6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•: Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1)]
•: QTc Interval Prolongation [see Warnings and Precautions (5.2)]
•: Hepatotoxicity [see Warnings and Precautions (5.3)]
•: Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.4)]

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 adagrasib as a single agent at 600 mg orally twice daily in 366 patients with NSCLC and other solid tumors enrolled in KRYSTAL-1 and KRYSTAL-12 (NCT04685135), respectively. Among 366 patients who received adagrasib, 39% of patients were exposed for 6 months or longer and 12% were exposed for greater than one year. In this pooled safety population, the most common (≥ 25%) adverse reactions were nausea (70%), diarrhea (69%), vomiting (57%), fatigue (55%), musculoskeletal pain (38%), hepatotoxicity (37%), renal impairment (33%), edema (30%), dyspnea (26%), and decreased appetite (29%). In this pooled safety population, the most common Grade 3 or 4 (≥ 2%) laboratory abnormalities were decreased lymphocytes (20%), decreased hemoglobin (7%), increased alanine aminotransferase (4.5%), increased aspartate aminotransferase (4.2%), hypokalemia (3.6%), hyponatremia (3.4%), increased lipase (2.5%), decreased leukocytes (2.5%), decreased neutrophils (2.3%), and increased alkaline phosphatase (2.0%).

The data described in WARNINGS AND PRECAUTIONS and below also reflects exposure to adagrasib in combination with cetuximab in 94 patients with KRAS G12C-mutated, locally advanced or metastatic CRC in KRYSTAL-1.

Non-Small Cell Lung Cancer

The safety of adagrasib was evaluated in patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC in KRYSTAL-1 [see Clinical Studies (14.1)]. Patients received adagrasib 600 mg orally twice daily (n = 116). Among patients who received adagrasib, 45% were exposed for 6 months or longer and 4% were exposed for greater than one year.

The median age of patients who received adagrasib was 64 years (range 25 to 89), 56% female, 84% White, 8% Black or African American, and 4.3% Asian.

Serious adverse reactions occurred in 57% of patients who received adagrasib. Serious adverse reactions in ≥ 2% of patients were pneumonia (17%), dyspnea (9%), renal impairment (8%), sepsis (5%), hypoxia (4.3%), pleural effusion (4.3%), respiratory failure (4.3%), anemia (3.4%), cardiac failure (3.4%), hyponatremia (3.4%), hypotension (3.4%), muscular weakness (3.4%), pyrexia (3.4%), dehydration (2.6%), diarrhea (2.6%), mental status changes (2.6%), pulmonary embolism (2.6%), and pulmonary hemorrhage (2.6%). Fatal adverse reactions occurred in 11% of patients who received adagrasib due to pneumonia (3.4%), respiratory failure (1.7%), sudden death (1.7%), cardiac failure (0.9%), cerebrovascular accident (0.9%), mental status change (0.9%), pulmonary embolism (0.9%), and pulmonary hemorrhage (0.9%).

Permanent discontinuation of adagrasib due to an adverse reaction occurred in 13% of patients. Adverse reactions which resulted in permanent discontinuation of adagrasib occurring in two patients each (1.7%) were pneumonia and pneumonitis and occurring in one patient each (0.9%) were cerebrovascular accident, dyspnea, decreased ejection fraction, encephalitis, gastrointestinal obstruction, hemorrhage, hepatotoxicity, hypotension, muscular weakness, pulmonary embolism, pyrexia, respiratory failure and sepsis.

Dose interruptions of adagrasib due to an adverse reaction occurred in 77% of patients. Adverse reactions requiring dosage interruption in ≥ 2% of patients who received adagrasib included nausea, hepatotoxicity, fatigue, vomiting, pneumonia, renal impairment, diarrhea, QTc interval prolongation, anemia, dyspnea, increased lipase, decreased appetite, dizziness, hyponatremia, muscular weakness, increased amylase, pneumonitis, sepsis and decreased weight.

Dose reductions of adagrasib due to an adverse reaction occurred in 28% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients who received adagrasib included hepatotoxicity, fatigue, nausea, diarrhea, vomiting, and renal impairment.

The most common adverse reactions (≥ 20%) were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium, and decreased potassium.

Table 3 summarizes the adverse reactions in KRYSTAL-1.

Table 3: Adverse Reactions (≥ 20%) in Patients with KRAS G12C-mutated NSCLC Who Received Adagrasib in KRYSTAL-1
* Grouped term. † Hepatotoxicity includes mixed liver injury, blood alkaline phosphatase increased, alanine aminotransferase increased, aspartate aminotransferase increased, liver function test increased, blood bilirubin increased, and bilirubin conjugated increased. ‡ Renal impairment includes acute kidney injury and increased blood creatinine.
Adverse Reaction	Adagrasib N = 116
	All Grades (%)	Grade 3 or 4 (%)
Gastrointestinal Disorders
Diarrhea*	70	0.9
Nausea	69	4.3
Vomiting*	56	0.9
Constipation	22	0
Abdominal pain*	21	0
General Disorders and Administration Site Conditions
Fatigue*	59	7
Edema*	32	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain*	41	7
Hepatobiliary Disorders
Hepatotoxicity*,†	37	10
Renal and Urinary Disorders
Renal impairment*,‡	36	6
Respiratory
Dyspnea*	35	10
Cough*	24	0.9
Metabolism and Nutrition Disorders
Decreased appetite	30	4.3
Infections and Infestations
Pneumonia*	24	17
Nervous System Disorders
Dizziness*	23	0.9
Cardiac Disorders
Electrocardiogram QT prolonged	20	6

Table 4 summarizes the laboratory abnormalities in KRYSTAL-1.

Table 4: Select Laboratory Abnormalities Occurring (≥ 25%) That Worsened from Baseline in Patients with KRAS G12C-mutated NSCLC Who Received Adagrasib in KRYSTAL-1
* Denominator used to calculate the rate varied from 106 to 113 based on the number of patients with a baseline value and at least one post-treatment value.
Laboratory Abnormality	Adagrasib*
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)
Hematology
Lymphocytes decreased	64	25
Hemoglobin decreased	51	8
Platelets decreased	27	0
Chemistry
Aspartate aminotransferase increased	52	6
Sodium decreased	52	8
Creatinine increased	50	0
Albumin decreased	50	0.9
Alanine aminotransferase increased	46	5
Lipase increased	35	1.8
Magnesium decreased	26	0
Potassium decreased	26	3.5

Colorectal Cancer

The safety of adagrasib combined with cetuximab was evaluated in 94 patients with KRAS G12C-mutated, locally advanced or metastatic CRC in KRYSTAL-1 [see Clinical Studies (14.2)]. Patients started treatment with adagrasib 600 mg twice daily in combination with cetuximab weekly (n = 17) or every two weeks (n = 77). Among patients who received adagrasib in combination with cetuximab, 60% were exposed for greater than 6 months and 12% were exposed for greater than 12 months.

Serious adverse reactions occurred in 30% of patients who received adagrasib in combination with cetuximab. The most common serious adverse reactions (≥ 2%) were pneumonia (4.3%), pleural effusion, pyrexia, acute kidney injury, dehydration, and small intestinal obstruction (2.1% each).

A fatal adverse reaction of pneumonia occurred in 1 patient who received adagrasib in combination with cetuximab.

Adverse reactions leading to discontinuation of adagrasib occurred in 2 patients. Adverse reactions which resulted in permanent discontinuation of adagrasib (1 patient each) included abdominal pain and prolonged QT interval.

Adverse reactions leading to dose interruptions of adagrasib occurred in 62% of patients. The most common adverse reactions or laboratory abnormalities leading to dose interruption in ≥ 2% of patients who received adagrasib included diarrhea, nausea, vomiting, abdominal pain, dizziness, headache, pneumonia, alanine aminotransferase increased, aspartate aminotransferase increased, dyspnea, fatigue, pleural effusion, rash, anemia, electrocardiogram QT prolongation, blood bilirubin increased, blood creatinine increased, decreased appetite, dehydration, hemorrhage, hypomagnesemia, lipase increased, muscular weakness, musculoskeletal pain, and pyrexia.

Adverse reactions leading to dose reductions of adagrasib occurred in 35% of patients. The most common adverse reactions or laboratory abnormalities leading to dose reductions in ≥ 2% of patients who received adagrasib included fatigue, increased aspartate aminotransferase, increased alanine aminotransferase, nausea, decreased appetite, electrocardiogram QT prolongation, dizziness, acute kidney injury, diarrhea, dysarthria, and vomiting.

The most common adverse reactions (≥ 20%) were rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, dizziness, cough, constipation, and peripheral neuropathy.

The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, increased alanine aminotransferase, decreased magnesium, decreased albumin, increased lipase, decreased potassium, increased aspartate aminotransferase, increased creatinine, decreased sodium, decreased calcium, increased amylase, and increased alkaline phosphatase.

Table 5 summarizes the adverse reactions in patients with metastatic CRC in KRYSTAL-1.

Table 5: Adverse Reactions (≥ 20 %) in Patients with KRAS G12C-mutated CRC Received Adagrasib in Combination with Cetuximab in KRYSTAL-1
* Graded per CTCAE version 5.0. † Grouped term; includes multiple related terms.
Adverse Reaction*	Adagrasib in Combination with Cetuximab N = 94
	All Grades (%)	Grade 3 or 4 (%)
Skin and subcutaneous tissue disorders
Rash†	84	4.3
Dry skin	36	0
Gastrointestinal Disorders
Nausea	68	2.1
Diarrhea†	65	5
Vomiting†	57	0
Abdominal pain†	30	4.3
Constipation	23	0
General Disorders and Administration Site Conditions
Fatigue†	57	3.2
Musculoskeletal pain†	47	4.3
Edema†	28	0
Hepatobiliary Disorders
Hepatotoxicity†	38	10
Nervous System Disorders
Headache	37	4.3
Dizziness†	24	2.1
Peripheral neuropathy†	20	1.1
Metabolism and Nutrition Disorders
Decreased appetite	30	0
Blood and lymphatic system disorders
Anemia	27	7
Respiratory
Cough†	25	0

Other clinically relevant adverse reactions observed in less than 20% of patients were infusion related reactions (15%).

Table 6 summarizes the laboratory abnormalities in patients with metastatic CRC in KRYSTAL-1.

Table 6: Selected Laboratory Abnormalities (≥ 25%) in Patients Who Received Adagrasib in Combination with Cetuximab in KRYSTAL-1
* The denominator used to calculate the rate varied from 82 to 92 based on the number of patients with a baseline value and at least one post-treatment value.
Laboratory Abnormality	Adagrasib in Combination with Cetuximab*
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)
Hematology
Lymphocytes decreased	63	17
Hemoglobin decreased	48	5
Leukocytes decreased	27	1.1
Chemistry
Alanine aminotransferase increased	51	2.2
Magnesium decreased	49	7
Albumin decreased	46	2.2
Lipase increased	41	3.3
Potassium decreased	40	9
Aspartate aminotransferase increased	39	4.3
Creatinine increased	30	1.1
Sodium decreased	30	0
Calcium decreased	29	1.1
Amylase increased	29	0
Alkaline phosphatase increased	29	1.1