Regulatory Decision Summary for Alunbrig

To support the proposed indication, the sponsor submitted the results from an ongoing open-label phase 2, single arm (13-201/ALTA) study with 222 adults with ALK-positive NSCLC who progressed on crizotinib. Patients were randomized in a 1:1 ratio to receive Arm A (n = 112) which was 90 mg once daily (OD) Alunbrig for 28 days per cycle; and Arm B (n = 110) which was a 7-day lead in dose at 90 mg increasing to a 180 mg dose OD regimen thereafter for 28 days per cycle.

Benefit

The 180 mg once daily dosing regimen of Alunbrig demonstrated an Objective Response Rate (ORR) (Independent review Committee (IRC)-assessed) of 54.5% and a median duration of response (DOR) of 14.8 months. These results were comparable to the 90 mg OD dose (ORR~50.9%) (DOR~13.8 months). However, the IRC-assessed median progression free survival (PFS) was lower at 9.2 months in the 90 mg dose arm than in the 180 mg arm (16.7 months). The median duration of follow-up was 18.6 months. For intracranial (IC) efficacy, the IRC-assessed intracranial ORR was 66.7% and 50% in patients with measurable brain metastases at baseline in the 180 mg and 90 mg OD dosing regimens, respectively. The results support the use of Alunbrig in patients with ALK+ NSCLC in the following dosing regimen:90 mg orally once daily for the first 7 days; if 90 mg is tolerated during the first 7 days, increase the dose to 180 mg orally once daily.

Risk

The safety data of brigatinib was based on 219 adult patients with metastatic ALKpositive NSCLC in the ALTA trial. The most frequently reported toxicities in the 180 mg dosing regimen were gastrointestinal, respiratory (including interstitial lung diseases [ILD]), neurological, rash, vascular, musculoskeletal, and visual disturbances. The most common serious toxicities were pneumonia (8.2%) and pneumonitis (8.2%). Toxicities were managed with dose reductions and treatment discontinuations. Treatment emergent adverse events (TEAEs) that led to discontinuation of Alunbrig occurred in 10.9% of patients and included pneumonitis, disease progression and pneumonia. TEAEs that led to dose reduction occurred in 30% of patients and included blood CPK increased (6.4%), pneumonitis (2.7%) and rash (2.7%).

Most of the key safety risks identified with brigatinib, including later onset pneumonitis, bradycardia/PT prolongation, vision impairment, CPK elevations, and pancreatic enzyme elevations were observed with other ALK inhibitor (crizotinib, ceritinib and alectinib). However, two events appear unique to brigatinib: early onset pulmonary events (EOPEs) and hypertension. EOPEs are a subset of pulmonary events occurring generally within 9 days of treatment initiation (or re-initiation following a dose interruption) and usually occurring within 2 days. The associated TEAEs of EOPEs included dyspnea, hypoxia, cough, pneumonia, and/or pneumonitis, often with chest imaging findings of linear or ground-glass pulmonary opacities. The etiology of these EOPEs is unknown. In addition, geriatric patients experienced increased TEAEs of EOPEs as compared with adults of less than 65 years of age. Hypertension (including Grade 3 and hypertensive retinopathy) was reported in 27% patients treated with the 180 mg dose of Alunbrig and was managed with dose interruption and standard anti-hypertensive treatments.

The Product Monograph (PM) of Alunbrig contains boxed warnings on toxicities including pulmonary, hypertension, and elevated enzymes (pancreatic, CPK and hyperglycemia). Other risks have been appropriately labeled in the PM. Alunbrig is not indicated in pregnant and nursing women due to its toxicity and teratogenicity. Alunbrig has not been studied and is therefore not recommended for treatment in children (<18 years of age). It is also not recommended in patients with moderate and severe hepatic impairment and severe renal impairment due to a paucity of data in that population.

Considering that the risks can be appropriately mitigated through PM labelling and that there appears to be a significant benefit to Alunbrig treatment in the indicated population, the benefit-risk profile of Alunbrig (brigatinib) is considered favourable. Post-approval commitments to confirm the efficacy for this indication have been made.