LORBRENA- lorlatinib_tablet, film coated
Function and Efficacy
Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors. In mice subcutaneously implanted with tumors harboring EML4 fusions with either ALK variant 1 or ALK mutations, including the G1202R and I1171T mutations detected in tumors at the time of disease progression on ALK inhibitors, administration of lorlatinib resulted in antitumor activity. Lorlatinib also demonstrated anti-tumor activity and prolonged survival in mice implanted intracranially with EML4-ALK-driven tumor cell lines. The overall antitumor activity of lorlatinib in in vivo models was dose-dependent and correlated with inhibition of ALK phosphorylation. Exposure-response relationships for Grade 3 or 4 hypercholesterolemia and for any Grade 3 or 4 adverse reaction were observed at steady-state exposures achieved at the recommended dosage, with higher probability of the occurrence of adverse reactions with increasing lorlatinib exposure. Cardiac Electrophysiology In 295 patients who received LORBRENA at the recommended dosage of 100 mg once daily and had an ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16. 4 ms (2-sided 90% upper confidence interval [CI] 19. Among the 284 patients with PR interval <200 ms at baseline, 14% had PR interval prolongation >=200 ms after starting LORBRENA. The prolongation of PR interval occurred in a concentration-dependent manner. Atrioventricular block occurred in 1% of patients. In 275 patients who received LORBRENA at the recommended dosage in the activity-estimating portion of Study B7461001, no large mean increases from baseline in the QTcF interval (i. , >20 ms) were detected. Steady-state lorlatinib maximum plasma concentration (C max max 0en dash24h Absorption The median lorlatinib T max The mean absolute bioavailability is 81% (90% CI 75. 2%) after oral administration compared to intravenous administration. Effect of Food There was no clinically significant effect on lorlatinib pharmacokinetics following administration of LORBRENA with a high fat, high calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat). Distribution Lorlatinib was 66% bound to plasma proteins at a concentration of 2. The blood-to-plasma ratio was 0. 99, in vitro ss Elimination The mean plasma half-life (t ½ Metabolism Lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3, in vitro In plasma, a benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib accounted for 21% of the circulating radioactivity. The oxidative cleavage metabolite, M8, is pharmacologically inactive. Excretion Following a single oral 100 mg dose of radiolabeled lorlatinib, 48% of the radioactivity was recovered in urine (<1% as unchanged) and 41% in feces (about 9% as unchanged). Specific Populations No clinically significant differences in lorlatinib pharmacokinetics were observed based on age (19 to 85 years), sex, race/ethnicity, body weight, mild to moderate renal impairment (CL cr [see Use in Specific Populations (8. 7) Patients with Severe Renal Impairment Following administration of a single oral 100 mg dose of LORBRENA, lorlatinib AUC inf cr cr Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Strong CYP3A Inducers on Lorlatinib: inf max [see Drug Interactions (7. 1) Effect of Moderate CYP3A Inducers on Lorlatinib: inf max [see Drug Interactions (7. 1) Effect of Strong CYP3A Inhibitors on Lorlatinib: inf max [see Drug Interactions (7. 1) Effect of Fluconazole on Lorlatinib: tau max [see Drug Interactions (7. 1) Effect of Moderate CYP3A Inhibitors on Lorlatinib: Effect of Lorlatinib on CYP3A Substrates: inf max [see Drug Interactions (7. 2) Effect of Lorlatinib on CYP2B6 Substrates: inf max Effect of Lorlatinib on CYP2C9 Substrates: inf max Effect of Lorlatinib on UGT1A Substrates: inf max Effect of Lorlatinib on P-gp Substrates: inf max [see Drug Interactions (7. 2) Effect of Acid-Reducing Agents on Lorlatinib In Vitro Studies Effect of Lorlatinib on CYP Enzymes: M8 does not induce CYP1A2, CYP2B6, or CYP3A. Effects of Lorlatinib on UDP-glucuronosyltransferase (UGT): Effect of Lorlatinib on Transporter Systems:.
Indication
LORBRENA registered LORBRENA is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
Usage and Dosage
Recommended dosage: 100 mg orally once daily. 2 Severe Renal Impairment: 75 mg orally once daily. 3 Select patients for the treatment of metastatic NSCLC with LORBRENA based on the presence of ALK positivity in tumor specimens [see Indications and Usage (1) Clinical Studies (14) Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www. gov/CompanionDiagnostics The recommended dosage of LORBRENA is 100 mg orally once daily, with or without food, until disease progression or unacceptable toxicity [see Clinical Pharmacology (12. 3) Swallow tablets whole. Do not chew, crush or split tablets. Do not ingest if tablets are broken, cracked, or otherwise not intact. Take LORBRENA at the same time each day. If a dose is missed, then take the missed dose unless the next dose is due within 4 hours. Do not take 2 doses at the same time to make up for a missed dose. Do not take an additional dose if vomiting occurs after LORBRENA but continue with the next scheduled dose. The recommended dose reductions are: Permanently discontinue LORBRENA in patients who are unable to tolerate 50 mg orally once daily. Dosage modifications for adverse reactions of LORBRENA are provided in Table 1. Table 1 Recommended LORBRENA Dosage Modifications for Adverse Reactions Adverse Reaction Grade based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4. Dosage Modifications Abbreviation: AV=atrioventricular; DBP=diastolic blood pressure; SBP=systolic blood pressure. Central Nervous System Effects [see Warnings and Precautions (5. 2) Grade 1 Continue at the same dose or withhold the dose until recovery to baseline. Resume LORBRENA at the same dose or at a reduced dose. Grade 2 OR Withhold dose until Grade 0 or 1. Resume LORBRENA at a reduced dose. Grade 4 Permanently discontinue LORBRENA. Hyperlipidemia [see Warnings and Precautions (5. 3) Grade 4 hypercholesterolemia OR Withhold LORBRENA until recovery of hypercholesterolemia and/or hypertriglyceridemia to less than or equal to Grade 2. Resume LORBRENA at the same dose. Atrioventricular (AV) Block [see Warnings and Precautions (5. 4) Second-degree AV block Withhold LORBRENA until PR interval is less than 200 ms. First occurrence of complete AV block Withhold LORBRENA until 1. If a pacemaker is placed, resume LORBRENA at the same dose. Recurrent complete AV block Place pacemaker or permanently discontinue LORBRENA. Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5. 5) Any Grade treatmenten dashrelated ILD/Pneumonitis Permanently discontinue LORBRENA. Hypertension [see Warnings and Precautions (5. 6) Grade 3 (SBP greater than or equal to 160 mmHg or DBP greater than or equal to 100 mmHg; medical intervention indicated; more than one antihypertensive drug, or more intensive therapy than previously used indicated) Withhold LORBRENA until hypertension has recovered to Grade 1 or less (SBP less than 140 mmHg and DBP less than 90 mmHg), then resume LORBRENA at the same dose. Grade 4 (life-threatening consequences, urgent intervention indicated) Withhold LORBRENA until recovery to Grade 1 or less, and resume at a reduced dose or permanently discontinue LORBRENA. Hyperglycemia [see Warnings and Precautions (5. 7) Grade 3 (greater than 250 mg/dL) despite optimal anti-hyperglycemic therapy OR Withhold LORBRENA until hyperglycemia is adequately controlled, then resume LORBRENA at the next lower dosage. Other Adverse Reactions Grade 1 OR Continue LORBRENA at same dose or reduced dose. Grade 3 OR Withhold LORBRENA until symptoms resolve to less than or equal to Grade 2 or baseline. Resume LORBRENA at reduced dose. LORBRENA is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA [see Contraindications (4) Warnings and Precautions (5. 1) Drug Interactions (7. 1) Clinical Pharmacology (12. 3) Avoid concomitant use of moderate CYP3A inducers with LORBRENA. If concomitant use with moderate CYP3A inducers is unavoidable, increase the LORBRENA dose to 125 mg once daily [see Drug Interactions (7. 3) Avoid concomitant use of LORBRENA with strong CYP3A inhibitors. If concomitant use with a strong CYP3A inhibitor is unavoidable, reduce the starting dose of LORBRENA from 100 mg orally once daily to 75 mg orally once daily. In patients who have had a dose reduction to 75 mg orally once daily due to adverse reactions and who initiate a strong CYP3A inhibitor, reduce the LORBRENA dose to 50 mg orally once daily. If concomitant use of a strong CYP3A inhibitor is discontinued, increase the LORBRENA dose (after 3 plasma half-lives of the strong CYP3A inhibitor) to the dose that was used before starting the strong inhibitor [see Drug Interactions (7. 3) Avoid concomitant use of LORBRENA with fluconazole [see Clinical Pharmacology (12. 3) [see Drug Interactions (7. 3) Reduce the recommended dosage of LORBRENA for patients with severe renal impairment (creatinine clearance [CL cr [see Use in Specific Populations (8. 7) Clinical Pharmacology (12.
Label
Adverse Reactions
The following 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) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) Most common (incidence >=20%) adverse reactions and Grade 3en dash4 laboratory abnormalities are edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, hypercholesterolemia, hypertriglyceridemia, and cough. 1 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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 section reflects exposure to LORBRENA in 476 patients who received 100 mg LORBRENA once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORBRENA, 75% were exposed for 6 months or longer and 61% were exposed for greater than 1 year. In this pooled safety population, the most frequent adverse reactions in >= 20% of 476 patients who received LORBRENA were edema (56%), peripheral neuropathy (44%), weight gain (31%), cognitive effects (28%), fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects (21%), and cough (21%). The most frequent Grade 3en dash4 laboratory abnormalities in >= 20% of 476 patients who received LORBRENA were hypercholesterolemia (21%) and hypertriglyceridemia (21%). Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study) The safety of LORBRENA was evaluated in 149 patients with ALK-positive NSCLC in a randomized, open-label, active-controlled trial for the treatment of patients with ALK-positive, locally advanced or metastatic, NSCLC who had not received previous systemic treatment for advanced disease [see Clinical Studies (14) Serious adverse reactions occurred in 34% of patients treated with LORBRENA; the most frequently reported serious adverse reactions were pneumonia (4. 7%), dyspnea (2. 7%), respiratory failure (2. 7%), cognitive effects (2. 0%), and pyrexia (2. Fatal adverse reactions occurred in 3. 4% of patients treated with LORBRENA and included pneumonia (0. 7%), respiratory failure (0. 7%), cardiac failure acute (0. 7%), pulmonary embolism (0. 7%), and sudden death (0. Permanent discontinuation of LORBRENA due to adverse reactions occurred in 6. 7% of patients. The most frequent adverse reaction that led to permanent discontinuation of LORBRENA was cognitive effects (1. Adverse reactions leading to dose interruptions occurred in 49% of patients treated with LORBRENA. The most frequent adverse reactions that led to dose interruptions of LORBRENA were hypertriglyceridemia (7%), edema (5%), pneumonia (4. 7%) cognitive effects (4. 0%), mood effects (4. 0%), and hypercholesterolemia (3. Adverse reactions leading to dose reductions occurred in 21% of patients treated with LORBRENA. The most frequent adverse reactions that led to dose reductions were edema (5%), hypertriglyceridemia (4. 0%), and peripheral neuropathy (3. Tables 2 and 3 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461006. Table 2 Adverse Reactions (>=10% for all NCI CTCAE Grades or >=2% for Grades 3en dash4) in Patients Treated with LORBRENA in Study B7461006 Adverse reactions were graded using NCI CTCAE version 4. Adverse Reaction LORBRENA N=149 Crizotinib N=142 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class. Psychiatric Mood effects Mood effects (including affective disorder, affect lability, agitation, anger, anxiety, bipolar I disorder, depressed mood, depression, depressive symptom, euphoric mood, intentional self-injury, irritability, mood altered, mood swings, stress). 16 2 5 0 Nervous system Peripheral neuropathy Peripheral neuropathy (including dysesthesia, gait disturbance, hypoesthesia, motor dysfunction, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy). 7 Cognitive effects Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: confusional state, delirium, disorientation). 21 2 6 0 Headache 17 0 18 0. 7 Dizziness 11 0 14 0 Sleep effects Sleep effects (including insomnia, nightmare, sleep disorder, somnambulism). 3 10 0 Respiratory Dyspnea 20 2. 1 Cough 16 0 18 0 Respiratory failure 2. 7 2 0 0 Vascular disorders Hypertension 18 10 2. 1 0 Ocular Vision disorder Vision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). 7 Gastrointestinal Diarrhea 21 1. 7 Nausea 15 0. 1 Constipation 17 0 30 0. 7 Vomiting 13 0. 4 Musculoskeletal and connective tissue Arthralgia 19 0. 7 11 0 Myalgia Myalgia (including musculoskeletal pain, myalgia). 7 7 0 Back pain 15 0. 7 11 0 Pain in extremity 17 0 8 0 General Edema Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). 4 Weight gain 38 17 13 2. 1 Fatigue Fatigue (including asthenia, fatigue). 8 Pyrexia 17 1. 4 Chest pain 11 1. 7 Infections Upper respiratory tract infection Upper respiratory tract infection (including upper respiratory infection). 4 Pneumonia 7. 5 Bronchitis 6. 1 0 Skin Rash Rash (including dermatitis acneiform, maculopapular rash, rash). 5 0 Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were speech effects (6. 7%) and psychotic effects (3. Table 3 Laboratory Abnormalities Worsening from Baseline in >=20% of Patients in Study B7461006 Laboratory Abnormality LORBRENA N=149 Crizotinib N=142 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; GGT=gamma glutamyl transferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; PTT=partial thromboplastin time. N=number of patients who had at least one on-study assessment for the parameter of interest. Chemistry Hypertriglyceridemia N=149 (LORBRENA). N=141 (crizotinib). 95 22 27 0 Hypercholesterolemia 91 19 12 0 Increased creatinine 81 0. 1 Increased GGT 52 6 41 6 Increased AST 48 2 75 3. 5 Hyperglycemia 48 7 27 2. 1 Increased ALT 44 2. 3 Increased CPK 39 2 64 5 Hypoalbuminemia 36 0. 7 61 6 Increased lipase 28 7 34 5 Increased alkaline phosphatase 23 0 50 0. 7 Hyperkalemia 21 1. 1 Increased amylase N=148 (LORBRENA). Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; GGT=gamma glutamyl transferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; PTT=partial thromboplastin time. 4 Hematology Anemia 48 2 38 2. 8 Activated PTT N=138 (LORBRENA). N=135 (crizotinib). 25 0 14 0 Lymphopenia 23 2. 7 43 6 Thrombocytopenia 23 0 7 0. 7 Previously Treated ALK-Positive Metastatic NSCLC The data described below reflect exposure to LORBRENA in 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who received LORBRENA 100 mg orally once daily in Study B7461001, a multi-cohort, non-comparative trial [see Clinical Studies (14) The most frequent (>=20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. Of the worsening laboratory values occurring in >=20% of patients, the most frequent were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase. Serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3. 4%), dyspnea (2. 7%), pyrexia (2%), mental status changes (1. 4%), and respiratory failure (1. Fatal adverse reactions occurred in 2. 7% of patients and included pneumonia (0. 7%), myocardial infarction (0. 7%), acute pulmonary edema (0. 3%), embolism (0. 3%), peripheral artery occlusion (0. 3%), and respiratory distress (0. Permanent discontinuation of LORBRENA for adverse reactions occurred in 8% of patients. The most frequent adverse reactions that led to permanent discontinuation were respiratory failure (1. 4%), dyspnea (0. 7%), cognitive effects (0. 7%) and mood effects (0. Approximately 48% of patients required dose interruption. The most frequent adverse reactions that led to dose interruptions were edema (7%), hypertriglyceridemia (6%), peripheral neuropathy (5%), cognitive effects (4. 4%), increased lipase (3. 7%), hypercholesterolemia (3. 4%), mood effects (3. 1%), dyspnea (2. 7%), pneumonia (2. 7%), and hypertension (2. Approximately 24% of patients required at least 1 dose reduction for adverse reactions. The most frequent adverse reactions that led to dose reductions were edema (6%), peripheral neuropathy (4. 7%), cognitive effects (4. 1%), and mood effects (3. Tables 4 and 5 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461001. Table 4 Adverse Reactions Occurring in >=10% of Patients in Study B7461001 Adverse reactions were graded using NCI CTCAE version 4. Adverse Reaction LORBRENA (N=295) All Grades (%) Grade 3 or 4 (%) Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class. Psychiatric Mood effects Mood effects (including affective disorder, affect lability, aggression, agitation, anxiety, depressed mood, depression, euphoric mood, irritability, mania, mood altered, mood swings, personality change, stress, suicidal ideation). 7 Nervous system Peripheral neuropathy Peripheral neuropathy (including burning sensation, carpal tunnel syndrome, dysesthesia, formication, gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral sensory neuropathy, sensory disturbance). 7 Cognitive effects Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, dementia, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: attention deficit/hyperactivity disorder, confusional state, delirium, disorientation, reading disorder). 27 2 Headache 18 0. 7 Dizziness 16 0. 7 Speech effects Speech effects (including aphasia, dysarthria, slow speech, speech disorder) 12 0. 3 Sleep effects Sleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism) 10 0 Respiratory Dyspnea 27 5 Cough 18 0 Ocular Vision disorder Vision disorder (including blindness, diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). 3 Gastrointestinal Diarrhea 22 0. 7 Nausea 18 0. 7 Constipation 15 0 Vomiting 12 1 Musculoskeletal and connective tissue Arthralgia 23 0. 7 Myalgia Myalgia (including musculoskeletal pain, myalgia). 17 0 Back pain 13 0. 7 Pain in extremity 13 0. 3 General Edema Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). 3 Weight gain 24 4. 4 Pyrexia 12 0. 7 Infections Upper respiratory tract infection Upper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection). 12 0 Skin Rash Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash). 3 Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were psychotic effects (7%). Table 5 Worsening Laboratory Values Occurring in >=20% of Patients in Study B7461001 Grades using NCI CTCAE version 4. Laboratory Abnormality LORBRENA All Grades (%) Grade 3 or 4 (%) Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events. Chemistry Hypercholesterolemia N=292. 96 18 Hypertriglyceridemia 90 18 Hyperglycemia N=293. 52 5 Increased AST 37 2. 1 Hypoalbuminemia N=291. 33 1 Increased ALT 28 2. 1 Increased lipase N=290. 24 10 Increased alkaline phosphatase 24 1 Increased amylase N=284. 9 Hypophosphatemia 21 4. 8 Hyperkalemia 21 1 Hypomagnesemia 21 0 Hematology Anemia 52 4. 8 Thrombocytopenia 23 0. 3 Lymphopenia 22 3.
Precautions
LORBRENA is contraindicated in patients taking strong CYP3A inducers, due to the potential for serious hepatotoxicity [see Warnings and Precautions (5. 1) Concomitant use with strong CYP3A inducers.
Special Population Medication
Lactation: Advise not to breastfeed. 2 Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12. 1) (see Data In the U. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively. Data Animal Data Preliminary embryo-fetal development studies investigating the administration of lorlatinib during the period of organogenesis were conducted in rats and rabbits. In rabbits, lorlatinib administration resulted in abortion and total loss of pregnancy at doses of 15 mg/kg (approximately 3 times the human exposure at the recommended dose of 100 mg) or greater. At a dose of 4 mg/kg (approximately 0. 6 times the human exposure at the recommended dose of 100 mg) toxicities included increased post-implantation loss and malformations including rotated limbs, malformed kidneys, domed head, high arched palate, and dilation of the cerebral ventricles. In rats, administration of lorlatinib resulted in total loss of pregnancy at doses of 4 mg/kg (approximately 5 times the human exposure at the recommended dose of 100 mg) or greater. At a dose of 1 mg/kg (approximately equal to the human exposure at the recommended dose of 100 mg) there was increased post-implantation loss, decreased fetal body weight, and malformations including gastroschisis, rotated limbs, supernumerary digits, and vessel abnormalities. Risk Summary There are no data on the presence of lorlatinib or its metabolites in either human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, instruct women not to breastfeed during treatment with LORBRENA and for 7 days after the final dose. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating LORBRENA [see Use in Specific Populations (8. 1) Contraception LORBRENA can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8. 1) Females Advise female patients of reproductive potential to use effective non-hormonal contraception during treatment with LORBRENA and for at least 6 months after the final dose. Advise females of reproductive potential to use a non-hormonal method of contraception, because LORBRENA can render hormonal contraceptives ineffective [see Drug Interactions (7. 2) Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with LORBRENA and for at least 3 months after the final dose [see Nonclinical Toxicology (13. 1) Infertility Males Based on findings from animal studies, LORBRENA may transiently impair male fertility [see Nonclinical Toxicology (13. 1) The safety and effectiveness of LORBRENA in pediatric patients have not been established. Of the patients in Study B7461001 (N=295) and Study B7461006 (N=149) who received 100 mg LORBRENA orally once daily, 18% and 40% of patients, respectively, were aged 65 years or older. No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients. No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin <= upper limit of normal [ULN] with AST > ULN or total bilirubin >1 to 1. 5 × ULN with any AST). The recommended dose of LORBRENA has not been established for patients with moderate (total bilirubin >= 1. 0 × ULN with any AST) or severe (total bilirubin > 3. 0 × ULN with any AST) hepatic impairment [see Clinical Pharmacology (12. 3) Reduce the dose when administering LORBRENA to patients with severe (CL cr [see Dosage and Administration (2. 8) Clinical Pharmacology (12. 3) No dose adjustment is recommended for patients with mild or moderate (CL cr [see Clinical Pharmacology (12.
Drug Interactions
1 : 2. 2 Strong CYP3A Inducers Concomitant use of LORBRENA with a strong CYP3A inducer decreased lorlatinib plasma concentrations [see Clinical Pharmacology (12. 3) Severe hepatotoxicity occurred in healthy subjects receiving LORBRENA with rifampin, a strong CYP3A inducer. In 12 healthy subjects receiving a single 100 mg dose of LORBRENA with multiple daily doses of rifampin, Grade 3 or 4 increases in ALT or AST occurred in 83% of subjects and Grade 2 increases in ALT or AST occurred in 8%. A possible mechanism for hepatotoxicity is through activation of the pregnane X receptor (PXR) by LORBRENA and rifampin, which are both PXR agonists. LORBRENA is contraindicated in patients taking strong CYP3A inducers [see Contraindication (4) [see Dosage and Administration (2. 3) Moderate CYP3A Inducers Concomitant use of LORBRENA with a moderate CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of LORBRENA [see Clinical Pharmacology (12. 3) [see Dosage and Administration (2. 4) Strong CYP3A Inhibitors Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations [see Clinical Pharmacology (12. 5) Fluconazole Concomitant use of LORBRENA with fluconazole may increase lorlatinib plasma concentrations [see Clinical Pharmacology (12. 7) Certain CYP3A Substrates LORBRENA is a moderate CYP3A inducer. Concomitant use of LORBRENA decreases the concentration of CYP3A substrates [see Clinical Pharmacology (12. 3) Certain P-glycoprotein (P-gp) Substrates LORBRENA is a moderate P-gp inducer. Concomitant use of LORBRENA decreases the concentration of P-gp substrates [see Clinical Pharmacology (12.
Other Information
NONCLINICAL TOXICOLOGY
Carcinogenicity studies have not been conducted with lorlatinib. Lorlatinib was aneugenic in an in vitro assay in human lymphoblastoid TK6 cells and positive for micronuclei formation in vivo in the bone marrow of rats. Lorlatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Dedicated fertility studies were not conducted with lorlatinib. Findings in male reproductive organs occurred in repeat-dose toxicity studies and included lower testicular, epididymal, and prostate weights; testicular tubular degeneration/atrophy; prostatic atrophy; and/or epididymal inflammation at 15 mg/kg/day and 7 mg/kg/day in rats and dogs, respectively (approximately 8 and 2 times, respectively, the human exposure at the recommended dose of 100 mg based on AUC). The effects on male reproductive organs were reversible. Distended abdomen, skin rash, and increased cholesterol and triglycerides occurred in animals. These findings were accompanied by hyperplasia and dilation of the bile ducts in the liver and acinar atrophy of the pancreas in rats at 15 mg/kg/day and in dogs at 2 mg/kg/day (approximately 8 and 0. 5 times, respectively, the human exposure at the recommended dose of 100 mg based on AUC). All effects were reversible within the recovery period.
CLINICAL STUDIES
Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study) The efficacy of LORBRENA for the treatment of patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease was established in an open-label, randomized, active-controlled, multicenter study (Study B7461006; NCT03052608). Patients were required to have an ECOG performance status of 0en dash2 and ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay. Neurologically stable patients with treated or untreated asymptomatic CNS metastases, including leptomeningeal metastases, were eligible. Patients were required to have finished radiation therapy, at least 2 weeks (for stereotactic or partial radiation) or 4 weeks (for whole brain irradiation) prior to randomization. Patients with severe acute or chronic psychiatric conditions, including recent (within the past year) or active suicidal ideation or behavior, were excluded. Patients were randomized 1:1 to receive LORBRENA 100 mg orally once daily or crizotinib 250 mg orally twice daily. Randomization was stratified by ethnic origin (Asian vs. non-Asian) and the presence or absence of CNS metastases at baseline. Treatment on both arms was continued until disease progression or unacceptable toxicity. The major efficacy outcome measure was progression-free survival (PFS) as determined by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1. Additional efficacy outcome measures were overall survival (OS) and tumor assessment related data by BICR, including overall response rate (ORR), and duration of response (DOR). In patients with measurable CNS metastases at baseline, additional outcome measures were intracranial overall response rate (IC-ORR) and intracranial duration of response (IC-DOR) by BICR. A total of 296 patients were randomized to LORBRENA (n=149) or crizotinib (n=147). The demographic characteristics of the overall study population were: median age 59 years (range: 26 to 90 years), age >=65 years (35%), 59% female, 49% White, 44% Asian, and 0. The ECOG performance status at baseline was 0 or 1 in 96% of patients. The majority of patients had adenocarcinoma (95%) and never smoked (59%). CNS metastases were present in 26% (n=78) of patients: of these, 30 patients had measurable CNS lesions. Efficacy results from Study B7461006 as assessed by BICR are summarized in Table 6 and Figure 1. Results demonstrated a significant improvement in PFS for the LORBRENA arm over the crizotinib arm. At the data cutoff point OS data was not mature. Table 6 Efficacy Results in Study B7461006 (CROWN) Efficacy Parameter LORBRENA N=149 Crizotinib N=147 Abbreviations: CI=confidence interval; N=number of patients; NE=not estimable; PFS=progression free survival. Progression-free survival Number of events, n (%) 41 (28%) 86 (59%) Progressive disease, n (%) 32 (22%) 82 (56%) Death, n (%) 9 (6%) 4 (3%) Median, months (95% CI) Based on the Brookmeyer and Crowley method. NE (NE, NE) 9. 1) Hazard ratio (95% CI) Hazard ratio based on Cox proportional hazards model. 41) p-value p-value based on 1-sided stratified log-rank test. 0001 Overall response rate Overall response rate (95% CI) Using exact method based on binomial distribution. 76% (68, 83) 58% (49, 66) Complete response 3% 0% Partial response 73% 58% Duration of response Number of responders, n 113 85 Median, months (Range) NE (0. 5) Response duration >=6 months, n (%) 101 (89%) 53 (62%) Response duration >=12 months, n (%) 79 (70%) 23 (27%) Response duration >=18 months, n (%) 34 (30%) 9 (11%) Figure 1: Kaplan-Meier Plot of Progression-Free Survival by BICR in Study B7461006 (CROWN) The results of prespecified exploratory analyses of intracranial response rate in 30 patients with measurable CNS lesions at baseline as assessed by BICR are summarized in Table 7. Table 7 Intracranial Response Rate in Patients with Measurable Intracranial Lesions in CROWN Intracranial Tumor Response Assessment LORBRENA N=17 Crizotinib N=13 Abbreviations: CI=confidence interval; N/n=number of patients. Intracranial response rate (95% CI) Using exact method based on binomial distribution. 82% (57, 96) 23% (5, 54) Complete response 71% 8% Duration of response Number of responders, n 14 3 Response duration >=12 months, n (%) 11 (79%) 0 Figure 1 ALK-Positive Metastatic NSCLC Previously Treated with an ALK Kinase Inhibitor The efficacy of LORBRENA was demonstrated in a subgroup of patients with ALK-positive metastatic NSCLC previously treated with one or more ALK kinase inhibitors who were enrolled in a non-randomized, dose-ranging and activity-estimating, multi-cohort, multicenter study (Study B7461001; NCT01970865). Patients included in this subgroup were required to have metastatic disease with at least 1 measurable target lesion according to RECIST v1. 1, ECOG performance status of 0 to 2, and documented ALK rearrangement in tumor tissue as determined by fluorescence in situ hybridization (FISH) assay or by Immunohistochemistry (IHC), and received LORBRENA 100 mg orally once daily. Patients with asymptomatic CNS metastases, including patients with stable or decreasing steroid use within 2 weeks prior to study entry, were eligible. Patients with severe, acute, or chronic psychiatric conditions including suicidal ideation or behavior were excluded. In addition, for patients with ALK-positive metastatic NSCLC, the extent and type of prior treatment was specified for each individual cohort (see Table 8 A total of 215 patients were enrolled across the subgroups in Table 8. The distribution of patients by type and extent of prior therapy is provided in Table 8. The demographic characteristics across all 215 patients were: 59% female, 51% White, 34% Asian, and the median age was 53 years (29 to 85 years) with 18% of patients >=65 years. All patients had metastatic disease and 95% had adenocarcinoma. Brain metastases as identified by ICR were present in 69% of patients; of these, 60% had received prior radiation to the brain and 60% (n=89) had measurable disease per ICR. Table 8 Extent of Prior Therapy in the Subgroup of Patients with Previously Treated ALK-Positive Metastatic NSCLC in Study B7461001 Extent of prior therapy Number of patients Abbreviations: ALK=anaplastic lymphoma kinase; NSCLC=non-small cell lung cancer. Prior crizotinib and no prior chemotherapy Chemotherapy administered in the metastatic setting. 29 Prior crizotinib and 1en dash2 lines of prior chemotherapy 35 Prior ALK inhibitor (not crizotinib) with or without prior chemotherapy 28 Two prior ALK inhibitors with or without prior chemotherapy 75 Three prior ALK inhibitors with or without prior chemotherapy 48 Total 215 Efficacy results for Study B7461001 are summarized in Tables 9 and 10. Table 9 Efficacy Results in Study B7461001 Efficacy Parameter Overall N=215 Abbreviations: CI=confidence interval; N=number of patients. Overall response rate Per Independent Central Review. Using exact method based on binomial distribution. 48% (42, 55) Complete response 4% Partial response 44% Duration of response Median, months Estimated using the Kaplan-Meier method. 7) An assessment of intracranial ORR and the duration of response for CNS metastases in the subgroup of 89 patients in Study B7461001 with baseline measurable lesions in the CNS according to RECIST v1. 1 are summarized in Table 10. Of these, 56 (63%) patients received prior brain radiation, including 42 patients (47%) who completed brain radiation treatment at least 6 months before starting treatment with LORBRENA. Table 10 Intracranial Response Rate in Patients with Measurable Intracranial Lesions in Study B7461001 Efficacy Parameter Intracranial N=89 Abbreviations: CI=confidence interval; N=number of patients; NR=not reached. Intracranial response rate Per Independent Central Review. 60% (49, 70) Complete response 21% Partial response 38% Duration of response Median, months Estimated using the Kaplan-Meier method. 4, NR) In exploratory analyses conducted in subgroups defined by prior therapy, the response rates to LORBRENA were: .