Summary Basis of Decision for Alunbrig

Clinical Pharmacology

Brigatinib, the medicinal ingredient in Alunbrig, is a tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (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.

In the ALTA study, a decreased heart rate (<50 beats per minute) was detected in 8.2% of patients on the recommended dosage regimen, 180 mg once daily with a seven-day lead-in at 90 mg once daily. This effect was initially observed in the dose finding study, Study 101, and was associated with higher plasma concentrations of brigatinib. This was also accompanied by a prolonged PR interval, and appeared to be concentration-dependent. Concurrent use of Alunbrig with drugs that decrease heart rate or increase the PR interval, including antiarrhythmics and beta adrenoceptor antagonists, should be avoided.

In patients given a single oral dose of 30 mg to 240 mg, the median time to peak plasma concentration of brigatinib was one to four hours postdose. Systemic exposure to brigatinib was dose proportional in patients receiving 60 mg to 240 mg once daily, following single and repeat dosing of Alunbrig. Alunbrig may be taken with or without food, as it was not found to significantly affect the bioavailability of brigatinib.

Brigatinib is mainly metabolized by CYP2C8 and CYP3A4 in vitro. To monitor the metabolism of brigatinib in humans, healthy male volunteers were given a single 180 mg dose of [¹⁴C]-brigatinib (radioactively tagged brigatinib). N-demethylation and cysteine conjugation were identified as major metabolic clearance pathways. Brigatinib remains primarily unchanged in circulation, and accounted for 92% of circulating radioactive components. Its primary metabolite, AP26123, constituted 3.5% of circulating radioactive components. The mean plasma elimination half-life was 25 hours, with 65% of the administered dose recovered in feces and 25% recovered in urine.

Results of a population pharmacokinetic study revealed that brigatinib pharmacokinetics is influenced by body weight. Patients weighing less than 50 kg or more than 100 kg should be closely monitored in case of loss of efficacy. This information is included in the Product Monograph, and the safety and efficacy of Alunbrig will be studied in these patient populations as part of the post-approval commitments.

The pharmacokinetics of brigatinib was not significantly impacted by mild hepatic impairment, or by mild to moderate renal impairment. No dose adjustment is recommended due to these conditions. However, Alunbrig is not recommended for patients with moderate to severe hepatic impairment or with severe renal impairment due to the absence of data on brigatinib pharmacokinetics in these patient populations. The lack of data has been addressed in the Serious Warnings and Precautions box of the Alunbrig Product Monograph.

For further details, please refer to the Alunbrig Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Evidence of the safety and efficacy of Alunbrig was provided by data from two clinical trials which were ongoing at the time of review: Study 101 and ALTA.

Study 101 was a Phase I/II open-label dose escalation study, conducted in patients with locally advanced or metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Results from this study were used to identify the most appropriate dosage regimens for further study in the pivotal trial, ALTA.

ALTA is a Phase II open-label study to evaluate the safety and efficacy of Alunbrig. All 222 patients enrolled in this study have ALK-positive NSCLC, and have progressed on crizotinib. Patients were randomized to one of two treatment groups, to receive either a 90 mg dose once daily, or a 180 mg dose once daily with a seven-day lead-in at 90 mg once daily (hereafter referred to as the 90 mg regimen and the 180 mg regimen, respectively). Treatment continued until the patient's condition progressed, or the patient experienced an unacceptable level of treatment-related toxicity. Results were evaluated by the investigative team as well as by an Independent Review Committee (IRC).

The primary endpoint was the confirmed objective response rate (ORR), which refers to the proportion of patients in which the tumour disappeared or reduced in size. The ORR was calculated according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1). This is a standardized approach used to measure the size of solid tumours, as well as changes in tumour size in response to treatment. The IRC calculated a slightly higher ORR than the investigators did for the 90 mg regimen (50.9% and 45.5%, respectively), but the two groups calculated similar ORRs for the 180 mg regimen (54.5% and 55.5%, respectively).

Progression-free survival was among the secondary endpoints evaluated in ALTA. Consistent findings were reported by the investigators and the IRC in favour of the 180 mg regimen. Progression-free survival for patients on the 180 mg regimen was calculated as 15.6 months by the investigators and 16.7 months by the IRC. Both groups calculated a progression-free survival period of 9.2 months in patients on the 90 mg regimen.

Other secondary endpoints included intracranial ORR and duration of intracranial response. These were assessed by the IRC in patients in both treatment groups who had measurable brain metastases at study initiation. Intracranial ORR was considerably higher in patients on the 180 mg regimen at 66.7%, versus 50.0% for those on the 90 mg regimen. Duration of intracranial response was 16.6 months for patients on the 180 mg regimen, but could not be measured for patients on the 90 mg regimen. Evidence of intracranial efficacy is especially important, as access to the central nervous system (CNS) has been a challenge with the first- and second-generation treatments currently available. The CNS is therefore the most common site for metastases, which contributes to the development of resistance to these treatments. The ability of brigatinib to access the CNS is a substantial improvement over existing treatments and contributes favourably to the benefit-harm-uncertainty profile of Alunbrig.

The results of bioequivalence studies between the 30 mg, 90 mg, and 180 mg strengths of Alunbrig were also included in the submission. Upon review, Health Canada concluded that all three strengths of Alunbrig will perform in an equivalent fashion when equivalent doses are administered. The bioavailability of brigatinib was also examined under fed and fasted conditions. Results from this study indicated that food does not significantly affect the absorption of brigatinib by the body. This study was considered acceptable upon review.

Indication

For more information, refer to the Alunbrig Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Along with clinical efficacy, the safety and tolerability of Alunbrig were assessed in ALTA. The design of this study is described in the Clinical Efficacy section.

Based on results from a dose finding study, the safety and efficacy of two dosage regimens were further evaluated in ALTA. Patients enrolled in ALTA were randomized in a 1:1 ratio to receive either 90 mg once daily (the 90 mg regimen), or 180 mg once daily with a seven-day lead-in at 90 mg once daily (the 180 mg regimen). The 180 mg regimen was approved as the recommended dosage regimen for Alunbrig due to its increased efficacy over the 90 mg regimen and its acceptable safety profile.

Malignant pleural effusion, pneumonia, and pneumonitis were the most common serious adverse reactions experienced by ALTA patients on the 180 mg regimen (≥2%). Interstitial lung disease/pneumonitis, hypertension, elevation of pancreatic enzymes, hyperglycemia, and creatinine phosphokinase (CPK) elevation were also among the identified serious adverse reactions. The most common adverse reactions, reported in ≥10% of patients, were nausea, diarrhea, fatigue, cough, headache, rash, vomiting, hypertension, dyspnea, myalgia, decreased appetite, muscle spasms, constipation, peripheral neuropathy, arthralgia, visual disturbances, abdominal pain, dizziness, edema, and interstitial lung disease/pneumonitis.

In total, 10.9% of patients on the 180 mg regimen discontinued treatment due to treatment-emergent adverse events. Those which most often led to discontinuation were pneumonitis, neoplasm progression, and pneumonia. Another 30% of patients experienced adverse events that resulted in dose reduction, including blood CPK elevation, pneumonitis, and rash.

While the majority of safety concerns identified for brigatinib are shared with other ALK inhibitors, two adverse events appear to be specific to brigatinib: early onset pulmonary events and hypertension. Early onset pulmonary events typically occur within two days of treatment initiation or re-initiation, or at most within nine days. While other related drugs are also associated with certain pulmonary events, the early onset is unique to brigatinib. In the clinical trials, it was more frequently observed in geriatric patients (≥65 years of age) than in adults under 65 years of age. However, the etiology of early onset pulmonary events in connection with brigatinib treatment remains unclear. Hypertension, including Grade 3 hypertension and hypertensive retinopathy, was detected in 27% of patients on the 180 mg regimen. These events were managed through dose interruption and standard antihypertensive treatments.

A population pharmacokinetics study revealed a significant relationship between body weight and the clearance and volume of distribution of brigatinib. Information has been included in the Product Monograph to support the safe use of Alunbrig in patients weighing less than 50 kg or greater than 100 kg. The safety and efficacy of Alunbrig in these patients are also being studied in a Phase III trial, ALTA-1L, as part of the post-approval conditions.

Decreased heart rate (<50 beats per minute) and a concentration-dependent increase in PR interval have also been associated with Alunbrig. Concurrent use with other drugs that elicit these effects, including antiarrhythmics and beta adrenoceptor antagonists, should be avoided.

As brigatinib is a substrate of CYP3A4, concurrent use with CYP3A4 inducers and CYP3A4 inhibitors will affect brigatinib pharmacokinetics. Concurrent use of Alunbrig with strong CYP3A inhibitors or strong or moderate CYP3A inducers should be avoided. If concomitant use with strong CYP3A inhibitors cannot be avoided, based on a clinical study, brigatinib dose should be reduced by approximately 50%. Additionally, the effect of brigatinib on CYP3A substrates and transporters has not been studied. Patients receiving (cyclosporine, cisapride, tacrolimus) or (digoxin, dabigatran, methotrexate, rosuvastatin, sulfasalazine, metformin) concomitantly with Alunbrig should be monitored closely for loss of their effectiveness or other adverse effects.

While dedicated reproductive toxicity tests were not carried out, the effects observed in the non-clinical repeat-dose toxicity studies were sufficient to determine that brigatinib impairs male fertility at doses lower than the clinical dose. In studies with pregnant rats, brigatinib was also shown to be a teratogen at doses lower than the clinical dose.

Post-Approval Conditions

The sponsor is expected to file an annual Periodic Safety Update Report (PSUR)/Periodic Benefit-Risk Evaluation Report (PBRER) two years after marketing, along with data from a Phase III study, ALTA-1L. This study addresses the outstanding questions in order to confirm the clinical benefit of Alunbrig. ALTA-1L will include an assessment of the efficacy of Alunbrig as a first-line treatment in crizotinib-naïve patients. The relationship between body weight and the pharmacokinetics of brigatinib will also be examined further, to evaluate the safety and efficacy of Alunbrig in weight extremes (patients weighing less than 50 kg or over 100 kg). Updates to the Risk Management Plan (RMP) are also expected.

For more information, refer to the Alunbrig Product Monograph, approved by Health Canada and available through the Drug Product Database.