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)]

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*
Adverse Reaction	LUMAKRAS N = 204
Adverse Reaction	All Grades (%)	Grades 3 to 4 (%)
* Grading defined by NCI CTCAE version 5.0. † Abdominal pain includes abdominal pain, abdominal pain upper, and abdominal pain lower. ‡ Hepatotoxicity includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatitis, hepatotoxicity, liver function test increased, and transaminases increased. § Cough includes cough, productive cough, and upper-airway cough syndrome. ¶ Dyspnea includes dyspnea and dyspnea exertional. # 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. Þ Fatigue includes fatigue and asthenia. ß Edema includes generalized edema, localized edema, edema, edema peripheral, periorbital edema, and testicular edema. à Pneumonia includes pneumonia, pneumonia aspiration, pneumonia bacterial, and pneumonia staphylococcal. è Rash includes dermatitis, dermatitis acneiform, rash, rash-maculopapular, and rash pustular.
Gastrointestinal disorders
Diarrhea	42	5
Nausea	26	1
Vomiting	17	1.5
Constipation	16	0.5
Abdominal pain†	15	1.0
Hepatobiliary disorders
Hepatotoxicity‡	25	12
Respiratory, thoracic, and mediastinal disorders
Cough§	20	1.5
Dyspnea¶	16	2.9
Musculoskeletal and connective tissue disorders
Musculoskeletal pain#	35	8
Arthralgia	12	1.0
General disorders and administration site conditions
FatigueÞ	26	2.0
Edemaß	15	0
Metabolism and nutrition disorders
Decreased appetite	13	1.0
Infections and infestations
Pneumoniaà	12	7
Skin and subcutaneous tissue disorders
Rashè	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*
Laboratory Abnormalities	Grades 1 to 4 (%)	Grades 3 to 4 (%)
* N = number of patients who had at least one on-study assessment for the parameter of interest.
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
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* 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. † Dry skin includes dry skin, xerosis, and xeroderma. ‡ Nail disorders includes nail avulsion, nail cuticle fissure, nail disorder, nail toxicity, and paronychia. § Diarrhea includes diarrhea, gastroenteritis, and diarrhea hemorrhagic. ¶ Stomatitis includes mucosal inflammation, stomatitis, mouth ulceration, angular cheilitis, and cheilitis. # Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, and hepatic pain. Þ Fatigue includes asthenia and fatigue. ß Musculoskeletal pain includes arthralgia, back pain, myalgia, musculoskeletal chest pain, bone pain, and pain in extremity. à Hemorrhage includes epistaxis, gastrointestinal hemorrhage, vaginal hemorrhage, rectal hemorrhage, hematochezia, hemorrhage, hemorrhage urinary tract, hematospermia, and hematuria. è Conjunctivitis includes conjunctival hyperemia, conjunctivitis, and conjunctivitis allergic.
Skin and subcutaneous tissue disorders
Rash*	87	26	8	2
Dry skin†	28	0	2	0
Pruritis	17	0	4	0
Nail Disorder‡	17	0	0	0
Skin fissure	13	0	0	0
Palmar-plantar erythrodysesthesia syndrome	13	0	10	4
Gastrointestinal disorders
Diarrhea§	28	6	26	0
Stomatitis¶	26	0	14	0
Nausea	17	2.1	36	4
Constipation	15	2.1	10	0
Abdominal pain#	15	0	18	2
Vomiting	13	2.1	10	2
General disorders
FatigueÞ	21	0	34	2
Musculoskeletal and connective tissue disorders
Musculoskeletal painß	21	2.1	14	2
Hematological disorders
Hemorrhageà	13	2.1	2	0
Eye disorders
Conjunctivitisè	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*
Laboratory Abnormalities	LUMAKRAS 960 mg in combination with panitumumab		Trifluridine/tipiracil or Regorafenib
Laboratory Abnormalities	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* 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.
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