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Pharmacology: Pharmacodynamics: Cardiac Electrophysiology: The QT interval prolongation potential of brigatinib was assessed in 123 patients following once daily brigatinib doses of 30 mg to 240 mg. Brigatinib did not prolong the QT interval to a clinically relevant extent.
Mechanism of Action: Brigatinib is a tyrosine kinase inhibitor that targets ALK, ROS1, and insulin-like growth factor 1 receptor (IGF-1R). Among these, brigatinib is most active against ALK. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalling protein STAT3 in in vitro and in vivo assays.
Brigatinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.
At concentrations (≤500 nM) that are achieved clinically, brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib. No ALK mutations associated with resistance to brigatinib were observed. Brigatinib demonstrated in vivo and clinical activity against multiple mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib.
Administration of brigatinib resulted in antitumor activity and prolonged survival in mice with an ALK-driven tumor cell line implanted intracranially.
Clinical Studies: Advanced ALK-Positive NSCLC Without Prior ALK-targeted Therapy (ALTA 1L, Study 301): The safety and efficacy of brigatinib was evaluated in a randomized (1:1), open-label, multicenter trial (ALTA 1L) in 275 adult patients with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy. Eligibility criteria permitted enrolment of patients with a documented ALK rearrangement based on a local standard of care testing and an ECOG Performance Status of 0-2. Patients were allowed to have up to 1 prior regimen of chemotherapy in the locally advanced or metastatic setting. Neurologically stable patients with treated or untreated central nervous system (CNS) metastases, including leptomeningeal metastases, were eligible. Patients with a history of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis were excluded.
Patients were randomized in a 1:1 ratio to receive brigatinib 180 mg once daily with a 7-day lead-in at 90 mg once daily (N=137) or crizotinib 250 mg orally twice daily (N=138). Randomization was stratified by brain metastases (present, absent) and prior chemotherapy use for locally advanced or metastatic disease (yes, no).
The major outcome measure was progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by a Blinded Independent Review Committee (BIRC). Additional outcome measures as evaluated by the BIRC include confirmed objective response rate (ORR), duration of response (DOR), time to response, disease control rate (DCR), intracranial ORR, intracranial PFS, and intracranial DOR. Investigator-assessed outcomes include PFS and overall survival.
Baseline demographics and disease characteristics in ALTA 1L (Table 2) were median age 59 years old (range 27 to 89; 32% 65 and over), 59% White and 39% Asian, 55% female, 39% ECOG PS 0 and 56% ECOG PS 1, 58% never smokers, 93% Stage IV disease, 96% adenocarcinoma histology, 30% CNS metastases at baseline, 14% prior radiotherapy to the brain, and 27% prior chemotherapy. Sites of extra-thoracic metastases include brain (30% of patients), bone (31% of patients), and liver (20% of patients).
At the primary analysis performed at a median follow-up duration of 11 months (range: 0-20) in the brigatinib arm, the ALTA 1L study met its primary endpoint demonstrating a statistically significant improvement in PFS by BIRC. A protocol specified efficacy analysis performed at a median follow-up duration of 24.9 months (range: 0-34.1) in the brigatinib arm formed the basis for the results from this study (Table 3 and Figure 1). (See Tables 2, 3 and Figure 1.)
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Click on icon to see table/diagram/imageAt the data cut-off point overall survival data was not mature.
BIRC assessment of intracranial efficacy according to RECIST v1.1 in patients with any brain metastases and patients with measurable brain metastases (≥10 mm in longest diameter) at baseline are summarized in Table 3 and Figure 2. (See Table 4 and Figure 2.)
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Click on icon to see table/diagram/imagePatient-reported symptoms, functioning and global health status (GHS)/quality of life (QOL) were measured using the EORTC QLQ-C30 and QLQ-LC13; 131 patients in the brigatinib arm and crizotinib arm, respectively, completed the EORTC QLQ-C30 at baseline and at least one post-baseline visit. Brigatinib delayed time to worsening in GHS/QOL measured by the EORTC QLQ-C30 (with worsening defined as ≥10 points worsening from baseline) compared with crizotinib (median 26.7 months versus 8.3 months; HR=0.70; 95% CI: 0.49, 1), as supported by multiple functional subscales (including physical, emotional and social), and symptom subscales (including fatigue, nausea and vomiting, appetite loss, and constipation).
ALK-Positive Advanced or Metastatic NSCLC Previously Treated with Crizotinib (ALTA, Study 201): The safety and efficacy of brigatinib was evaluated in a randomized (1:1), open-label, multicenter trial (ALTA) in 222 adult patients with locally advanced or metastatic ALK-positive NSCLC who had progressed on crizotinib. Eligibility criteria permitted enrolment of patients with a documented ALK rearrangement based on a validated ALK test, ECOG Performance Status of 0-2, prior chemotherapy, and central nervous system (CNS) metastases provided they were neurologically stable and did not require an increasing dose of corticosteroids. Patients with a history of pulmonary interstitial disease or drug-related pneumonitis were excluded.
Patients were randomized in a 1:1 ratio to receive brigatinib either 90 mg once daily (90 mg regimen, n=112) or 180 mg once daily with 7-day lead-in at 90 mg once daily (180 mg regimen, n=110). The median duration of follow-up was 22.9 months (range: 0.1-39.2). Randomization was stratified by brain metastases (present, absent) and best prior response to crizotinib therapy (complete or partial response, any other response/unknown).
The major outcome measure was confirmed objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by investigator. Additional outcome measures included confirmed ORR as evaluated by an Independent Review Committee (IRC); time to response; progression-free survival (PFS); duration of response (DOR); overall survival; quality of life (QOL); and intracranial ORR, intracranial DOR and intracranial PFS as evaluated by an IRC. The analysis of study measured outcomes across both arms informed the recommended dose.
Baseline demographics and disease characteristics in ALTA (Table 5) were median age 54 years old (range 18 to 82; 23% 65 and over), 67% White and 31% Asian, 57% female, 36% ECOG PS 0 and 57% ECOG PS 1, 95% never or former smokers, 98% Stage IV, 97% adenocarcinoma, and 74% prior chemotherapy. The most common sites of extra-thoracic metastasis included 69% brain (of whom 62% had received prior radiation to the brain), 40% bone, and 26% liver.
Efficacy results from ALTA analysis are summarized in Table 6 and the Kaplan-Meier (KM) curves for investigator-assessed and IRC-assessed systemic PFS are shown in Figure 3 and Figure 4, respectively. (See Tables 5, 6 and Figures 3, 4.)
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Click on icon to see table/diagram/imageIn ALTA, 201 patients had at least 1 evaluable post-baseline assessment out of the 222 patients. Waterfall plots displaying the maximum decrease from baseline in the sum of the longest tumor diameters shows that the majority of patients treated with brigatinib had a reduction in tumor burden in both the 90 mg and 180 mg regimens in ALTA (Figure 5 and Figure 6). (See Figures 5 and 6.)
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Click on icon to see table/diagram/imageOf the 222 enrolled patients, baseline tumor tissue samples were evaluable in 17 patients. Responses were seen in patients with and without secondary ALK kinase domain mutations, including one patient with a secondary ALK kinase domain mutation of G1202R.
IRC assessments of intracranial ORR and duration of intracranial response in patients from ALTA with measurable brain metastases (≥10 mm in longest diameter) at baseline are summarized in Table 7. (See Table 7.)
Click on icon to see table/diagram/imageIn ALTA, patients overall experienced positive changes relative to baseline in QOL during treatment with brigatinib. The mean QOL, measured by the summary Global Health Status/QOL score of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, was maintained above baseline mean values throughout follow-up (median: 22.9 months) across both dose groups.
Study 101: In Study 101, 25 patients with ALK-positive NSCLC that progressed on crizotinib were administered brigatinib at 180 mg once daily with 7-day lead-in at 90 mg once daily regimen. Of these, 19 patients had an investigator-assessed confirmed objective response (76%; 95% CI: 55, 91) and the KM median PFS was 16.3 months (95% CI: 9.2, NE) and the 12-month probability of overall survival was 84.0% (95% CI: 62.8, 93.7).
Pharmacokinetics: Absorption: Following administration of single oral doses of brigatinib of 30 to 240 mg, the median time to peak concentration (Tmax) ranged from 1 to 4 hours postdose. The geometric mean (CV%) steady-state Cmax of brigatinib at doses of 90 mg and 180 mg once daily was 552 (65%) and 1452 (60%) ng/mL, respectively, and the corresponding AUC0-tau was 8165 (57%) and 20276 (56%) h·ng/mL, respectively. After a single dose and repeat dosing of brigatinib, systemic exposure was dose proportional over the dose range of 60 mg to 240 mg once daily. The mean accumulation ratio after repeat dosing was 1.9 to 2.4.
Brigatinib Cmax was reduced by 13% with no effect on AUC in healthy subjects administered brigatinib after a high-fat meal compared to the Cmax and AUC after overnight fasting.
Distribution: Brigatinib was 91% bound to human plasma proteins and the binding was not concentration-dependent. The blood-to-plasma concentration ratio is 0.69. Following oral administration of brigatinib 180 mg once daily, the geometric mean apparent volume of distribution (Vz/F) at steady-state was 307 L.
Metabolism: In vitro studies demonstrated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4.
Following oral administration of a single 180 mg dose of [14C]-brigatinib to healthy subjects, N-demethylation and cysteine conjugation were the two major metabolic clearance pathways. Unchanged brigatinib (92%) and its primary metabolite, AP26123 (3.5%), were the major circulating radioactive components. In patients, the steady-state AUC of AP26123 was less than 10% of brigatinib exposure. The metabolite, AP26123, inhibited ALK with approximately 3-fold lower potency than brigatinib in vitro.
Excretion and Elimination: Following oral administration of brigatinib 180 mg once daily, the geometric mean apparent oral clearance (CL/F) of brigatinib at steady-state was 8.9 L/h and the mean plasma elimination half-life was 25 h.
Following administration of a single 180 mg oral dose of [14C]-brigatinib to six healthy male subjects, 65% of the administered dose was recovered in feces and 25% of the administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of the total radioactivity in feces and urine, respectively.
Special Populations: Impaired Renal Function: The pharmacokinetics of brigatinib is similar in patients with normal renal function and in patients with mild or moderate renal impairment (eGFR ≥30 mL/min/1.73 m2) based on the results of population pharmacokinetic analyses. In a pharmacokinetic study, unbound AUC0-INF was 92% higher in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2, N=8) as compared to patients with normal renal function (eGFR ≥90 mL/min/1.73 m2, N = 8) (see Dosage & Administration).
Impaired Hepatic Function: The pharmacokinetics of brigatinib was characterized in patients with normal hepatic function (N=9), mild hepatic impairment (Child-Pugh class A, N=6), moderate hepatic impairment (Child-Pugh class B, N=6), or severe hepatic impairment (Child-Pugh class C, N=6). The pharmacokinetics of brigatinib was similar between patients with normal hepatic function and patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Unbound AUC0-INF was 37% higher in patients with severe hepatic impairment (Child-Pugh class C) as compared to patients with normal hepatic function (see Dosage & Administration).
Age, Gender, Race: Population pharmacokinetic analyses showed that age, gender or race had no clinically meaningful effect on the pharmacokinetics of brigatinib.
Drug Interactions: Agents that May Increase Brigatinib Plasma Concentrations: CYP3A Inhibitors: In vitro studies demonstrated that brigatinib is a substrate of CYP3A4/5. Coadministration of multiple 200 mg twice daily doses of itraconazole, a strong CYP3A inhibitor, with a single 90 mg brigatinib dose increased brigatinib Cmax by 21%, AUC0-INF by 101% (2-fold), and AUC0-120 by 82% (<2-fold), relative to a 90 mg brigatinib dose administered alone. The concomitant use of strong CYP3A inhibitors with brigatinib, including but not limited to certain antivirals (e.g., indinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (e.g., clarithromycin, telithromycin, troleandomycin), antifungals (e.g., ketoconazole, voriconazole), and nefazodone should be avoided. If concomitant use of strong CYP3A inhibitors cannot be avoided, the dose of brigatinib should be reduced by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a strong CYP3A inhibitor, brigatinib should be resumed at the dose that was tolerated prior to the initiation of the strong CYP3A inhibitor.
Moderate CYP3A inhibitors (e.g., diltiazem and verapamil) may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. The concomitant use of moderate CYP3A inhibitors (e.g., diltiazem and verapamil) with brigatinib should be avoided. If concomitant use of moderate CYP3A inhibitors cannot be avoided, the dose of brigatinib should be reduced by approximately 40% (e.g., from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a moderate CYP3A inhibitor, brigatinib should be resumed at the dose that was tolerated prior to the initiation of the moderate CYP3A inhibitor.
Grapefruit or grapefruit juice may also increase plasma concentrations of brigatinib and should be avoided.
CYP2C8 Inhibitors: In vitro studies demonstrated that brigatinib is a substrate of CYP2C8. Coadministration of multiple 600 mg twice daily doses of gemfibrozil, a strong CYP2C8 inhibitor, with a single 90 mg brigatinib dose decreased brigatinib Cmax by 41%, AUC0-INF by 12%, and AUC0-120 by 15%, relative to a 90 mg brigatinib dose administered alone. No dose adjustment is required for brigatinib during coadministration with strong CYP2C8 inhibitors.
P-gp and BCRP Inhibitors: Brigatinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro. Brigatinib exhibits high solubility and high permeability. Additionally, simulations from a physiologically-based pharmacokinetic model suggested that inhibition of P-gp and BCRP is not expected to result in a clinically meaningful change in the systemic exposure of brigatinib. No dose adjustment is required for brigatinib during coadministration with P-gp and BCRP inhibitors.
Agents That May Decrease Brigatinib Plasma Concentrations: CYP3A Inducers: Coadministration of multiple 600 mg daily doses of rifampin, a strong CYP3A inducer, with a single 180 mg brigatinib dose decreased brigatinib Cmax by 60%, AUC0-INF by 80% (5-fold), and AUC0-120 by 80% (5-fold), relative to a 180 mg brigatinib dose administered alone. The concomitant use of strong CYP3A inducers with brigatinib, including but not limited to rifampin, carbamazepine, phenytoin, rifabutin, phenobarbital, and St. John's Wort should be avoided.
Moderate CYP3A inducers may decrease the AUC of brigatinib by approximately 50% based on simulations from a physiologically-based pharmacokinetic model. The concomitant use of moderate CYP3A inducers with brigatinib, including but not limited to efavirenz, modafinil, bosentan, etravirine, and nafcillin should be avoided. If concomitant use of moderate CYP3A inducers cannot be avoided, the dose of brigatinib may be increased in 30 mg increments after 7 days of treatment with the current brigatinib dose as tolerated, up to a maximum of twice the brigatinib dose that was tolerated prior to the initiation of the moderate CYP3A inducer. After discontinuation of a moderate CYP3A inducer, brigatinib should be resumed at the dose that was tolerated prior to the initiation of the moderate CYP3A inducer.
Agents That May Have Their Plasma Concentrations Altered by Brigatinib: CYP3A Substrates: In vitro studies in hepatocytes have shown that brigatinib is an inducer of CYP3A.
Coadministration of multiple 180 mg daily doses of brigatinib with a single 3 mg oral dose of midazolam, a sensitive CYP3A substrate, decreased midazolam Cmax by 16%, AUC0-INF by 26%, and AUC0-last by 30%, relative to a 3 mg oral dose of midazolam administered alone. Brigatinib reduces plasma concentrations of coadministered medications that are predominantly metabolized by CYP3A.
Brigatinib may also induce other enzymes and transporters (e.g., CYP2C, P-gp) via the same mechanisms responsible for induction of CYP3A (e.g., pregnane X receptor activation).
Transporter Substrates: Brigatinib is an inhibitor of P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Coadministration of brigatinib with substrates of P-gp, (e.g. digoxin, dabigatran, colchicine, pravastatin), BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine), OCT1, MATE1, and MATE2K may increase their plasma concentrations.
Toxicology: Nonclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity: Carcinogenicity studies have not been performed with brigatinib.
Mutagenicity: Brigatinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) or the mammalian cell chromosomal aberration assays, but slightly increased the number of micronuclei in a rat bone marrow micronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity) and not a clastogenic effect on chromosomes. This effect was observed at approximately five fold the human exposure at the 180 mg once daily dose.
Impairment of Fertility: Brigatinib may impair male fertility. Testicular toxicity was observed in repeat-dose animal studies. In rats, findings included lower weight of testes, seminal vesicles and prostate gland, and testicular tubular degeneration; these effects were not reversible during the recovery period. In monkeys, findings included reduced size of testes along with microscopic evidence of hypospermatogenesis; these effects were reversible during the recovery period. Overall, these effects on the male reproductive organs in rats and monkeys occurred at exposures as low as 0.2-times the AUC in patients at the 180 mg once daily dose. No apparent adverse effects on female reproductive organs were observed in general toxicology studies in rats and monkeys.
Animal Toxicology and/or Pharmacology: Nonclinical safety assessment in rats and monkeys identified potential risk for toxicity in multiple organs such as gastrointestinal system, bone marrow, eyes, testes, liver, kidney, bone, and heart. These effects were generally reversible during the non-dosing recovery period; however, effects in the eyes and testes were notable exceptions due to lack of recovery.
