FDA Grants Priority Review to Brigatinib in ALK-Positive Metastatic NSCLC

The FDA has granted Priority Review to the New Drug Application for brigatinib (Alunbrig) as first-line treatment for patients withALK-positive metastatic non—small cell lung cancer (NSCLC) as detected by an FDA-approved test, the Takeda Pharmaceutical Company announced in a press release.¹

The NDA was submitted based on positive data from the long-term analysis of the phase III ALTA-1L trial, which were presented at the 2019 European Society of Medical Oncology (ESMO) Asia Congress. The analysis showed that the median progression-free survival (PFS) observed with brigatinib was 3 times longer than the PFS observed with crizotinib (Xalkori).

Per investigator assessment, brigatinib reduced the risk of disease progression or death by 76% (HR, 0.24; 95% CI, 0.12-0.45) in newly diagnosed patients whose disease had spread to the brain at the time of enrollment compared with crizotinib. Among all patients, brigatinib reduced the risk of disease progression or death by 57% (HR, 0.43; 95% CI, 0.31-0.61). Results from the study were also assessed by a blinded independent review committee (BIRC) which calculated a reduction in the risk of progression or death of 51% (HR 0.49; 95% CI, 0.35-0.68;P<0001).²

Per BIRC, brigatinib reduced the risk of intracranial disease progression or death by 69% in patients with brain metastases at baseline (HR, 0.31; 95% CI, 0.17-0.56) compared with crizotinib, demonstrating a median intracranial PFS of 24 months versus 5.6 months. The median PFS by investigator assessment for patients with brain metastases at baseline was not reached with brigatinib and was 5.9 months with crizotinib.

The confirmed intracranial objective response rate (ORR) among patients with measurable brain metastases at baseline was 78% (95% CI, 52%-94%) in the brigatinib arm and 26% (95% CI, 10%-48%) in the crizotinib arm by BICR. Median intracranial duration of response (DOR) in confirmed responders with measurable brain metastases at baseline was not reached (NR) in the brigatinib arm (95% CI, 5.7-NR) and was 9.2 months (95% CI, 3.9-9.2) in the crizotinib arm. These data indicate that newly diagnosed patients benefitted from brigatinib regardless of whether they had brain metastases at baseline.

At a longer follow-up of 25 months, the median PFS per investigator assessment was 29.4 months in the brigatinib group (95% CI, 21.2-NR) versus 9.2 months in the crizotinib group (95% CI, 7.4-12.9). The median PFS per BIRC assessment was 24.0 months with brigatinib (95% CI, 18.5-NR) compared with 11.0 months in the crizotinib arm (95% CI, 9.2-12.9). The confirmed ORR per BIRC in the intention-to-treat population with brigatinib and crizotinib was 74% (95% CI, 65.5-9) and 62% (95% CI, 52.9-69.7), respectively. In the brigatinib arm, the median DOR was not reached (95% CI, 19.4-NR) and was 13.8 months with crizotinib (95% CI, 9.3-20.8) per BIRC assessment.

Brigatinib also showed a significant improvement in the health-related quality of life in patients overall. Specifically, brigatinib delayed the median time to worsening in Global Health Score (GHS)/quality of life (QoL) score by 27 months compared to the 8-month delay observed with crizotinib. Those treated with brigatinib also had a longer duration of improvement in GHS/QoL. The duration of improvement was not yet reached versus 12 months with crizotinib. Treatment with brigatinib also delayed the time to worsening and prolonged duration of improvement in multiple toxicities, including fatigue, nausea, vomiting, appetite loss, and emotional and social functioning.

The safety profile observed with brigatinib in this study was consistent with existing data on the drug. The most common grade &ge;3 treatment-emergent adverse events (TEAEs) observed with brigatinib were creatine phosphokinase (24.3%), increased lipase (14.0%), hypertension (11.8%). Among patients treated with crizotinib, the most common TEAEs were increased alanine transaminase, (10.2%), aspartate transaminase (6.6%), and lipase (6.6%). Pulmonary adverse events (AEs) occurred in 5.1 % of patients who received brigatinib and 2.2% of those who received crizotinib. AEs also led to discontinuation of treatment in 12.5% of patients in the brigatinib arm and 8.8% of patients in the crizotinib arm.

ALTA-1L is an ongoing, randomized, open-label, comparative multicenter trial of 275 patients. The brigatinib arm includes 137 patients, and the crizotinib arm included 138 patients. Those in the brigatinib arm received 180 mg once daily with a 7-day lead-in at 90 mg once daily, whereas patients in the crizotinib arm received 250 mg twice daily.

The primary end point of the study BIRC-assessed PFS and the secondary end points were ORR, intracranial ORR, intracranial PFS, overall survival, and safety and tolerability.

To enroll, patients were required to have a histologically or cytologically confirmed stage IIIB or stage IV NSCLC with a documentedALKrearrangement. Patients were required to have at least 1 measurable lesion per RECIST v1.1, have sufficient tissues for central analysis, an ECOG performance status of 2 or lower, and adequate organ function. Some patients were excluded from the study due to prior treatments or problematic toxicities, infections, and uncontrolled diseases.

&ldquo;ALK-positive NSCLC is a rare and serious form of lung cancer that is complex to treat. While progress has been made, unmet needs still exist for the approximately 40,000 patients diagnosed with this disease worldwide each year,&rdquo; said Christopher Arendt, Head, Oncology Therapeutic Area Unit, Takeda, in a statement. &ldquo;This is an important first step in expanding treatment options for people with ALK-positive metastatic NSCLC in the US, and we look forward to continuing to work with regulatory authorities around the world to bring Alunbrig to newly diagnosed patients.&rdquo;

The Prescription Drug User Fee Act (PDUFA) target action date for the potential approval of brigatinib as first-line treatment forALK-positive metastatic NSCLC is June 23, 2020.¹

References

1. Takeda announces U.S. FDA grants Priority Review for supplemental new drug application for alunbrig&reg;&nbsp;(brigatinib) as a first-line treatment for alk+ metastatic non-small cell lung cancer [news release]. Cambridge, Massachusetts and Osaka, Japan: Takeda Pharmaceutical Company; February 24, 2020. https://bit.ly/38TiTNu. Accessed February 24, 2020.
2. Cambridge E, Kim HR, Ahn M, et al. Brigatinib vs crizotinib in patients with ALK inhibitor-naive advanced alk+ nsclc: updated results from the phase iii alta-1l trial.Annals of Oncol. (2019) 30 (suppl_9)L: ix183-ix202.