Lazcluze lazertinib 240 mg Tablet, Film Coated, 14-count — NDC 57894-240-99 (Billing 57894-0240-99)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Lazertinib is a kinase inhibitor of epidermal growth factor receptor (EGFR) that inhibits EGFR exon 19 deletions and exon 21 L858R substitution mutations at lower concentrations than wild-type EGFR. In human NSCLC cells and mouse xenograft models of EGFR exon 19 deletions or EGFR L858R substitution mutations, lazertinib demonstrated anti-tumor activity. Treatment with lazertinib in combination with amivantamab increased in vivo anti-tumor activity compared to either agent alone in a mouse xenograft model of human NSCLC with an EGFR L858R mutation.

12.2Pharmacodynamics The exposure-response relationship and time-course of pharmacodynamic response of lazertinib have not been fully characterized. Cardiac Electrophysiology At a dose of 320 mg (1.3 times the approved recommended dosage) once daily, a mean increase in the QTc interval > 20 ms is unlikely.

12.3Pharmacokinetics Lazertinib pharmacokinetics are presented as mean (CV%) for descriptive parameters unless otherwise specified. Lazertinib maximum plasma concentration (C max ) and area under plasma concentration time curve (AUC) increased dose proportionally from 20 mg to 320 mg (0.08 to 1.3 times the approved recommended dosage) following a single administration and once daily administration. Lazertinib steady state plasma exposure was achieved by day 15 with approximately 2-fold accumulation for AUC.

Absorption The median time to reach C max is from 2 to 4 hours. Effect of Food A high-fat meal (800 to 1000 kcal, approximately 50% fat) did not have a clinically significant effect on lazertinib pharmacokinetics compared to that under fasted conditions. Distribution The mean apparent volume of distribution is 2680 L (51%).

Lazertinib is approximately 99.2% bound to human plasma proteins. Elimination The mean terminal half-life is 3.7 days (56%). The mean apparent clearance is

36.4L/h (47%). Metabolism Lazertinib is primarily metabolized by glutathione conjugation, either enzymatic via glutathione-S-transferase (GST) or non-enzymatic, as well as by CYP3A4. Excretion Following a single oral dose of radiolabeled lazertinib, approximately 86% of the dose was recovered in feces (< 5% as unchanged) and 4% in urine (< 0.2% as unchanged).

Specific Populations No clinically significant differences in pharmacokinetics of lazertinib were observed based on age (21 to 88 years), sex, body weight (28 to 122 kg), race (White, Asian, Black or African American), ethnicity (Hispanic/Latino or not Hispanic/Latino), baseline laboratory assessments (creatinine clearance, albumin, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase), mild or moderate renal impairment (eGFR 30 to 89 mL/min, estimated by CKD-EPI equation), mild [total bilirubin ≤ ULN and AST > ULN or total bilirubin ≤ 1.5 times ULN and any AST] or moderate [total bilirubin ≤ 1.5 to 3×ULN and any AST] hepatic impairment, ECOG performance status, EGFR mutation type, initial diagnosis cancer stage, prior therapies, brain metastasis, and history of smoking.

The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR < 15 mL/min) or severe hepatic impairment (total bilirubin > 3 times ULN with any AST) on the pharmacokinetics of lazertinib has not been studied. GSTM1 Genotype Patients with at least one GSTM1 normal function allele have 44% lower systemic levels of lazertinib compared with those with the two GSTM1 no-function alleles (i.e., no enzyme activity). No clinically significant differences in safety or efficacy were observed as a function of GSTM1 genotype in patients receiving LAZCLUZE in combination with amivantamab.

Drug Interactions Clinical Studies and Model-Informed Approaches Effect of CYP3A4 inducers on lazertinib: Concomitant use of rifampin (strong CYP3A4 inducer) with LAZCLUZE decreased lazertinib C max by 72% and AUC by 83%. Concomitant use of efavirenz (moderate CYP3A4 inducer) with LAZCLUZE is predicted to decre… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Lazertinib is a kinase inhibitor of epidermal growth factor receptor (EGFR) that inhibits EGFR exon 19 deletions and exon 21 L858R substitution mutations at lower concentrations than wild-type EGFR. In human NSCLC cells and mouse xenograft models of EGFR exon 19 deletions or EGFR L858R substitution mutations, lazertinib demonstrated anti-tumor activity. Treatment with lazertinib in combination with amivantamab increased in vivo anti-tumor activity compared to either agent alone in a mouse xenograft model of human NSCLC with an EGFR L858R mutation.

12.3Pharmacokinetics Lazertinib pharmacokinetics are presented as mean (CV%) for descriptive parameters unless otherwise specified. Lazertinib maximum plasma concentration (C max ) and area under plasma concentration time curve (AUC) increased dose proportionally from 20 mg to 320 mg (0.08 to 1.3 times the approved recommended dosage) following a single administration and once daily administration. Lazertinib steady state plasma exposure was achieved by day 15 with approximately 2-fold accumulation for AUC.

Absorption The median time to reach C max is from 2 to 4 hours. Effect of Food A high-fat meal (800 to 1000 kcal, approximately 50% fat) did not have a clinically significant effect on lazertinib pharmacokinetics compared to that under fasted conditions. Distribution The mean apparent volume of distribution is 2680 L (51%).

Lazertinib is approximately 99.2% bound to human plasma proteins. Elimination The mean terminal half-life is 3.7 days (56%). The mean apparent clearance is

36.4L/h (47%). Metabolism Lazertinib is primarily metabolized by glutathione conjugation, either enzymatic via glutathione-S-transferase (GST) or non-enzymatic, as well as by CYP3A4. Excretion Following a single oral dose of radiolabeled lazertinib, approximately 86% of the dose was recovered in feces (< 5% as unchanged) and 4% in urine (< 0.2% as unchanged).

Specific Populations No clinically significant differences in pharmacokinetics of lazertinib were observed based on age (21 to 88 years), sex, body weight (28 to 122 kg), race (White, Asian, Black or African American), ethnicity (Hispanic/Latino or not Hispanic/Latino), baseline laboratory assessments (creatinine clearance, albumin, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase), mild or moderate renal impairment (eGFR 30 to 89 mL/min, estimated by CKD-EPI equation), mild [total bilirubin ≤ ULN and AST > ULN or total bilirubin ≤ 1.5 times ULN and any AST] or moderate [total bilirubin ≤ 1.5 to 3×ULN and any AST] hepatic impairment, ECOG performance status, EGFR mutation type, initial diagnosis cancer stage, prior therapies, brain metastasis, and history of smoking.

The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR < 15 mL/min) or severe hepatic impairment (total bilirubin > 3 times ULN with any AST) on the pharmacokinetics of lazertinib has not been studied. GSTM1 Genotype Patients with at least one GSTM1 normal function allele have 44% lower systemic levels of lazertinib compared with those with the two GSTM1 no-function alleles (i.e., no enzyme activity). No clinically significant differences in safety or efficacy were observed as a function of GSTM1 genotype in patients receiving LAZCLUZE in combination with amivantamab.

Drug Interactions Clinical Studies and Model-Informed Approaches Effect of CYP3A4 inducers on lazertinib: Concomitant use of rifampin (strong CYP3A4 inducer) with LAZCLUZE decreased lazertinib C max by 72% and AUC by 83%. Concomitant use of efavirenz (moderate CYP3A4 inducer) with LAZCLUZE is predicted to decrease lazertinib steady state C max by at least 32% and AUC by at least 44%. The effect of concomitant use of weak CYP3A4 inducers on lazertinib C max or AUC is unknown.

Effect of strong CYP3A4 inhibitors on lazertinib: Concomitant use of itraconazole (strong CYP3A4 inhibitor) with LAZCLUZE increased lazertinib C max by 1.2-fold and AUC by 1.5-fold. Effect of gastric acid reducing agents on lazertinib: No clinically significant differences in lazertinib C max and AUC were observed when used concomitantly with gastric acid reducing agents. Effect of lazertinib on certain CYP3A4 substrates: Concomitant use of LAZCLUZE increased midazolam (CYP3A4 substrate) C max by 1.4-fold and AUC by 1.5-fold.

Effect of lazertinib on BCRP substrates: Concomitant use of LAZCLUZE increased rosuvastatin (BCRP substrate) C max by 2.2-fold and AUC by 2-fold. No clinically significant differences in the pharmacokinetics of th… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The exposure-response relationship and time-course of pharmacodynamic response of lazertinib have not been fully characterized. Cardiac Electrophysiology At a dose of 320 mg (1.3 times the approved recommended dosage) once daily, a mean increase in the QTc interval > 20 ms is unlikely.

14 CLINICAL STUDIES The efficacy of LAZCLUZE, in combination with amivantamab, was evaluated in MARIPOSA [NCT04487080], a randomized, active-controlled, multicenter trial. Eligible patients were required to have untreated locally advanced or metastatic NSCLC with either exon 19 deletions or exon 21 L858R substitution EGFR mutations identified by local testing, not amenable to curative therapy. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll.

Patients were randomized (2:2:1) to receive LAZCLUZE in combination with amivantamab (N=429), osimertinib monotherapy (N=429), or LAZCLUZE monotherapy (an unapproved regimen for NSCLC) until disease progression or unacceptable toxicity. The evaluation of efficacy for the treatment of untreated metastatic NSCLC relied upon comparison between: LAZCLUZE administered at 240 mg orally once daily in combination with amivantamab administered intravenously at 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5.

Osimertinib administered at a dose of 80 mg orally once daily. Randomization was stratified by EGFR mutation type (exon 19 deletion or exon 21 L858R substitution mutation), Asian race (yes or no), and history of brain metastasis (yes or no). Tumor assessments were performed every 8 weeks for 30 months, and then every 12 weeks until disease progression.

The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR) and duration of response (DOR). A total of 858 patients were randomized between the two study arms, 429 to the LAZCLUZE in combination with amivantamab arm and 429 to the osimertinib arm.

The median age was 63 (range: 25–88) years; 61% were female; 58% were Asian, and 38% were White, 1.6% were American Indian or Alaska Native, 0.8% were Black or African American, 0.2% were Native Hawaiian or other Pacific Islander, 0.6% were unknown race or multiple races; and 12% were Hispanic or Latino. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and 89% had Stage IV cancer at initial diagnosis. Sixty percent of patients had tumors harboring exon 19 deletions and the remaining 40% had exon 21 L858R substitution mutations.

Among the 858 patients with EGFR exon 19 deletion or L858R substitution mutations that were randomized between the amivantamab plus LAZCLUZE arm versus the osimertinib arm, available tissue samples from 544 (63%) patients had evaluable results when tested retrospectively using the cobas EGFR Mutation Test v2. Of the 544 patients with evaluable results, 527 (97%) patients were positive for EGFR exon 19 deletion or L858R substitution mutations, while 17 (3%) patients were negative. Available plasma samples from patients were retrospectively tested using an FDA-approved test to confirm the biomarker status.

The trial demonstrated a statistically significant improvement in PFS by BICR assessment and OS for LAZCLUZE in combination with amivantamab compared to osimertinib (see Table 5 and Figures 1 and 2 ). Efficacy results are provided in Table 5. Table 5: Efficacy Results in MARIPOSA by BICR Assessment LAZCLUZE in combination with amivantamab (N=429) Osimertinib (N=429) CI = confidence interval; NR = not reached; NE = not estimable Progression-free survival (PFS) Number of events (%) 192 (45) 252 (59) Median, months (95% CI) 23.7 (19.1, 27.7) 16.6 (14.8, 18.5) HR Stratified by mutation type (Exon 19del or Exon 21 L858R), prior brain metastases (yes or no), and Asian race (yes or no). , Stratified Cox proportional hazards regression.

(95% CI); p-value , Stratified log-rank test. 0.70 (0.58, 0.85); p=0.0002 Overall survival (OS) Number of events (%) 173 (40) 217 (51) Median, months (95% CI)… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with lazertinib. Lazertinib was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration assay, or an in vivo micronucleus assay in rats. In a dedicated fertility and early embryonic development study, male and female rats received oral doses of 7.5, 15, or 30 mg/kg/day of lazertinib.

Males were dosed for 10 weeks (29 days prior to pairing, during mating period and continuing post-pairing). Females were dosed for 15 days prior to pairing, during mating period and up to Gestation Day 7. Lazertinib did not have clear effects on estrous cyclicity, mating, fertility, or sperm parameters, but induced an increase in post-implantation loss and decreased number of live fetuses at 30 mg/kg/day (approximately 1.2 times the recommended human dose of 240 mg based on body surface area).

In repeat-dose oral general toxicology studies up to 13-weeks duration, lazertinib induced histologic tubular degeneration in the testis; cellular lumen debris, degeneration/necrosis, and reduced sperm in the epididymis; decreased corpora lutea in the ovary; and atrophy in the uterus and vagina. These effects were observed at exposures approximately equivalent to the human exposure at the recommended dose of 240 mg in males, and at exposures approximately 2 times the human exposure at the recommended dose of 240 mg dose in females.

Findings in female reproductive organs were reversible. The tubular degeneration in the testis observed in rats at exposures approximately 4 times the human exposure at the recommended dose was not reversible within a 2-week recovery period.

13.2Animal Toxicology and/or Pharmacology In repeat-dose oral general toxicology studies up to 13-weeks duration in rats and dogs, lazertinib induced multi-organ histologic hyperplasia at exposures approximately equivalent or greater to the human exposure at the recommended dose of 240 mg. Hyperplasia was not reversible in the mandibular lymph node in the 4-week rat study. In rats, lazertinib induced renal toxicity characterized by histologic hyperplasia and inflammation in the kidney at doses ≥ 25 mg/kg (approximately 0.9 times the human exposure at the recommended dose of 240 mg/day based on AUC), along with increased urea nitrogen and histologic papillary necrosis, tubule degeneration/regeneration, and tubule dilatation at exposures approximately 4.4 times the human exposure at the recommended dose of 240 mg/day based on AUC.

Increased urea nitrogen, papillary necrosis, and tubule dilatation showed evidence of recovery. In the 13-week toxicology study in dogs, one high dose animal exhibited unilateral tubule cell renal carcinoma at 8 mg/kg/day (approximately 2 times the human exposure at the recommended dose of 240 mg/day based on AUC). Other renal findings in high dose dogs included tubule degeneration/regeneration and infarct, which showed evidence of recovery.

In the 4-week toxicology study, lazertinib induced cardiac toxicity in two dogs characterized by histologic findings in the heart (degeneration/necrosis of the myocardium and vessels, fibrosis, hemorrhage, thrombus, mixed cell/vessel inflammation) at 20 mg/kg (approximately 4.8 times the clinical AUC at the 240 mg human dose). One of these dogs also exhibited increased cardiac troponin I and premature ventricular complexes. These cardiac findings were not seen after a 2-week recovery period.