Takeda Canada Inc. is pleased to announce that Health Canada has issued ALUNBRIG (brigatinib tablets) marketing authorization without conditions as monotherapy for the first-line treatment of adult patients with anaplastic lymphoma kinase positive (ALK+) locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC).

brigatinib (Alunbrig®) is accepted for use within NHSScotland...as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor.

Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)‑positive advanced non‑small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor....Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase ALK positive advanced NSCLC previously treated with crizotinib.

ALUNBRIG is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

ALUNBRIG is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib

Brigatinib is recommended, within its marketing authorisation, for treating anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC) in adults who have already had crizotinib.

Brigatinib is associated with longer PFS than crizotinib at the first interim analysis and showed activity against CNS disease in previously untreated patients with ALK-positive NSCLC…

…the NCCN NSCLC Panel preference stratified the first-line therapy regimens and decided that brigatinib and ceritinib are "other recommended" options for patients with ALK-positive metastatic NSCLC; alectinib is the preferred first-line therapy option for ALK-positive metastatic NSCLC.

Brigatinib treatment demonstrated clinically meaningful systemic and intracranial efficacy in this integrated analysis of pts with ALK TKI-naive advanced or metastatic ALK+ NSCLC in the ALTA-1L or J-ALTA trials.

There were significant improvements in QA-PFS and Q-TWiST for BRG vs CRZ using BIRC and INV-assessed PROG (Table)….In patients with advanced ALK+ NSCLC, frontline treatment with BRG was associated with significant and clinically important gains in QA-PFS and Q-TWiST compared to CRZ.

The pooled objective response rate (ORR) and disease control rate (DCR) were 64% (95% CI 45%-83%) and 88% (95% CI 80%-96%), respectively. Nine studies reported median progression-free survival (mPFS) in any treatment lines. The pooled mPFS was 10.52 months (95% CI 7.66-13.36)....Brigatinib is effective in the treatment of patients with ALK-positive NSCLC, particularly showing robust intracranial PFS.

Brigatinib was associated with better ORR than crizotinib (OR=1.73, 95% CI: 1.04, 2.88), and comparable with other ALK-inhibitors....Brigatinib was superior to crizotinib and ceritinib in PFS and intracranial ORR, and had comparable efficacy and safety profile with other 2nd generation ALK-inhibitors in first-line treatments for patients with ALK-positive NSCLC.

In a multinational, phase III study (ALTA-1L) in this patient population, brigatinib significantly improved median blinded independent review committee-assessed progression-free survival (PFS), the confirmed objective response (OR) rate and the confirmed intracranial OR rate compared with crizotinib.

...phase II or III randomized controlled trials (RCTs) in ALK inhibitor-naïve ALK-positive NSCLC patients...brigatinib significantly reduced the risk of disease progression or death....Brigatinib significantly prolonged PFS in ALK inhibitor-naïve patients with ALK-positive NSCLC...

Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137...) With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio [HR], 0.49 [95% CI, 0.35 to 0.68]; log-rank P < .0001; median, 24.0 v 11.0 months)...Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 [95% CI, 0.49 to 1.00]; log-rank P = .049)...Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.

...efficacy benefit was consistent across the range of exposures achieved with the 180 mg dosing regimen including after dose modifications....results support a favorable benefit/risk profile of the proposed 180 mg qd brigatinib dose (with a 7-day lead-in at 90 mg) for the front-line treatment of patients with ALK+ NSCLC.

275 patients were randomized to receive either 180 mg of brigatinib once daily, with a 7-day lead in at 90 mg once daily, or 250 mg of crizotinib twice daily….Results indicated that after more than 2 years of follow-up, 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 time of enrollment. There was also a 57% reduction in risk of disease progression or death in all patients (HR = 0.43; 95% CI, 0.31-0.61)....The ongoing phase III ALTA-1L trial of brigatinib (Alunbrig) versus crizotinib (Xalkori) suggested that brigatinib reduced the risk of disease progression or death in adults with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC)...

...Histologically confirmed, locally advanced (stage III) and not suitable for curative treatment, i.e. R0 operation or definitive chemo-/radiation, or metastatic (stage IV) ALK+ NSCLCNOTE: Documentation of ALK rearrangement by a positive result of any ALK assay approved in Germany [i.e. positivity for at least one of the three: immunohistochemistry (IHC), NGS, fluorescence in situ hybridisation (FISH)] must be available at baseline. ...

...With ALK-positive advanced or metastatic NSCLC....

...Adult (aged ≥18) ALK positive NSCLC participants receiving brigatinib as a first-line treatment in the scope of NDP....

...With either a diagnosis of ALK positive metastatic NSCLC previously treated with crizotinib OR a diagnosis of ALK positive metastatic NSCLC previously...

...- With locally advanced or metastatic ALK-positive NSCLC who have progressed on or are intolerant to treatment with at least 1 other ALK inhibitor....

...a positive result from the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit; or 2....

...Participants with unresectable advanced/recurrent ALK fusion gene-positive non-small cell lung cancer....

...Documentation of ALK rearrangement by a positive result of any ALK assay approved in Germany [i.e. positivity for at least one of the three: immunohistochemistry (IHC), NGS, fluorescence in situ hybridisation (FISH)] must be available at baseline....

...Have documented ALK rearrangement by a positive result from the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit; or 2....

...Have documentation of ALK rearrangement by a positive result from the Vysis ALK Break Apart fluorescence in situ hybridization (FISH) Probe Kit, the Nichirei Histofine ALK iAEP Kit, or the Ventana ALK (D5F3) Companion Diagnostics (CDx) Assay at any time during prior disease course....

...- Have documentation of ALK rearrangement by a positive result from the Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit or the Ventana ALK (D5F3) CDx Assay or Foundation Medicine's FoundationOne CDx....

The second expansion cohort enrolled patients with TKI-naive ALK+ NSCLC. All patients received brigatinib 180 mg once daily (7-day lead-in at 90 mg daily)....Among 32 patients in the TKI-naive cohort, 25 (78%) remained on brigatinib (median follow-up: 22 months); 2-year IRC-assessed PFS was 73% (90% CI, 55%-85%); IRC-assessed ORR was 97% (95% CI, 84%-100%); the median duration of response was not reached (95% CI, 19.4-not reached); 2-year duration of response was 70%.

In cycle 1, patients with ALK+ or ROS1+ solid tumors, including NSCLC, received a single 3-mg dose of midazolam as an oral solution alone on day 1 and then coadministered with brigatinib on day 21 (brigatinib 90 mg once daily on days 2-8; 180 mg once daily on days 9-28). After cycle 1, patients could continue to receive brigatinib in 28-day treatment cycles....Among the 10 patients with ALK+ NSCLC, the confirmed objective response rate was 30% and median progression-free survival was 7.2 months.

With brigatinib treatment, confirmed ORR was 30.8% (95% CI, 23.1‒39.4), with 1 CR and 40 PR, and median DOR was 9.2 months (95% CI, 5.5‒not estimable); median PFS was 5.2 months (95% CI, 3.7‒7.3) by BIRC, and median OS was not reached as of this analysis. In patients with BIRC-assessed baseline brain metastases, confirmed intracranial ORR by BIRC was 13.6% (95% CI, 6.4‒24.3), with 6 CR and 3 PR. Brigatinib treatment demonstrated clinically meaningful efficacy in this integrated analysis of patients with advanced or metastatic ALK+ NSCLC who progressed on prior alectinib in the ALTA-2 or J-ALTA trials.

...BRG vs CRZ in pts with ALK inhibitor-naive advanced ALK+ NSCLC….In BRG/CRZ arms, 76%-100% shrinkage was observed in 56%/34% of pts, 51%-75% shrinkage in 27%/30%, and ≤50% shrinkage in 16%/35%, respectively….In this exploratory post hoc analysis, BRG demonstrated significantly deeper target lesion response vs CRZ.

We retrospectively analyzed the treatment history of 104 patients with ALK[+] NSCLC....In particular, the ORR of Alectinib and Brigatinib was significantly higher than that of Ceritinib and Ensartinib (P < 0.000), while the mPFS of Alectinib was significantly better than Ensartinib (P = 0.029)....For patients with CNS metastases, treatment with Alectinib and Brigatinib results in higher ORR and PFS.

Confirmed ORR was 34% (95% CI: 21–49) by IRC with 16 partial responses (PR) in the alectinib-refractory cohort and 32% (21–44; 22 PR) in the total refractory cohort….Brigatinib demonstrated a favorable benefit-risk profile and is an important option for Japanese pts with ALK+ NSCLC regardless of TKI treatment history.

In intent-to-treat (ITT) patients, brigatinib significantly prolonged blinded independent review committee-assessed PFS compared with crizotinib (HR: 0.48, 95% CI: 0.35 to 0.66) and ceritinib (HR: 0.38, 95% CI: 0.23, 0.60) and had a comparable PFS with other 2nd-generation ALK inhibitors....Brigatinib had significantly superior effects in ORR and intracranial ORR compared to crizotinib....Brigatinib had longer PFS compared to crizotinib and ceritinib and had comparable efficacy and safety profile with other 2nd-generation ALK inhibitors in first-line treatments for patients with ALK-positive non-small-cell lung cancer.

The efficacy of brigatinib was retrospectively assessed in patients with aNSCLCs included in the brigatinib...The median follow-up from brigatinib initiation was 40.4 months (95% CI 38.4–42.4). InvPFS was 7.4 months (95% CI 5.9–9.6), median duration of treatment (mDOT) was 7.3 months (95% CI 5.8–9.4) and median overall survival (mOS) was 20.3 months (95% CI 15.6–27.6)....The results of the brigALK2 study confirm the efficacy of brigatinib in a population of heavily pretreated ALK+ aNSCLC patients...

Median OS was not reached in either group(events: 41/51; HR 0.81 [0.53e1.22]; 3-yr OS 71%/68%. In pts with BL BM, PFS HR 0.25(0.14e0.46); OS HR 0.43 (0.21e0.89. BRG demonstrated durable overall and intracranial efficacy withmanageable tolerability with extended treatment, confirming BRG as a standard ofcare in treatment-naive ALK+ NSCLC.

BRG mPFS was 24.0 mo (95% CI: 18.4–43.2) vs CRZ 11.1 mo (95% CI: 9.1–13.0); 3-yr PFS rate was (BRG/CRZ) 43%/19%. Investigator-assessed PFS HR was 0.43 (95% CI: 0.31–0.58, mPFS 30.8 vs 9.2 mo). mDoR (BIRC) was 33/14 mo….BRG demonstrated durable overall and intracranial efficacy, and the tolerability profile remained consistent and manageable despite extended treatment duration, confirming BRG as an effective standard-of-care treatment in pts with treatment-naive ALK+ NSCLC.

Median OS from brigatinib initiation was 20.3 months (95%CI: 15.6-27.6)....For patients who received 1 (n=23), 2 (n=146) or 3 (n= 14) ALKi before brigatinib...median OS from brigatinib initiation was 24.3 (95%CI 9.7-NR), 20.3 (95%CI 16.2-28.7) and 18.1 (95%CI 3.3-34.5) months, respectively....The analysis of the EAP confirms the effectiveness of brigatinib in a cohort of heavily pretreated ALK-positive aNSCLC patients...

...the IRC-assessed intracranial cORR in pts with measurable baseline brain metastases was 50% (13/26) in arm A and 67% (12/18) in arm B; Kaplan-Meier (KM) estimated median intracranial DoR was 9.4 mo (95% CI, 3.7, not reached [NR]) in arm A and 16.6 mo (3.7, NR) in arm B....BRG showed sustained long-term activity, PFS, and manageable safety in pts with CRZ-refractory ALK+ NSCLC.

We report primary analysis results with brigatinib in Japanese patients with ALK-positive NSCLC who have not previously been treated with an ALK TKI in the phase 2 J-ALTA study….Confirmed ORR was 97% (90% CI, 84–100) by IRC, with 2 complete responses and 29 partial responses....In the J-ALTA TKI-naive cohort, brigatinib demonstrated substantial efficacy and manageable safety in the Japanese patient population.

Brigatinib showed a superior efficacy in terms of ORR (71% vs 60%) and of intracranial response rate (78% vs 29%) compared to Crizotinib....ALTA-1L trial showed high efficacy and good tolerability of Brigatinib as upfront treatment in ALK+ metastatic NSCLC.

Of the 72 ALK+ NSCLC patients enrolled...Brigatinib demonstrated meaningful activity in ALK TKI-resistant patients regardless of the presence of secondary ALK mutations and EML4-ALK fusion status in plasma.

Brigatinib has shown promising antitumour activity, including substantial activity against central nervous system metastases, in crizotinib-treated (ALTA trial) patients and crizotinib-naïve (ALTA-1L trial) patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. In addition, brigatinib improved progression-free survival compared with crizotinib in anaplastic lymphoma kinase inhibitor-naïve patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma.

The objective response rate was 40% (95% confidence intervals (CI): 19% to 62%), and duration of response was 5.3 months (95% CI: 3.6 to non-evaluable). With follow-up of 22 months, the median progression-free survival (PFS) was 7.0 months (95% CI: 4.6 to 10.1)....Brigatinib has activity in ALK+ NSCLC following prior next generation ALK TKIs.

From January 2018 to March 2020, 46 patients with advanced ALK-positive NSCLC received brigatinib as second or further line of therapy in Mexico and Colombia….At a median follow-up of 9.3 months, the median PFS was 15.2 months (95% CI: 11.6-18.8), and TTD was 18.46 months (95% CI: 9.54-27.38). The estimated overall survival at 12 months was 80%.

Brigatinib yielded substantial intracranial responses and durable iPFS in ALK-positive, crizotinib-treated NSCLC, with highest iPFS in patients receiving 180 mg once daily (with lead-in).

A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib….The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]....Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib.

A total of 413 patients treated with brigatinib were analyzed…. The median time to treatment discontinuation (TTD) for brigatinib was 10.3 months (95% CI, 8.2-15.0), with 45% remaining on therapy at 12 months….Brigatinib appears to be effective and well-tolerated in the real-world ALK+ NSCLC population in the US, showing benefit in patients after a next-generation ALK-TKI.

...a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase–positive NSCLC….Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients.

We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC...With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively.