KRAZATI- adagrasib_tablet, coated

Adagrasib is an irreversible inhibitor of KRAS G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state that prevents downstream signaling without affecting wild-type KRAS protein. Adagrasib inhibited tumor cell growth and viability in cells harboring KRAS KRAS KRAS Adagrasib exposure-response relationships and the time course of pharmacodynamic response are unknown. Cardiac Electrophysiology Adagrasib increased QTc in a concentration-dependent manner. Based on the concentration-QTcF relationship, the mean (90% CI) QTcF change from baseline (ΔQTcF) was 18 (15, 21) ms at the mean steady-state maximum concentration (C max,ss [see Warnings and Precautions (5. 2) The pharmacokinetics of adagrasib were studied in healthy subjects and in patients with KRAS Adagrasib AUC and C max Absorption The median (min, max) T max Effect of Food No clinically significant differences in the pharmacokinetics of adagrasib were observed following administration of a high-fat and high-calorie meal (containing approximately 900 to 1000 calories, 50% from fat). Distribution The apparent volume of distribution of adagrasib is 942 L (57%). Human plasma protein binding of adagrasib is approximately 98% in vitro. Elimination The adagrasib terminal elimination half-life is 23 hours (16%) and the apparent oral clearance (CL/F) is 37 L/h (54%) in patients. Metabolism Adagrasib is metabolized primarily by CYP3A4 following single dose administration. Adagrasib inhibits its own CYP3A4 metabolism following multiple dosing to steady-state which permits CYP2C8, CYP1A2, CYP2B6, CYP2C9, and CYP2D6 to contribute to its metabolism at steady-state. Excretion Following a single oral dose of radiolabeled adagrasib, approximately 75% of the dose was recovered in feces (14% as unchanged) and 4. 5% recovered in urine (2% as unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of adagrasib based on age (19 to 89 years), sex, race (White, Black or African American, or Asian), body weight (36 to 146 kg), ECOG PS (0, 1), tumor type (NSCLC or CRC), or tumor burden. No clinically significant differences in the pharmacokinetics of adagrasib are expected in patients with mild to severe renal impairment (CLcr 15 to < 90 mL/min estimated by Cockcroft-Gault equation) or in patients with mild to severe hepatic impairment (Child-Pugh classes A to C). Drug Interaction Studies Clinical Studies and Model-Informed Approaches The following table describes the effect of other drugs on the pharmacokinetics of adagrasib. Table 7: Effect of Other Drugs on Adagrasib C max Concomitant Drug Adagrasib Dosage Changes in C max C max % Decrease AUC % Decrease Rifampin 600 mg single dose 88% 95% 600 mg multiple doses > 61% Predicted changes in C max > 66% Strong CYP3A Inhibitors: max No clinically significant differences in the pharmacokinetics of adagrasib were predicted or observed when used concomitantly with efavirenz (a moderate CYP3A inducer), pantoprazole (a proton pump inhibitor), or rosuvastatin (a BCRP/OATP substrate). The following table describes the effect of adagrasib on the pharmacokinetics of other drugs. Table 8: Effect of Adagrasib on Other Drugs C max Concomitant Drug Adagrasib Dosage Fold Increase of Concomitant Drug C max AUC Midazolam 400 mg 0. 66 times the approved recommended dosage. 8-fold 21-fold 600 mg twice daily 3. 1-fold Predicted changes in C max 31-fold Warfarin 600 mg twice daily 1. 9-fold Dextromethorphan 400 mg 1. 8-fold 600 mg twice daily 1. 4-fold Digoxin 600 mg twice daily 1. 5-fold In Vitro Studies Cytochrome P450 (CYP) Enzymes: Transporter Systems:.

KRAZATI is an inhibitor of the RAS GTPase family indicated for: Non-small cell lung cancer (NSCLC)* KRAS 1. 1 Colorectal cancer (CRC)* KRAS 1. 2 *These indications are approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for these indications may be contingent upon verification and description of a clinical benefit in confirmatory trials. 2 KRAZATI, as a single-agent, is indicated for the treatment of adult patients with KRAS [see Dosage and Administration (2. 1) This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR) [see Clinical Studies (14. 1) KRAZATI in combination with cetuximab is indicated for the treatment of adult patients with KRAS [see Dosage and Administration (2. 1) This indication is approved under accelerated approval based on ORR and DOR [see Clinical Studies (14.

2 Non-Small Cell Lung Cancer Select patients for treatment of locally advanced or metastatic NSCLC with KRAZATI based on the presence of KRAS [see Clinical Studies (14. 1) Colorectal Cancer Select patients for treatment of locally advanced or metastatic CRC with KRAZATI based on the presence of KRAS [see Clinical Studies (14. 2) Information on FDA-approved tests for the detection of a KRAS https://www. gov/CompanionDiagnostics The recommended dosage of KRAZATI as a single agent or in combination with cetuximab Refer to the cetuximab prescribing information for cetuximab dosage information [see Clinical Studies (14. 2) Take KRAZATI at the same time every day with or without food [see Clinical Pharmacology (12. 3) If vomiting occurs after taking KRAZATI, do not take an additional dose. Resume dosing at the next scheduled time. If a dose is inadvertently missed, it should be skipped if greater than 4 hours have elapsed from the expected dosing time. Recommended dose reductions for adverse reactions for use of KRAZATI as a single agent or in combination with cetuximab Table 1: Recommended KRAZATI Dosage Reductions for Adverse Reactions Dose Reduction Dosage First dose reduction 400 mg twice daily Second dose reduction 600 mg once daily Refer to the cetuximab prescribing information for dose modifications for adverse reactions associated with cetuximab. When KRAZATI is administered in combination with cetuximab, withhold or permanently discontinue cetuximab when KRAZATI is withheld or permanently discontinued. Treatment with KRAZATI as a single agent may be continued if cetuximab is permanently discontinued. [see Clinical Pharmacology (12. 1) Clinical Studies (14. 2) The recommended dosage modifications for adverse reactions are provided in Table 2. Table 2: Recommended KRAZATI Dosage Modifications for Adverse Reactions ALT = alanine aminotransferase; AST = aspartate aminotransferase; ILD = Interstitial Lung Disease; ULN = upper limit of normal Adverse Reaction Severity Grading defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5. Dosage Modification When KRAZATI is administered in combination with cetuximab, withhold or permanently discontinue treatment with cetuximab when withholding or permanently discontinuing treatment with KRAZATI. Nausea or vomiting despite appropriate supportive care (including anti-emetic therapy) [see Warnings and Precautions (5. 1) Grade 3 or 4 Diarrhea despite appropriate supportive care (including anti-diarrheal therapy) [see Warnings and Precautions (5. 1) Grade 3 or 4 QTc Interval Prolongation [see Warnings and Precautions (5. 2) QTc absolute value greater than 500 ms Torsade de pointes, polymorphic ventricular tachycardia or signs or symptoms of serious or life-threatening arrhythmia Hepatotoxicity [see Warnings and Precautions (5. 3) Grade 2 Grade 3 or 4 AST or ALT > 3 × ULN with total bilirubin > 2 × ULN in the absence of alternative causes Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5. 4) Any Grade Other Adverse Reactions [see Adverse Reactions (6. 1) Grade 3 or 4 .

The following clinically significant adverse reactions are described elsewhere in the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) Single agent use in NCSLC: 6. 1 In combination with cetuximab in CRC: 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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. The data described in WARNINGS AND PRECAUTIONS and below also reflects exposure to adagrasib in combination with cetuximab in 94 patients with KRAS Non-Small Cell Lung Cancer The safety of adagrasib was evaluated in patients with KRAS [see Clinical Studies (14. 1) 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. 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. 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. 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 Adverse Reaction Adagrasib N = 116 All Grades (%) Grade 3 or 4 (%) Gastrointestinal Disorders Diarrhea Grouped term. 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 , 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. 37 10 Renal and Urinary Disorders Renal impairment , Renal impairment includes acute kidney injury and increased blood creatinine. 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 Laboratory Abnormality Adagrasib 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. 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 [see Clinical Studies (14. 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. 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 Adverse Reaction Graded per CTCAE version 5. Adagrasib in Combination with Cetuximab N = 94 All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped term; includes multiple related terms. 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 Laboratory Abnormality Adagrasib in Combination with Cetuximab 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. 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.

Lactation 8. 2 Risk Summary There are no available data on the use of KRAZATI in pregnant women. In animal reproduction studies, oral administration of adagrasib to pregnant rats and rabbits during the period of organogenesis did not cause adverse development effects or embryo-fetal lethality at exposures below the human exposure at the recommended dose of 600 mg twice daily (see Data) In the U. 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 adagrasib to pregnant rats during the period of organogenesis resulted in maternal toxicity (reduced body weight and food intake, and adverse clinical signs leading to moribund condition and early termination) and lower fetal body weight at 270 mg/kg dose level (approximately 2 times the recommended dose of 600 mg twice daily based on body surface area [BSA]). Adagrasib induced skeletal malformations, such as bent limbs, and skeletal variations, such as bent scapula, wavy ribs, and supernumerary short cervical ribs at 270 mg/kg, which were secondary to maternal toxicity and reduced fetal body weight. In a rabbit embryo-fetal development study, once daily oral administration of adagrasib during the period of organogenesis resulted in lower fetal body weight and increased litter frequency of unossified sternebra at 30 mg/kg (approximately 0. 11 times the human exposure based on area under the curve [AUC] at the clinical dose of 600 mg twice daily). This skeletal variation was associated with maternal toxicities, including reduced mean body weight and decreased food consumption. Adagrasib exposure did not cause adverse developmental effects and did not affect embryo-fetal survival in rabbits at doses up to 30 mg/kg once daily. Risk Summary There are no data on the presence of adagrasib or its metabolites in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KRAZATI and for 1 week after the last dose. Infertility Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13. 1) The safety and effectiveness of KRAZATI has not been established in pediatric patients. Of 116 patients with metastatic NSCLC who received adagrasib 600 mg orally twice daily in KRYSTAL-1, 49% (57 patients) were >= 65 years of age and 13% (15 patients) were >= 75 years of age. No overall differences in safety or effectiveness were observed between older and younger patients. Of 94 patients with metastatic CRC who received adagrasib 600 mg orally twice daily in combination with cetuximab in KRISTAL-1, 33% (31 patients) were >= 65 years of age and 2. 1% (2 patients) were >= 75 years of age.

See full prescribing information for clinically significant drug interactions with KRAZATI. ( 7 Strong CYP3A4 Inducers 7. 1 Strong CYP3A4 Inhibitors 7. 1 Sensitive CYP3A4 Substrates 7. 2 Sensitive CYP2C9 or CYP2D6 Substrates or P-gp Substrates 7. 2 Drugs That Prolong QT Interval 7. 3 Strong CYP3A4 Inducers Avoid concomitant use of KRAZATI with strong CYP3A inducers. Adagrasib is a CYP3A4 substrate. Concomitant use of KRAZATI with a strong CYP3A inducer reduces adagrasib exposure [see Clinical Pharmacology (12. 3) Strong CYP3A4 Inhibitors Avoid concomitant use of KRAZATI with strong CYP3A inhibitors until adagrasib concentrations have reached steady state (after approximately 8 days). If adagrasib concentrations have not reached steady state, concomitant use of a strong CYP3A inhibitor will increase adagrasib concentrations, [see Clinical Pharmacology (12. 3) Sensitive CYP3A Substrates Avoid concomitant use of KRAZATI with sensitive CYP3A substrates unless otherwise recommended in the Prescribing Information for these substrates. Adagrasib is a CYP3A inhibitor. Concomitant use with KRAZATI increases exposure of CYP3A substrates [see Clinical Pharmacology (12. 3) Sensitive CYP2C9 Substrates Avoid concomitant use of KRAZATI with sensitive CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information for these substrates. Adagrasib is a CYP2C9 inhibitor. Concomitant use with KRAZATI increases exposure of CYP2C9 substrates [see Clinical Pharmacology (12. 3) Sensitive CYP2D6 Substrates Avoid concomitant use of KRAZATI with sensitive CYP2D6 substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information for these substrates. Adagrasib is a CYP2D6 inhibitor. Concomitant use with KRAZATI increases exposure of CYP2D6 substrates [see Clinical Pharmacology (12. 3) P-gp Substrates Avoid concomitant use of KRAZATI with P-gp substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information for these substrates. Adagrasib is a P-gp inhibitor. Concomitant use with KRAZATI increases exposure of P-gp substrates [see Clinical Pharmacology (12. 3) Avoid concomitant use of KRAZATI with other product(s) with a known potential to prolong the QTc interval. If concomitant use cannot be avoided, monitor electrocardiogram and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated [see Warnings and Precautions (5. 2) [see Dosage and Administration (2. 3) Adagrasib causes QTc interval prolongation [see Clinical Pharmacology (12. 2) [see Warnings and Precautions (5.

NONCLINICAL TOXICOLOGY
Carcinogenicity studies have not been conducted with adagrasib. Adagrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not genotoxic in an in vitro chromosomal aberration assay or an in vivo micronucleus assay in rats. Fertility studies were not conducted with adagrasib. In toxicology studies of up to 13-weeks in duration in rats, oral administration of adagrasib induced phospholipidosis which increased vacuolation in female reproductive organs, including vacuolation in ovaries (corpora lutea, macrophage or interstitial cells) and uterus (glandular epithelium), and atrophy with mucification of the vaginal mucosa at doses >= 150 mg/kg (approximately equal to or greater than the human exposure at the recommended dose based on area under the curve [AUC]). These findings reversed after cessation of dosing in the 28-day study but in the 13-week study, pigmented macrophage aggregates were observed in the ovaries of female rats after the recovery period. In a 28-day repeat-dose toxicology study, oral administration of adagrasib to male rats induced atrophy and epithelial vacuolation of the prostate gland and seminal vesicles at 300 mg/kg (approximately 1. 6 times the human exposure at the recommended dose based on AUC). These findings resolved after cessation of treatment. Phospholipidosis (vacuolation and/or presence of foamy macrophages) was observed in multiple organs (e. , lung, trachea, heart, skeletal, ovaries, uterus, adrenal gland, kidney, liver, lymph nodes, spleen, thymus, and thyroid in rats; and heart and lung in dogs) after repeated oral administration of adagrasib in rats and dogs. In toxicology studies of up to 13-week duration in rats, phospholipidosis was observed at doses >= 150 mg/kg (approximately >= 2 times the human exposure at the recommended dose based on AUC). In a dog 28-day toxicity study, this effect was observed at 25 mg/kg (approximately equal to the human exposure at the recommended dose based on AUC). The extent of vacuolization and the presence of foamy macrophages were more prominent in the rat compared to dogs, and evidence of reversibility after cessation of treatment was noted for most organs. The significance of this finding in humans in unknown.
CLINICAL STUDIES
The efficacy of adagrasib was evaluated in KRYSTAL-1 (NCT03785249), a multicenter, single-arm, open-label expansion cohort study. Eligible patients were required to have locally advanced or metastatic KRAS KRAS In the efficacy population, KRAS KRAS therascreen KRAS KRAS KRAS KRAS A total of 112 patients had at least one measurable lesion at baseline as assessed by BICR according to RECIST v1. The baseline demographic and disease characteristics in the efficacy population were: median age 64 years (range: 25 to 89), 55% female, 83% White, 8% were Black or African American, 4% Asian, 4% race not reported, 0. 9% American Indian or Alaska Native, 16% Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 and 83% ECOG PS 1. Tumor histology was 97% adenocarcinoma and 89% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1 to 7); 43% received 1 prior line, 35% received 2 prior lines, 10% received 3 prior lines and 12% received 4 or more prior lines, 98% received both prior platinum and prior anti-PD-1/PD-L1 therapy. Sites of extra-thoracic disease included bone 42%, brain 30%, adrenals 21%, and liver 21%. Efficacy results are summarized in Table 9. Table 9: Efficacy Results for KRYSTAL-1 CI = Confidence Interval Efficacy Parameter Adagrasib (n = 112) Objective Response Rate (95% CI) Assessed by BICR. 43 (34, 53) Complete response rate, % 0. 9 Partial response rate, % 42 Duration of Response Median Estimate using Kaplan-Meier method. 8) Patients with duration >= 6 months Observed proportion of patients with duration of response beyond landmark time. 58 The efficacy of adagrasib in combination with cetuximab was evaluated in KRYSTAL-1, a multicenter, single-arm, open-label expansion cohort study. Eligible patients were required to have locally advanced or metastatic KRAS Patients initiated treatment with adagrasib 600 mg orally twice daily in combination with cetuximab administered either biweekly (77 patients with 500 mg/m 2 2 2 [see Dosage and Administration (2. 3) The major efficacy outcome measures were confirmed ORR and DOR according to RECIST v1. 1 as assessed by BICR. In the efficacy population, KRAS KRAS therascreen KRAS KRAS The baseline demographic and disease characteristics in the efficacy population were: median age 57 years (range: 24 to 75 years), 53% female, 71% White, 14% were Black or African American, 5% Asian, 1. 1% American Indian or Alaska Native, 9% reported as other; 51% ECOG PS 0 and 49% ECOG PS 1. Tumor histology was 100% adenocarcinoma and 99% of patients had metastatic disease. Patients received a median of 3 prior systemic therapies (range 1 to 9); 9% received 1 prior line, 36% received 2 prior lines, 31% received 3 prior lines and 25% received 4 or more prior lines. Sites of metastatic disease included lung (71%), liver (64%) and bone (14%). Efficacy results are summarized in Table 10. Table 10: Efficacy Results for KRYSTAL-1 CI = Confidence Interval Efficacy Parameter Adagrasib (n = 94) Objective Response Rate (95% CI) Assessed by BICR. 34 (25, 45) Complete response rate, % 0 Partial response rate, % 34. 0 Duration of Response Median Estimate using Kaplan-Meier method. 6) Patients with duration >= 6 months Observed proportion of patients with duration of response beyond landmark time.

Mirati Therapeutics, Inc

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