Takeda Presents Long-Term Data in ALK+ NSCLC Showing ALUNBRIG® (brigatinib) Continues to Demonstrate Superiority in the First-Line After Two Years of Follow-Up

  • ALUNBRIG Reduced the Risk of Disease Progression or Death by 76% in Patients whose Disease Had Spread to the Brain, and by 57% in All Patients, when Compared to Crizotinib 
  • Median Progression-Free Survival with ALUNBRIG was Three Times Longer than that with Crizotinib 

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) today announced updated data from the Phase 3 ALTA-1L trial, which evaluated ALUNBRIG versus crizotinib in adults with advanced anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) who had not received a prior ALK inhibitor. Results show after more than two years of follow-up, ALUNBRIG reduced the risk of disease progression or death by 76% (hazard ratio [HR] = 0.24, 95% CI: 0.12–0.45) as assessed by investigators in newly diagnosed patients whose disease had spread to the brain at time of enrollment. ALUNBRIG also demonstrated a 57% (HR = 0.43, 95% CI: 0.31–0.61) reduction in risk of disease progression or death in all patients. These data will be presented during the Presidential Session at the 2019 European Society for Medical Oncology (ESMO) Asia Congress on Saturday, November 23 in Singapore.

Results from the ALTA-1L trial were evaluated by two separate review bodies – study investigators and a blinded independent review committee (BIRC) – and results from both assessments were reported. At the data cutoff for the second interim analysis (June 28, 2019), the BIRC-assessed HR of progression-free survival (PFS), which is the primary endpoint, was 0.49 (95% CI: 0.35–0.68, log-rank P<0.0001), demonstrating a reduced risk of disease progression or death by 51%.

“Given the complexity of this disease and the expected longevity of the population, it is important for physicians to have multiple well-tolerated and durable treatment options to address the needs of their patients,” said D. Ross Camidge, M.D., Ph.D., Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center and the lead investigator of ALTA-1L. “With 25 months of follow up from the ALTA-1L trial, brigatinib continues to demonstrate overall and intracranial effectiveness, while also significantly improving quality of life compared to crizotinib, reinforcing its potential as a first-line therapy for ALK+ NSCLC.”

Additional data from the long-term analysis showed that newly diagnosed patients treated with ALUNBRIG benefited regardless of the presence or absence of brain metastases at baseline, which is one of the most common sites of first progression and associated with poor quality of life.

  • ALUNBRIG demonstrated high and durable responses in the brain, with patients with baseline brain metastases having superior efficacy compared to crizotinib, as assessed by a BIRC, and an early separation of the PFS curves in these patients was observed.
    • ALUNBRIG 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), with a median intracranial PFS of 24 months compared to 5.6 months with crizotinib. Median PFS for patients with brain metastases at baseline was not reached with ALUNBRIG and was 5.9 months with crizotinib, as assessed by investigators.
    • Confirmed intracranial objective response rate (ORR) for patients with measurable brain metastases at baseline was 78% (95% CI: 52.4–93.6) for patients treated with ALUNBRIG and 26% (95% CI: 10.2–48.4) for patients treated with crizotinib.
    • Median intracranial duration of response (DOR) in confirmed responders with measurable brain metastases at baseline was not reached (95% CI: 5.7–NE) with ALUNBRIG and was 9.2 months (95% CI: 3.9–9.2) with crizotinib.
  • ALUNBRIG demonstrated consistent overall efficacy (intent to treat population) with a longer follow-up of 25 months.
    • Median PFS with ALUNBRIG was 29.4 months (95% CI: 21.2–NE) versus 9.2 months (95% CI: 7.4–12.9) with crizotinib, as assessed by investigators. The BIRC-assessed median PFS was 24.0 months (95% CI: 18.5–NE) for ALUNBRIG and 11.0 months (95% CI: 9.2–12.9) for crizotinib.
    • Confirmed ORR was 74% (95% CI: 65.5–80.9) for ALUNBRIG and 62% (95% CI: 52.9–69.7) for crizotinib as assessed by a BIRC.
    • Median DOR was not reached (95% CI: 19.4–NE) with ALUNBRIG and was 13.8 months (95% CI: 9.3–20.8) with crizotinib as assessed by a BIRC.
  • Quality of life (QoL) for newly diagnosed ALK+ NSCLC patients was also evaluated, with results showing patients treated with ALUNBRIG experienced significant improvements in health-related QoL (HRQoL).
    • ALUNBRIG 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.
    • Patients treated with ALUNBRIG had longer duration of improvement in GHS/ QoL, with duration of improvement not yet reached versus 12 months with crizotinib.
    • ALUNBRIG 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.

“At Takeda, we are committed to developing products that seek to advance the lung cancer treatment landscape and address the unmet needs of patients,” said Phil Rowlands, Head, Oncology Therapeutic Area Unit. “We are proud of the progress made thus far, including these updated results from the ALTA-1L trial, which show that ALUNBRIG delayed disease progression by more than two years and significantly reduced the risk of disease progression in patients with baseline brain metastasis. We look forward to submitting these data to regulatory authorities around the globe with the goal of making ALUNBRIG available to ALK+ NSCLC patients worldwide.”

“Individual treatment needs for patients with ALK+ NSCLC are diverse because cancer is not a one-size-fits-all disease,” said Bonnie Addario, Co-Founder, Board Chair, GO2 Foundation for Lung Cancer. “Ongoing research and clinical trials such as ALTA-1L are critical to achieving our goal of improving outcomes and quality of life for patients early on in their treatment journey. We’re grateful for the patients, families and investigators who participated in this clinical trial, which shows meaningful results for those with newly diagnosed ALK+ NSCLC.”

The safety profile of ALUNBRIG in the ALTA-1L trial was generally consistent with the existing U.S. prescribing information.

  • Most common treatment-emergent adverse events (TEAEs) Grade ≥3 in the ALUNBRIG arm were increased CPK (24.3%), increased lipase (14.0%) and hypertension (11.8%); and for crizotinib were increased ALT (10.2%), AST (6.6%), and lipase (6.6%).
  • The frequency of early pulmonary events (interstitial lung disease/pneumonitis) in the ALTA-1L trial was slightly lower compared with the ALTA study in a post-crizotinib population.
  • Pulmonary events at any time occurred in 5.1% of patients in the ALUNBRIG arm and 2.2% in the crizotinib arm.
  • Discontinuations due to AEs occurred in 12.5% of patients in the ALUNBRIG arm and 8.8% in the crizotinib arm.
  • ALUNBRIG is not currently approved for use in the first-line.

About the ALTA-1L Trial

The Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial of ALUNBRIG in adults is a global, ongoing, randomized, open-label, comparative, multicenter trial, which enrolled 275 patients (ALUNBRIG, n=137, crizotinib, n=138) with anaplastic lymphoma kinase-positive (ALK+) locally advanced or metastatic non-small cell lung cancer (NSCLC) who have not received prior treatment with an ALK inhibitor. Patients received either ALUNBRIG, 180 mg once daily with seven-day lead-in at 90 mg once daily, or crizotinib, 250 mg twice daily.

The median age was 58 years in the ALUNBRIG arm and 60 years in the crizotinib arm. Twenty-nine percent of patients had brain metastases at baseline in the ALUNBRIG arm versus 30% in the crizotinib arm. Twenty-six percent of patients received prior chemotherapy for advanced or metastatic disease in the ALUNBRIG arm versus 27% in the crizotinib arm.

Blinded independent review committee (BIRC)-assessed progression-free survival (PFS) was the primary endpoint. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, intracranial ORR, intracranial PFS, overall survival (OS), safety and tolerability.

About ALUNBRIG® (brigatinib)

ALUNBRIG is a potent and selective next-generation tyrosine kinase inhibitor (TKI) that was designed to target and inhibit the anaplastic lymphoma kinase (ALK) fusion protein in non-small cell lung cancer (NSCLC). In April 2017, ALUNBRIG received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for anaplastic lymphoma kinase-positive (ALK+) metastatic NSCLC patients who have progressed on or are intolerant to crizotinib. This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

ALUNBRIG is currently approved in more than 40 countries, including the U.S., Canada and the European Union, for the treatment of people with ALK+ metastatic NSCLC whose disease has worsened during crizotinib treatment or they could not tolerate taking crizotinib.

ALUNBRIG received Breakthrough Therapy Designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib and was granted Orphan Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.

Takeda in Lung Cancer

Takeda is dedicated to expanding experience in the ALK+ NSCLC and EGFR exon 20 treatment landscapes. Our comprehensive programs include the following clinical trials to continue to address unmet needs for people living with lung cancer:

ALUNBRIG

  • Phase 1/2 trial, which was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ALUNBRIG.
  • Pivotal Phase 2 ALTA trial investigating the efficacy and safety of ALUNBRIG at two dosing regimens in patients with ALK+ locally advanced or metastatic NSCLC who had progressed on crizotinib.
  • Phase 3 ALTA-1L, global, randomized trial assessing the efficacy and safety of ALUNBRIG in comparison to crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor.
  • Phase 2 J-ALTA, single-arm, multicenter trial in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib. This trial is now enrolling.
  • Phase 2 ALTA 2, global, single-arm trial evaluating ALUNBRIG in patients with advanced ALK+ NSCLC who have progressed on alectinib or ceritinib. This trial is now enrolling.
  • Phase 3 ALTA 3, global randomized trial comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK+ NSCLC who have progressed on crizotinib. This trial is now enrolling.

TAK-788

  • Phase 1/2 study evaluating the safety, pharmacokinetics and antitumor activity of oral EGFR/HER2 inhibitor TAK-788 in patients with NSCLC.
  • Phase 2 EXCLAIM, pivotal extension cohort of the Phase 1/2 trial, which was designed to evaluate the efficacy and safety of TAK-788 at 160 mg once daily in previously treated patients with EGFR exon 20 insertion mutations. This trial is closed to enrollment.
  • Phase 3 EXCLAIM 2, global, randomized study evaluating the efficacy of TAK-788 as a first-line treatment compared to platinum-based chemotherapy in treatment-naïve patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations.
  • Phase 1, open-label, multicenter, dose-escalation study evaluating the safety, tolerability and pharmacokinetics of TAK-788 in Japanese patients with locally advanced or metastatic NSCLC. This trial has been fully enrolled.
  • Phase 2, open label, single-arm study evaluating the efficacy of TAK-788 in treatment-naïve patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations.
  • Phase 1, open-label, two-period, fixed-sequence study designed to characterize drug-drug interaction between TAK-788 and either a strong cytochrome P-450 (CYP)3A inhibitor, itraconazole (Part 1) or a strong CYP3A inducer, rifampin (Part 2) in healthy adult subjects.
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