FDA Grants Brigatinib Priority Review for Frontline ALK+ NSCLC

The FDA has granted a priority review designation to a supplemental New Drug Application (sNDA) for brigatinib (Alunbrig) for the first-line treatment of patients with ALK-positive metastatic non—small cell lung cancer (NSCLC), as detected by an FDA-approved test.¹

The sNDA is based on the phase III ALTA-1L trial, in which treatment with brigatinib demonstrated a 57% reduction in the risk of disease progression or death compared with crizotinib (Xalkori) in patients with advanced ALK-positive NSCLC who had not received a prior ALK inhibitor.^2,3

The 2-year investigator-assessed results, which were presented during the 2019 ESMO Asia Congress, showed that brigatinib led to a 76% (HR, 0.24; 95% CI, 0.12-0.45) reduction in the risk of disease progression or death in newly diagnosed patients who had brain metastases at time of enrollment.

With the 2-year follow-up data, the trial’s results were evaluated and reported by study investigators as well as a blinded independent review committee (BIRC). At the data cutoff for the second interim analysis, which was June 28, 2019, results showed that by BIRC assessment, there was a 51% reduction in the risk of disease progression or death with brigatinib over crizotinib (HR, 0.49; 95% CI, 0.35-0.68; log-rank P <.0001).

Under the Prescription Drug User Fee Act, the action date for the sNDA is June 23, 2020.

“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,” Christopher Arendt, head, Oncology Therapeutic Area Unit, Takeda, the manufacturer of brigatinib, said in a press release. “This is an important first step in expanding treatment options for people with ALK-positive metastatic NSCLC in the United States, and we look forward to continuing to work with regulatory authorities around the world to bring Alunbrig to newly diagnosed patients.”

In the international, open-label, comparative, multicenter, phase III ALTA-1L trial, investigators compared the efficacy and safety of brigatinib with crizotinib in 275 patients with stage IIIB/IV ALK-positive NSCLC who have not received prior treatment with an ALK inhibitor, but may have received ≤1 prior regimen of chemotherapy in the advanced setting.

The investigators randomized patients 1:1 to receive either 180 mg of brigatinib once daily (n = 137), with a 7-day lead-in period at 90 mg, or 250 mg of crizotinib twice daily (n = 138). Crossover from the crizotinib arm to receive brigatinib was permitted at BICR-assessed progression-free survival (PFS).

The median age was 59 years, and 55% of patients were female. Twenty-nine percent had brain metastases at baseline with comparable pre-enrollment central nervous system (CNS) radiotherapy rates among both cohorts. Overall, 27% of patients had prior chemotherapy in the locally advanced or metastatic setting.

The primary endpoint was BICR-assessed PFS, and secondary endpoints included objective response rate (ORR) per RECIST v1.1 criteria, intracranial ORR, intracranial PFS, overall survival (OS), safety, and tolerability.

At the first interim analysis, results showed that brigatinib reduced the risk of disease progression or death by 51% compared with crizotinib (HR, 0.49; 95% CI, 0.33-74; P = .0007).^3,4 At a follow-up of 25 months in the intent-to-treat population, the investigator-assessed median PFS was 29.4 months (95% CI, 21.2—not estimated [NE]) and 9.2 months (95% CI, 7.4-12.9) with brigatinib and crizotinib, respectively. The BIRC-assessed median PFS was 24.0 months (95% CI, 18.5–NE) with brigatinib and 11.0 months (95% CI, 9.2-12.9) for crizotinib.

When assessed by BICR, the confirmed ORR was 74% with brigatinib and 62% for crizotinib; the median duration of response (DOR) was not reached (95% CI, 19.4—NE) and 13.8 months (95% CI, 9.3-8) with brigatinib and crizotinib, respectively. When assessed by BICR, 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). The median intracranial PFS was 24 months compared with 5.6 months for crizotinib; the median PFS was not reached with brigatinib and was 5.9 months with crizotinib, as assessed by investigators.

Additionally, the confirmed intracranial ORR for patients with measurable brain metastases at baseline was 78% for patients treated with brigatinib and 26% for those who received crizotinib. The median intracranial DOR in confirmed responders with measurable brain metastases at baseline was not reached with brigatinib and 9.2 months with crizotinib, respectively.

Patients on the brigatinib arm also experienced significant improvements in health-related quality of life (HRQoL). Brigatinib led to a delayed median time to worsening in Global Health Score (GHS)/QoL score (≥10 point worsening in score) by 27 months versus 8 months with crizotinib.

Moreover, the duration of improvement in GHS/QoL with brigatinib was not reached versus 12 months with crizotinib. Brigatinib also delayed time to worsening and prolonged duration of improvement in multiple subscales such as fatigue, nausea and vomiting, appetite loss, and emotional and social functioning.

Brigatinib is currently approved by the FDA for the treatment of people with ALK-positive metastatic NSCLC whose disease has progressed on or were intolerant of crizotinib.

References

1. Takeda Announces U.S. FDA Grants Priority Review for Supplemental New Drug Application for ALUNBRIG® (brigatinib) as a First-Line Treatment for ALK+ Metastatic Non-Small Cell Lung Cancer. Takeda. February 24, 2020. https://bwnews.pr/3c7P1z0. February 24, 2020.
2. Camidge R, 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. Ann Oncol. 2019;30(suppl_9):ix183-ix202. doi: 10.1093/annonc/mdz446.
3. Camidge R, Kim HR, Ahn M, et al. Brigatinib vs crizotinib in patients with ALK inhibitor-naïve advanced ALK+ NSCLC: first report of a phase 3 trial (ALTA-1L). Presented at: the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract PL02.03.
4. Camidge R, Kim HR, Ahn M, et al. Brigatinib versus crizotinib in ALK-positive non—small-cell lung cancer [published online September 25, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1810171.