without crushing. No other liquids should be used. Stir or swirl the cup for approximately 3 minutes until tablets are dispersed into small pieces (the tablets will not completely dissolve) and drink immediately or within 2 hours. The appearance of the mixture may range from pale yellow to bright yellow. Swallow the tablet dispersion. Do not chew pieces of the tablet. Rinse the container with an additional 120 mL (4 ounces) of water and drink. If the mixture is not consumed immediately, stir the mixture again to ensure that tablets are dispersed. 2.3 Dosage Modifications for Adverse Reactions LUMAKRAS dose reduction levels are summarized in Table 1. If adverse reactions occur, a maximum of two dose reductions are permitted. Discontinue LUMAKRAS if patients are unable to tolerate the minimum dose of 240 mg once daily. When LUMAKRAS is administered in combination with panitumumab, and LUMAKRAS is temporarily withheld or permanently discontinued, temporarily withhold or permanently discontinue panitumumab, respectively [see Clinical Studies (14.2) ] . Refer to the full prescribing information of panitumumab for dose modifications for adverse reactions associated with the use of panitumumab. Treatment with LUMAKRAS as a single agent may be continued if panitumumab is permanently discontinued [see Clinical Pharmacology (12.1) , Clinical Studies (14.2) ]. Refer to Table 2 for dose modification guidelines and management of adverse reactions associated with the use of LUMAKRAS as a single agent or as combination therapy with panitumumab. Table 1. Recommended LUMAKRAS Dose Reduction Levels for Adverse Reactions Dose Reduction Level Dose First dose reduction 480 mg (two 240 mg or four 120 mg tablets) once daily Second dose reduction 240 mg (one 240 mg or two 120 mg tablets) once daily Table 2. Recommended LUMAKRAS Dosage Modifications for Adverse Reactions Adverse Reaction Severity Grading defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 . Dosage Modification When LUMAKRAS is administered in combination with panitumumab, withhold or permanently discontinue treatment with panitumumab when withholding or permanently discontinuing treatment with LUMAKRAS. ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal Hepatotoxicity [see Warnings and Precautions (5.1) ] AST or ALT > 3 × and up to 5 × ULN (or > 3 × and up to 5 × baseline if baseline abnormal) with symptoms or AST or ALT > 5 × ULN (or > 5 × baseline if baseline abnormal) Withhold LUMAKRAS until recovery to ≤ 3 × ULN or to ≤ 3 × baseline if baseline abnormal. Resume LUMAKRAS at the next lower dose level. AST or ALT > 3 × ULN with total bilirubin > 2 × ULN Permanently discontinue LUMAKRAS if no alternative cause is identified. If alternative cause is identified, do not resume LUMAKRAS until AST/ALT/bilirubin return to baseline. Interstitial Lung Disease (ILD)/ pneumonitis [see Warnings and Precautions (5.2) ] Any Grade Withhold LUMAKRAS if ILD/pneumonitis is suspected. Permanently discontinue LUMAKRAS if ILD/pneumonitis is confirmed. Nausea or vomiting despite appropriate supportive care (including anti-emetic therapy) [see Adverse Reactions (6.1) ] Grade 3 to 4 Withhold LUMAKRAS until recovery to ≤ Grade 1 or baseline. Resume LUMAKRAS at the next lower dose level. Diarrhea despite appropriate supportive care (including anti-diarrheal therapy) [see Adverse Reactions (6.1) ] Grade 3 to 4 Withhold LUMAKRAS until recovery to ≤ Grade 1 or baseline. Resume LUMAKRAS at the next lower dose level. Other adverse reactions [see Adverse Reactions (6.1) ] Grade 3 to 4 Withhold LUMAKRAS until recovery to ≤ Grade 1 or baseline. Resume LUMAKRAS at the next lower dose level. 2.4 Coadministration of LUMAKRAS with Acid-Reducing Agents Avoid coadministration of proton pump inhibitors (PPIs) and H 2 receptor antagonists with LUMAKRAS. If treatment with an acid-reducing agent cannot be avoided, take LUMAKRAS 4 hours before or 10 hours after administration of a local antacid [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor liver function tests every 3 weeks for the first 3 months of treatment then once monthly as clinically indicated. Consider administering systemic corticosteroids and withhold, reduce the dose, or permanently discontinue LUMAKRAS based on the severity. ( 2.3 , 5.1 ) Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms. Immediately withhold LUMAKRAS for suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified. ( 2.3 , 5.2 ) 5.1 Hepatotoxicity LUMAKRAS can cause hepatotoxicity and increased alanine aminotransferase (ALT) or increased aspartate aminotransferase (AST) which may lead to drug-induced liver injury and hepatitis. In the pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg [see Adverse Reactions (6.1) ] , hepatotoxicity occurred in 27% of patients, of which 16% were Grade ≥ 3. Among patients with hepatotoxicity who required dosage modifications, 64% required treatment with corticosteroids. In this pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg, 17% of patients who received LUMAKRAS had increased ALT/increased AST; of which 9% were Grade ≥ 3. The median time to first onset of increased ALT/AST was 6.3 weeks (range: 0.4 to 42). Increased ALT/AST leading to dose interruption or reduction occurred in 9% of patients treated with LUMAKRAS. LUMAKRAS was permanently discontinued due to increased ALT/AST in 2.7% of patients. Drug-induced liver injury occurred in 1.6% (all grades) including 1.3% (Grade ≥ 3). In this pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg, a total of 40% patients with recent (≤ 3 months) immunotherapy prior to starting LUMAKRAS had an event of hepatotoxicity. An event of hepatotoxicity was observed in 18% of patients who started LUMAKRAS more than 3 months after last dose of immunotherapy and in 17% of those who never received immunotherapy. Regardless of time from prior immunotherapy, 94% of hepatotoxicity events improved or resolved with dosage modification of LUMAKRAS, with or without corticosteroid treatment. In the pooled safety population of patients with CRC who received LUMAKRAS 960 mg in combination with panitumumab [see Adverse Reactions (6.1) ] , hepatotoxicity occurred in 15% of patients, of which 4.8% were Grade 3. A total of 7% of patients who received LUMAKRAS had increased ALT or increased AST, of which 0.8% were Grade 3. The median time to first onset of increased ALT or increased AST was 10 weeks (range: 2 to 22). Increased ALT or increased AST leading to dose interruption occurred in 2.4% of patients. A total of 3.2% of patients who received LUMAKRAS had hyperbilirubinemia, of which 2.4% were Grade 3. The median time to first onset of hyperbilirubinemia was 12 weeks (range: 0, 29). Hyperbilirubinemia leading to dose interruption occurred in 1.6% of patients. Among patients with hepatotoxicity, 21% received corticosteroids. Monitor liver function tests (ALT, AST, alkaline phosphatase and total bilirubin) prior to the start of LUMAKRAS, every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations. Withhold, reduce the dose or permanently discontinue LUMAKRAS based on severity of the adverse reaction [see Dosage and Administration (2.3) and Adverse Reactions (6.1) ]. Consider administering systemic corticosteroids for the management of hepatotoxicity. 5.2 Interstitial Lung Disease (ILD)/Pneumonitis LUMAKRAS can cause ILD/pneumonitis that can be fatal. In the pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg [see Adverse Reactions (6.1) ] , ILD/pneumonitis occurred in 2.2% of patients, of which 1.1% were Grade ≥ 3, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 8.6 weeks (range: 2.1 to 36.7 weeks). LUMAKRAS was permanently discontinued due to ILD/pneumonitis in 1.3% of LUMAKRAS-treated patients. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.3) and Adverse Reactions (6.1) ] . In the pooled safety population of patients with CRC who received LUMAKRAS 960 mg in combination with panitumumab, 1 patient experienced a Grade 1 event of ILD/pneumonitis [see Adverse Reactions (6.1) ] .

7 DRUG INTERACTIONS Acid-Reducing Agents: Avoid coadministration with proton pump inhibitors (PPIs) and H 2 receptor antagonists. If an acid-reducing agent cannot be avoided, administer LUMAKRAS 4 hours before or 10 hours after a local antacid. ( 2.4 , 7.1 ) Strong CYP3A4 Inducers: Avoid coadministration with strong CYP3A4 inducers. ( 7.1 ) CYP3A4 Substrates: Avoid coadministration with CYP3A4 substrates for which minimal concentration changes may lead to therapeutic failures of the substrate. If coadministration cannot be avoided, adjust the substrate dosage in accordance to its Prescribing Information. ( 7.2 ) P-gp substrates: Avoid coadministration with P-gp substrates for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the substrate dosage in accordance to its Prescribing Information. ( 7.2 ) 7.1 Effects of Other Drugs on LUMAKRAS Acid-Reducing Agents The solubility of sotorasib is pH-dependent. Coadministration of LUMAKRAS with gastric acid-reducing agents decreased sotorasib concentrations [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of sotorasib. Avoid coadministration of LUMAKRAS with proton pump inhibitors (PPIs), H 2 receptor antagonists, and locally acting antacids. If coadministration with an acid-reducing agent cannot be avoided, administer LUMAKRAS 4 hours before or 10 hours after administration of a locally acting antacid [see Dosage and Administration (2.4) ] . Strong CYP3A4 Inducers Sotorasib is a CYP3A4 substrate. Coadministration of LUMAKRAS with a strong CYP3A4 inducer decreased sotorasib concentrations [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of sotorasib. Avoid coadministration of LUMAKRAS with strong CYP3A4 inducers . 7.2 Effects of LUMAKRAS on Other Drugs CYP3A4 Substrates Sotorasib is a CYP3A4 inducer. Coadministration of LUMAKRAS with a CYP3A4 substrate decreased its plasma concentrations [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of the substrate. Avoid coadministration of LUMAKRAS with CYP3A4 sensitive substrates, for which minimal concentration changes may lead to therapeutic failures of the substrate. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information . P-glycoprotein (P-gp) Substrates Sotorasib is a P-gp inhibitor. Coadministration of LUMAKRAS with a P-gp substrate increased its plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the adverse reactions of the substrate. Avoid coadministration of LUMAKRAS with P-gp substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the P-gp substrate dosage in accordance with its Prescribing Information . Breast Cancer Resistance Protein (BCRP) Substrates Sotorasib is a BCRP-inhibitor. Coadministration of LUMAKRAS with a BCRP substrate increased its plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions of the substrate. When coadministered with LUMAKRAS, monitor for adverse reactions of the BCRP substrate and decrease the BCRP substrate dosage in accordance with its Prescribing Information.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ] Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.2) ] Single agent in NSCLC: The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium. ( 6.1 ) In combination with panitumumab in CRC: The most common adverse reactions (≥ 20%) in clinical trials of LUMAKRAS in combination with panitumumab are rash, dry skin, diarrhea, stomatitis, fatigue and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities in ≥ 2 patients (4.3%) were decreased magnesium, decreased potassium, decreased corrected calcium, and increased potassium. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to LUMAKRAS as a single agent at 960 mg orally once daily until disease progression or unacceptable toxicity in 549 patients with NSCLC with KRAS G12C mutation in the following trials: CodeBreaK 200 (NCT04303780), CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883) and CodeBreaK 105 (NCT04380753). Among these 549 patients who received LUMAKRAS, 44% were exposed for 6 months or longer and 21% were exposed for greater than one year. The pooled safety population described in WARNINGS AND PRECAUTIONS also reflects exposure to LUMAKRAS 960 mg once daily in combination with panitumumab in 126 patients who received LUMAKRAS in combination with panitumumab for mCRC in CodeBreaK 300 (NCT05198934) and CodeBreaK 101 (NCT04185883). Among the 126 patients who received LUMAKRAS 960 mg in combination with panitumumab, 40% were exposed for 6 months or longer and 10% were exposed for greater than one year. Metastatic Non-Small Cell Lung Cancer The safety of LUMAKRAS was evaluated in a subset of patients with KRAS G12C -mutated locally advanced or metastatic NSCLC in CodeBreaK 100 [see Clinical Studies (14.1) ] . Patients received LUMAKRAS 960 mg orally once daily until disease progression or unacceptable toxicity (n = 204). Among patients who received LUMAKRAS, 39% were exposed for 6 months or longer and 3% were exposed for greater than one year. The median age of patients who received LUMAKRAS was 66 years (range: 37 to 86); 55% female; 80% White, 15% Asian, and 3% Black. Serious adverse reactions occurred in 50% of patients treated with LUMAKRAS. Serious adverse reactions in ≥ 2% of patients were pneumonia (8%), hepatotoxicity (3.4%), and diarrhea (2%). Fatal adverse reactions occurred in 3.4% of patients who received LUMAKRAS due to respiratory failure (0.8%), pneumonitis (0.4%), cardiac arrest (0.4%), cardiac failure (0.4%), gastric ulcer (0.4%), and pneumonia (0.4%). Permanent discontinuation of LUMAKRAS due to an adverse reaction occurred in 9% of patients. Adverse reactions resulting in permanent discontinuation of LUMAKRAS in ≥ 2% of patients included hepatotoxicity (4.9%). Dosage interruptions of LUMAKRAS due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients were hepatotoxicity (11%), diarrhea (8%), musculoskeletal pain (3.9%), nausea (2.9%), and pneumonia (2.5%). Dose reductions of LUMAKRAS due to an adverse reaction occurred in 5% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients included increased ALT (2.9%) and increased AST (2.5%). The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium. Table 3 summarizes the common adverse reactions observed in CodeBreaK 100. Table 3. Adverse Reactions (≥ 10%) of Patients with KRAS G12C-Mutated NSCLC who Received LUMAKRAS in CodeBreaK 100 Grading defined by NCI CTCAE version 5.0. Adverse Reaction LUMAKRAS N = 204 All Grades (%) Grades 3 to 4 (%) Gastrointestinal disorders Diarrhea 42 5 Nausea 26 1 Vomiting 17 1.5 Constipation 16 0.5 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, and abdominal pain lower. 15 1.0 Hepatobiliary disorders Hepatotoxicity Hepatotoxicity includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatitis, hepatotoxicity, liver function test increased, and transaminases increased. 25 12 Respiratory, thoracic, and mediastinal disorders Cough Cough includes cough, productive cough, and upper-airway cough syndrome. 20 1.5 Dyspnea Dyspnea includes dyspnea and dyspnea exertional. 16 2.9 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, and pain in extremity. 35 8 Arthralgia 12 1.0 General disorders and administration site conditions Fatigue Fatigue includes fatigue and asthenia. 26 2.0 Edema Edema includes generalized edema, localized edema, edema, edema peripheral, periorbital edema, and testicular edema. 15 0 Metabolism and nutrition disorders Decreased appetite 13 1.0 Infections and infestations Pneumonia Pneumonia includes pneumonia, pneumonia aspiration, pneumonia bacterial, and pneumonia staphylococcal. 12 7 Skin and subcutaneous tissue disorders Rash Rash includes dermatitis, dermatitis acneiform, rash, rash-maculopapular, and rash pustular. 12 0 Table 4 summarizes the selected laboratory adverse reactions observed in CodeBreaK 100. Table 4. Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients with KRAS G12C-Mutated NSCLC who Received LUMAKRAS in CodeBreaK 100 Laboratory Abnormalities LUMAKRAS N = 204 N = number of patients who had at least one on-study assessment for the parameter of interest. Grades 1 to 4 (%) Grades 3 to 4 (%) Chemistry Increased aspartate aminotransferase 39 9 Increased alanine aminotransferase 38 11 Decreased calcium 35 0 Increased alkaline phosphatase 33 2.5 Increased urine protein 29 3.9 Decreased sodium 28 1.0 Decreased albumin 22 0.5 Hematology Decreased lymphocytes 48 2 Decreased hemoglobin 43 0.5 Increased activated partial thromboplastin time 23 1.5 Metastatic Colorectal Cancer The safety of LUMAKRAS in combination with panitumumab was evaluated in the CodeBreaK 300 study [see Clinical Studies (14.2) ] . Patients with KRAS G12C-mutated mCRC received LUMAKRAS 960 mg orally once daily in combination with panitumumab 6 mg/kg intravenously (IV) once every 2 weeks (N = 47), LUMAKRAS 240 mg orally once daily in combination with panitumumab 6 mg/kg IV once every 2 weeks (N = 50), or the investigator's choice of standard of care (SOC) trifluridine/ tipiracil or regorafenib (N = 50). Among patients who received LUMAKRAS 960 mg orally once daily in combination with panitumumab, 36% were exposed to LUMAKRAS for greater than 6 months and 6% were exposed for greater than 12 months. The median age of patients who received LUMAKRAS 960 mg in combination with panitumumab arm was 63 years (range: 37-79 years); 38% were age 65 years or older; 49% were female; 79% were White and 13% were Asian. Serious adverse reactions occurred in 26% of patients receiving LUMAKRAS 960 mg in combination with panitumumab. Serious adverse reactions in ≥ 2 patients receiving LUMAKRAS 960 mg in combination with panitumumab were sepsis (6%) and intestinal obstruction (4.3%). Fatal adverse reactions occurred in 2 patients (4.3%) receiving LUMAKRAS 960 mg in combination with panitumumab, consisting of cardiac arrest and sepsis (1 patient each). Permanent discontinuation of LUMAKRAS due to an adverse reaction occurred in 1 patient for decreased corrected calcium. Dosage interruptions of LUMAKRAS due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dosage interruption in ≥ 2 patients were rash, hepatotoxicity and intestinal obstruction. A dose reduction of LUMAKRAS due to an adverse reaction occurred in 1 patient for nausea. The most common adverse reactions (≥ 20%) in patients receiving LUMAKRAS 960 mg in combination with panitumumab were rash, dry skin, diarrhea, stomatitis, fatigue and musculoskeletal pain. The most common Grade 3-4 laboratory abnormalities in ≥ 2 patients (4.3%) were decreased magnesium, decreased potassium, decreased corrected calcium, and increased potassium. Table 5 and Table 6 summarize the adverse reactions and laboratory abnormalities, respectively, identified in CodeBreaK 300. Table 5. Adverse Reactions (≥ 10%) in Patients with KRAS G12C-Mutated mCRC who Received LUMAKRAS 960 mg in Combination with Panitumumab in CodeBreaK 300 Adverse Reaction LUMAKRAS 960 mg in combination with panitumumab N = 47 Trifluridine/tipiracil or regorafenib N = 50 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Rash includes dermatitis acneiform, dermatosis, drug eruption, eczema, erythema, hand dermatitis, rash, rash erythematous, rash maculo-papular, rash papular, rash pruritic, rash pustular, and skin toxicity. 87 26 8 2 Dry skin Dry skin includes dry skin, xerosis, and xeroderma. 28 0 2 0 Pruritis 17 0 4 0 Nail Disorder Nail disorders includes nail avulsion, nail cuticle fissure, nail disorder, nail toxicity, and paronychia. 17 0 0 0 Skin fissure 13 0 0 0 Palmar-plantar erythrodysesthesia syndrome 13 0 10 4 Gastrointestinal disorders Diarrhea Diarrhea includes diarrhea, gastroenteritis, and diarrhea hemorrhagic. 28 6 26 0 Stomatitis Stomatitis includes mucosal inflammation, stomatitis, mouth ulceration, angular cheilitis, and cheilitis. 26 0 14 0 Nausea 17 2.1 36 4 Constipation 15 2.1 10 0 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, and hepatic pain. 15 0 18 2 Vomiting 13 2.1 10 2 General disorders Fatigue Fatigue includes asthenia and fatigue. 21 0 34 2 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes arthralgia, back pain, myalgia, musculoskeletal chest pain, bone pain, and pain in extremity. 21 2.1 14 2 Hematological disorders Hemorrhage Hemorrhage includes epistaxis, gastrointestinal hemorrhage, vaginal hemorrhage, rectal hemorrhage, hematochezia, hemorrhage, hemorrhage urinary tract, hematospermia, and hematuria. 13 2.1 2 0 Eye disorders Conjunctivitis Conjunctivitis includes conjunctival hyperemia, conjunctivitis, and conjunctivitis allergic. 11 0 2 0 Table 6. Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients with KRAS G12C-Mutated mCRC who Received LUMAKRAS 960 mg in combination with panitumumab in CodeBreaK 300 The denominator used to calculate the rate varied from 44 to 46 in the LUMAKRAS + panitumumab arm and 18 to 50 in the trifluridine/tipiracil or regorafenib arm based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormalities LUMAKRAS 960 mg in combination with panitumumab Trifluridine/tipiracil or Regorafenib All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Magnesium decreased 76 24 8 0 Calcium (corrected) decreased 74 4.3 46 0 Aspartate aminotransferase increased 39 0 22 2 Alkaline Phosphatase increased 33 2.2 33 0 Creatine kinase increased 30 2.3 7 0 Alanine Aminotransferase increased 28 0 16 2 Potassium decreased 26 7 12 0 Albumin decreased 26 2.2 22 0 Urine protein increased 23 0 22 6 Potassium increased 22 4.3 6 0 Glucose decreased 22 0 2 0 Hematology Hemoglobin decreased 30 0 58 6 Lymphocytes decreased 26 2.2 56 8 White blood cells decreased 24 0 48 14

8.1 Pregnancy Risk Summary There are no available data on LUMAKRAS use in pregnant women. In rat and rabbit embryo-fetal development studies, oral sotorasib did not cause adverse developmental effects or embryo-lethality at exposures up to 4.6 times the human exposure at the 960 mg clinical dose (see Data ) . Refer to the Full Prescribing Information of panitumumab for pregnancy risk information and contraception recommendations when LUMAKRAS is administered in combination with panitumumab. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In a rat embryo-fetal development study, once daily oral administration of sotorasib to pregnant rats during the period of organogenesis resulted in maternal toxicity at the 540 mg/kg dose level (approximately 4.6 times the human exposure based on area under the curve (AUC) at the clinical dose of 960 mg). Sotorasib did not cause adverse developmental effects and did not affect embryo-fetal survival at doses up to 540 mg/kg. In a rabbit embryo-fetal development study, once daily oral administration of sotorasib during the period of organogenesis resulted in lower fetal body weights and a reduction in the number of ossified metacarpals in fetuses at the 100 mg/kg dose level (approximately 2.6 times the human exposure based on AUC at the clinical dose of 960 mg), which was associated with maternal toxicity including decreased body weight gain and food consumption during the dosing phase. Sotorasib did not cause adverse developmental effects and did not affect embryo-fetal survival at doses up to 100 mg/kg.