Brigatinib In Patients Research Articles

Real-world evidence of brigatinib as second-line treatment after crizotinib for ALK+ non-small cell lung cancer using South Korean claims data (K-AREAL).

There is a lack of real-world data in Asian populations for brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor for patients with non-small cell lung cancer (NSCLC). This study analysed real-world outcomes and dosing patterns for brigatinib in patients with crizotinib-refractory ALK+ NSCLC in South Korea. This retrospective, non-interventional, cohort study used South Korean Health Insurance and Review Assessment claims data for adults with ALK+ NSCLC who initiated brigatinib between 19 April 2019 and 31 March 2021 after receiving prior crizotinib. Patients' characteristics, time to discontinuation (TTD), time to dose reduction, overall survival (OS) and treatment adherence were assessed. The study included 174 patients (56.9% male; 27.0% with a history of brain metastases). Median duration of prior crizotinib was 17 (range 0.3-48) months. Median follow-up after brigatinib initiation was 18 (range 0-34) months. Overall, 88.5% of patients received full-dose brigatinib (180 mg/day) and 93.1% of patients were adherent (proportion of days covered ≥0.8). The median TTD was 24.9 months (95% CI 15.2-not reached). The probability of continuing treatment was 63.2% at 1 year and 51.5% at 2 years. The probability of continuing at full or peak dose was 79.7% at 1 year and 75.6% at 2 years. Median OS was not reached. The 2-year OS rate was 68.7%. In this first nationwide retrospective study using national insurance claim data, brigatinib demonstrated real-world clinical benefit as second-line treatment after prior crizotinib in ALK+ NSCLC patients in South Korea.

Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors

BackgroundNF2-related schwannomatosis (NF2-SWN, formerly called neurofibromatosis type 2) is a tumor predisposition syndrome that is manifested by multiple vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas. The condition is relentlessly progressive with no approved therapies. On the basis of preclinical activity of brigatinib (an inhibitor of multiple tyrosine kinases) in NF2-driven nonvestibular schwannoma and meningioma, data were needed on the use of brigatinib in patients with multiple types of progressive NF2-SWN tumors.MethodsIn this phase 2 platform trial with a basket design, patients who were 12 years of age or older with NF2-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes.ResultsA total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (−0.013 units per month; 95% CI, −0.002 to −0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported.ConclusionsBrigatinib treatment resulted in radiographic responses in multiple tumor types and clinical benefit in a heavily pretreated cohort of patients with NF2-SWN. (Funded by the Children’s Tumor Foundation and others; INTUITT-NF2 ClinicalTrials.gov number, NCT04374305.)

Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

Real-world tolerability of front-line brigatinib in patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) with and without brain metastases in the United States.

535 Background: Brigatinib, a next-generation ALK tyrosine kinase inhibitor (TKI), is approved for treatment in patients with ALK+ NSCLC with a dosing schedule of 180 mg/day after a 7-day lead-in at 90 mg/day. Brigatinib has been shown through clinical trials to have improved intracranial efficacy compared to crizotinib. There is limited information regarding the real-world tolerability of brigatinib in patients with brain metastases (BM). Our study aims to assess treatment tolerability via dose reduction rates and adherence in patients treated with front-line (FL) brigatinib and stratified by evidence of BM. Methods: This retrospective cohort study utilized the IQVIA open-source pharmacy and medical claims databases. Adults (≥18 years) with ≥1 claim for brigatinib between 22 May 2020 and 31 December 2022 with no prior claims for brigatinib or other ALK-TKI therapies were identified from the pharmacy claims database and followed until the earliest of dose reduction, treatment discontinuation, or end of follow-up. Average daily dose (ADD) was calculated as the product of pill strength and quantity of pills dispensed divided by day supply. Dose reduction was defined as ≥30 days of treatment with ADD < 180 mg/day. Time to dose reduction from 180 mg/day and probability of continued therapy at ≥180 mg/day were assessed by Kaplan-Meier analysis. Adherence was defined using medication possession ratio (MPR) and calculated as the total day supply divided by the number of days from the first claim date to the last supply date of FL brigatinib. BM was defined as having ≥1 claim in the medical claims database with a diagnosis code for secondary malignant neoplasm of the brain. Results: Overall 126 patients treated with FL brigatinib were identified (median age: 57.5; 57.1% female). Median (min-max) follow-up time was 11.7 (1.0-30.7) months; 114 (90.5%) patients reached a dose of 180 mg/day, and among these 27 (23.7%) had evidence of BM. Of patients who reached a dose of 180 mg/day, 14.8% of those with BM and 18.4% with no BM (p=0.779) had a dose reduction. The probability of remaining on therapy at 180 mg/day was 86.2% at 3, 6 and 9 months and 71.8% at 12 months in patients with BM. In patients with no BM, the probabilities of remaining on therapy at a dose of 180 mg/day at 3, 6, 9 and 12 months were 89.1%, 82.6%, 70.8% and 67.1%, respectively (P=.761). Adherence was high irrespective of BM with 81.5% of patients with BM and 94.3% those without BM having MPR > 80%. Results in the overall FL brigatinib sample (with and without BM) were similar. Conclusions: Real-world data suggest that FL brigatinib is well tolerated regardless of brain metastasis status. Most FL brigatinib patients in the study achieved and maintained a daily dose of 180 mg. Dose reductions and probability of remaining on therapy were similar for patients with or without brain metastases.

O7-3 Phase II study of brigatinib in patients with TKI-naive ROS1-rearranged non-small cell lung cancer (NSCLC): Barossa study

O7-3 Phase II study of brigatinib in patients with TKI-naive ROS1-rearranged non-small cell lung cancer (NSCLC): Barossa study

Longitudinal tracking of ALK-positive lung cancer from plasma using circulating-tumor RNA and circulating-tumor DNA in the BRIGHTSTAR clinical trial.

e21072 Background: While the administration of specific tyrosine-kinase inhibitors (TKIs) in ALK-fusion positive lung cancer has led to significant improvement in clinical outcomes, detection of gene fusions remains challenging, especially from liquid biopsies. In tissue biopsies, assays which incorporate RNA-based detection have demonstrated increased sensitivity for gene fusion detection. We therefore hypothesized that a liquid biopsy assay equally including assessment of gene fusions using circulating-tumor RNA (ctRNA) in addition to circulating-tumor DNA (ctDNA), will improve detection. Furthermore, we hypothesized that detection of gene fusions as well as mutations will also correlate with clinical treatment. Methods: We retrospectively analyzed 89 samples from 35 patients included in the BRIGHTSTAR clinical trial assessing local consolidative therapy (LCT) and brigatinib in patients with stage IV or recurrent Non-small Cell Lung Cancer and confirmed ALK rearrangement (NCT03707938). Samples were included at baseline (N = 31), prior to LCT after 8 weeks of brigatinib treatment (N = 29), after LCT ( < 3 weeks; N = 25) and at progression (N = 4). We used a targeted next generation sequencing (NGS) assay assessing both ctDNA as well as ctRNA (LiquidHALLMARK, Lucence Health, Palo Alto) to detect ALK fusions as well as mutations in 80 genes. Up to 5 ml of plasma was analyzed per sample. Results: At baseline, ALK fusions were detected in 15/31 patients (48%) of which 8 were detected using both ctDNA and ctRNA, while four were exclusively detected in ctDNA and three in ctRNA. Plasma ctDNA concentrations for patients with detectable ALK fusions at baseline were significantly higher than for those without detectable gene fusions (mean 26.1 ng/mL versus 16.6 ng/mL; p = 0.0044). ALK fusions were detected in two patients pre-LCT, exclusively in ctRNA, while ALK fusions cleared completely post-LCT. At progression, ALK fusions were detected in 2/4 samples (50%) in both ctDNA and ctRNA. Of the two negative samples tissue biopsies were available confirming the absence of an ALK rearrangement, including one transformation to squamous cell carcinoma. Overall, including analysis of ctRNA led to a 36% relative additional detection of ALK fusions compared to analyzing ctDNA alone. Furthermore, ctDNA mutation positivity in genes other than ALK was 17/31 (55%), 9/29 (31%), 8/25 (32%) and 3/4 (75%) for baseline, pre-LCT, post-LCT and progression, respectively. Conclusions: We highlight that ALK fusions can be reliably detected in plasma of lung cancer patients and detectability of ALK fusions correlate with exposure to treatment. Analyzing ctRNA in addition to ctDNA improves sensitivity of fusion detection and is a highly promising strategy in this setting.

Integrated efficacy and safety of brigatinib in patients with ALK TKI-naive advanced ALK+ NSCLC in the ALTA-1L and J-ALTA studies.

9078 Background: Brigatinib demonstrated efficacy and manageable safety in patients (pts) with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI)-naive ALK+ non-small cell lung cancer (NSCLC) in phase 3 (ALTA-1L) and phase 2 (J-ALTA) trials. We present results of integrated efficacy and safety analyses of ALTA-1L and J-ALTA. Methods: ALTA-1L (NCT02737501) and J-ALTA (NCT03410108; conducted in Japan) were open-label, multicenter studies in pts with advanced or metastatic ALK+ NSCLC. Pts in ALTA-1L and in part 3 of J-ALTA were ALK TKI-naive. Stable or asymptomatic brain metastases were allowed in both studies. Pts received brigatinib 180 mg qd (7-day lead-in at 90 mg). Primary endpoints were blinded independent review committee (IRC)-assessed progression-free survival (PFS) in ALTA-1L and IRC-assessed 12-month PFS in the J-ALTA ALK TKI-naive cohort (both per RECIST v 1.1). Secondary endpoints included IRC-assessed objective response rate (ORR), duration of response, intracranial ORR, intracranial PFS, overall survival, and safety. Pooled efficacy and safety data from both studies are presented. Results: The pooled analysis population included 169 pts (ALTA-1L, N = 137; J-ALTA ALK TKI-naive cohort, N = 32). Median follow-up overall was 35.8 months (last pt last contact: ALTA-1L, January 2021; J-ALTA, July 2021). Most (66%) pts were aged < 65 years, 24% had baseline brain metastases, 95% had stage IV disease at study entry, and 21% had received prior chemotherapy for locally advanced or metastatic disease. With brigatinib treatment, median PFS by IRC was 29.3 months (95% CI, 23.9‒44.7). The confirmed ORR was 79% (95% CI, 72‒85%), with 36 complete responses and 97 partial responses. Median duration of response was 38.1 months (95% CI, 22.9‒not reached). Median overall survival was not reached; the 3-year survival rate was 74% (95% CI: 66‒80%; 84 pts at risk). Intracranial ORR and intracranial PFS will be presented. Grade 3/4 treatment-emergent adverse events were reported in 74% of pts; the most common were increased blood creatine phosphokinase (31%), hypertension (18%), and increased lipase (16%). Any grade interstitial lung disease/pneumonitis was reported in 12 (7%) of pts. Adverse events led to treatment discontinuation in 11% of pts. Conclusions: 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. Safety results were consistent with the known profile for brigatinib, with no new safety findings. Clinical trial information: NCT02737501 ; NCT03410108 .

Brigatinib in patients with ALK‐positive anaplastic large cell lymphoma who have failed brentuximab vedotin

ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) patients (pts) who have failed brentuximab vedotin (BV) have a poor prognosis with a median OS after BV failure of 2.9 months and 2-year OS of 27.1% (Chihara D, 2019). ALK-inhibitors have shown interesting results in relapsed ALK+ ALCL, but in these studies, most pts had not received prior BV, which does not correspond to current standards of treatment in adults. Furthermore, there are currently several ALK-inhibitors, but too few pts available to test them in this rare and difficult-to-treat population. It is therefore important to evaluate these ALK-inhibitors in preclinical studies, before selecting one for a clinical study. We carried out a preclinical study and then a real-life clinical study. We generated a patient-derived xenograft (PDX) model from a fresh lymph node biopsy of a 41-year-old man newly diagnosed with ALK+ ALCL. Our PDX closely mimicked the patient’s primary tumor, as assessed by pathology, FISH, TCR gene rearrangement, WES and RNA-seq. We used this model to assess 8 ALK-inhibitors (alectinib, brigatinib, ceritinib, crizotinib, ensartinib, entrectinib, lorlatinib, gilteritinib). We selected and recommended brigatinib for clinical off-label use based on our preclinical results and the safety profile in pts with ALK-positive non-small cell lung cancer (NSCLC). Between Jan 2020 and Oct 2022, 15 French adults who have failed BV started brigatinib. At brigatinib initiation, the median age was 35 y (19–73; 2 pts > 60 y), 8/15 were male, the median number of prior treatment lines was 2 (1–8), 4/15 (27%) had received prior crizotinib, including 3 crizotinib-resistant (crizo-R) and 1 crizotinib-sensitive (crizo-S) who relapsed after discontinuation of the drug. 4 pts had previously undergone stem cell transplantation (3 autoSCT, 1 alloSCT). ALCL was refractory to the last treatment in 10/15 pts. 10/11 pts had detectable ALK transcript in blood by RT-PCR. Pts received brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg), as recommended in ALK-positive NSCLC. The best ORR was 93% (14/15) with 73% (11/15) CR according to Lugano response criteria. 2 crizo-R and the crizo-S pts achieved CR, and 1 crizo-R pt reached PR. Time to achieve CR ranged from 8 to 325 days. 9 pts were monitored for ALK transcript in blood over time and kinetics correlated with response. 5 CR pts were bridged to alloSCT. There were 4 progressions/relapses after brigatinib initiation, all occurring within the first 6 months. After a median follow-up of 1.3 years, 1-year PFS and OS were 72% and 85%, respectively. There was no permanent discontinuation of brigatinib related to adverse event (AE), and 3 pts had dose reduction for moderate AE (1 dyspnea and 2 cramps), with complete resolution. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. D. Sibon Consultant or advisory role: Takeda, AbbVie, Janssen, Roche

Efficacy and safety of brigatinib in ALK-positive non-small cell lung cancer treatment: A systematic review and meta-analysis

Brigatinib is a central nervous system-active second-generation anaplastic lymphoma kinase (ALK) inhibitor that targets a broad range of ALK rearrangements in patients with non-small cell lung cancer (NSCLC). The current study aimed to analyze the pooled effects and adverse events of brigatinib in patients with ALK-positive NSCLC. The pooled estimates and 95% confidence intervals (CI) were calculated with DerSimonian-Laird method and the random effect model. The pooled objective response rate (ORR) and disease control rate (DCR) of brigatinib were 64% (95% CI 45%-83%) and 88% (95% CI 80%-96%), respectively. The pooled mPFS was 10.52 months (95% CI 7.66-13.37). In the subgroup analyses by treatment line, the highest mPFS was reached in first-line treatment (24.00 months, 95% CI 18.40-43.20), followed by post-crizotinib second-line treatment (mPFS=16.26 months, 95% CI 12.87-19.65), and second-line with any prior ALK tyrosine kinase inhibitors (mPFS=12.96 months, 95% CI 11.14-14.78). Among patients with any baseline brain metastases, the pooled intracranial ORR (iORR) was estimated as 54% (95% CI 35%-73%) for any treatment line, and 60% (95% CI 39%-81%) for first-line treatment. Intracranial PFS (iPFS) reached 19.26 months (95% CI 14.82-23.70) in patients with any baseline brain metastases. Creatine phosphokinase (CPK) increased (44%, 95% CI 26%-63%), diarrhea (37%, 95% CI 27%-48%), and nausea (28%, 95% CI 17%-39%) of any grade were the most common adverse events. Brigatinibis effective in the treatment of patients with ALK-positive NSCLC, particularly showingrobust intracranial PFS. Brigatinib used as first-line treatment yielded superior PFS compared with brigatinib used as other treatment lines. These results suggested a benefit of using brigatinib earlier in the patient's management. All adverse events are manageable, with CPK increased and gastrointestinal reactions found to be the most common types. https://inplasy.com/inplasy-2022-3-0142/, identifier (INPLASY202230141).

Efficacy of Brigatinib in Patients With Advanced ALK-Positive NSCLC Who Progressed on Alectinib or Ceritinib: ALK in Lung Cancer Trial of brigAtinib-2 (ALTA-2)

IntroductionBrigatinib is a potent next-generation ALK tyrosine kinase inhibitor approved for treatment-naive and crizotinib-refractory advanced ALK-positive (ALK+) NSCLC. We evaluated brigatinib after other next-generation ALK tyrosine kinase inhibitors. MethodsIn this single-arm, phase 2, ALK in Lung Cancer Trial of brigAtinib-2 (NCT03535740), patients with advanced ALK+ NSCLC whose disease progressed on alectinib or ceritinib received brigatinib 180 mg once daily (after 7-d 90-mg lead-in). Primary end point was independent review committee (IRC)-assessed overall response rate (ORR). Circulating tumor DNA (ctDNA) was analyzed. ResultsAmong 103 patients (data cutoff: September 30, 2020; median follow-up [range]: 10.8 [0.5–17.7] mo), confirmed IRC-ORR was 26.2% (95% confidence interval [CI]: 18.0–35.8), median duration of response, 6.3 months (95% CI: 5.6–not reached), and median progression-free survival (mPFS), 3.8 months (95% CI: 3.5–5.8). mPFS was 1.9 months (95% CI: 1.8–3.7) in patients with ctDNA-detectable baseline ALK fusion (n = 64). Among 86 patients who progressed on alectinib, IRC-ORR was 29.1% (95% CI: 19.8–39.9); mPFS was 3.8 months (95% CI: 1.9–5.4). Resistance mutations were present in 33.3% (26 of 78) of baseline ctDNA; 54% (14 of 26) of mutations were G1202R; 52% (33 of 64) of patients with detectable ALK fusion had EML4-ALK variant 3. Most common all-grade treatment-related adverse events were increased creatine phosphokinase (32%) and diarrhea (27%). The mean dose intensity of brigatinib (180 mg once daily) was 85.9%. ConclusionsIn ALK in Lung Cancer Trial of brigAtinib-2, brigatinib was found to have a limited activity in patients with ALK+ NSCLC post-ceritinib or post-alectinib therapy. mPFS was longer with brigatinib in patients without baseline detectable plasma ALK fusion.

977P Phase II study of brigatinib in patients with tyrosine kinase inhibitor (TKI)-naïve ROS1-rearranged advanced non-small cell lung cancer (NSCLC): Barossa cohort 1

Barossa is a multicenter, phase II basket study of brigatinib in patients with ROS1-rearranged solid tumors. We report the results of the cohort 1, in which TKI-naïve ROS1-rearranged NSCLC patients were enrolled. Patients with advanced, TKI-naïve ROS1-rearranged advanced NSCLC received brigatinib at a dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary end point was objective response rate (ORR; RECIST 1.1) by independent review. Key secondary endpoints were PFS, OS, and safety. The sample size was set at 28 patients, with a one-sided alpha of 0.05, beta of 0.2, and threshold and expected values for primary endpoint of 50% and 75%, respectively. Between September 2019 and May 2020, 28 patients were enrolled from 9 institutions. Baseline characteristics as follows: median age (range): 65 (38-81) years; women, n=18 (64%); ECOG PS of 0-1, n=28 (100%); never smoker, n= 16 (57%); tumor histopathological type: adenocarcinoma, n=27 (96%); brain metastasis, n=8 (29%). The median duration of follow-up for PFS was 9.3 months. Seventeen patients (61%) continued study treatment at the data cutoff date of 30 Nov 2021. The primary endpoint was met as 19 patients achieved PR with ORR at 67.9% (90%CI, 50.6-82.1%). Another 3 patients achieved SD and the disease control rate was 78.6% (95%CI, 59.0-91.7%). The PFS and OS were not yet mature: the median PFS was 12.0 months (95% CI, 5.8-not evaluable). Twenty-five out of the 28 patients remained alive at the data cutoff. Grade 3 pneumonitis, which was considered treatment-related, was observed in 3 patients (10.7%), and all 3 cases resulted in treatment discontinuation. Pneumonitis was improved with steroid therapy in all 3 patients. Other grade ≥3 TRAEs were CPK increased (28.6%), hypertension (21.4%), AST increased (10.7%), ALT increased (7.1%), nausea (3.6%), hyperglycemia (3.6%). No treatment-related deaths were observed. Brigatinib demonstrated encouraging antitumor activity in patients with TKI-naïve ROS1-rearranged advanced NSCLC. The safety profile of brigatinib was consistent with previous studies.

Real-World Efficacy and Tolerability of Brigatinib in Patients with Non-Small Cell Lung Cancer with Prior ALK-TKIs in the United States.

BackgroundReal-world evidence for brigatinib, a next-generation anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) used in ALK-rearranged non-small cell lung cancer, is scarce. This retrospective study evaluated real-world brigatinib utilization in the US post other ALK-TKIs.Materials and MethodsAdults with ≥1 brigatinib claim (index date) between 1 April 2017 and 30 September 2020 in the IQVIA longitudinal pharmacy claims database were followed until dose reduction, discontinuation, or end of follow-up. Patients had ≥12 months pre– and ≥1-month post–index observations.ResultsA total of 413 patients treated with brigatinib were analyzed. Over 80% received ≥1 prior ALK-TKI; alectinib and crizotinib were the most common (58.8% and 51.3% patients, respectively). The median follow-up was 8.4 months. 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. The TTD was shortest (~8 months) in patients receiving both crizotinib and alectinib and longest in patients who received alectinib only prior to brigatinib (11.8 months). Adherence was high, with 92.7% of patients having a medication possession ratio of >80%. The mean dose compliance score was 1.0. Most patients reached the brigatinib dose of 180 mg/day (77%); 13.2% of patients had a dose reduction, with 89.3% and 84.6% continuing 180 mg/day therapy at 3 and 6 months, respectively.ConclusionsBrigatinib 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. Notably, dose reduction rates appeared markedly less than those seen in trials when most trial-related dose reductions were for asymptomatic laboratory abnormalities.

O13-1 Phase II study of brigatinib in ROS1-positive non-small cell lung cancer patients previously treated with crizotinib

Barossa is a multicenter, phase II basket study of brigatinib in patients with ROS1-positive solid tumors. This study is composed of three cohorts. ROS1 inhibitor-naÏve ROS1-positive non-small cell lung cancer (NSCLC) patients were enrolled in the cohort 1, and ROS1-positive NSCLC patients previously treated with crizotinib were enrolled in the cohort 2. Patients with ROS1-positive solid tumors other than NSCLC were enrolled in the cohort 3. This time we report the cohort 2 results.

Short communication: The activity of brigatinib in patients with disease progression after next generation anaplastic lymphoma tyrosine kinase inhibitors and an exploratory analysis of circulating tumor DNA

BackgroundBrigatinib, a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is central nervous system (CNS) penetrant and active against anaplastic lymphoma kinase (ALK) resistance mutations. We prospectively studied the activity of brigatinib in patients with disease progression after second generation ALK TKIs. MethodsPatients with stage IIIB/IV ALK + non-small cell lung cancer (NSCLC), and progressive disease after second ALK TKIs were eligible. Cohort A enrolled patients with disease progression on any second ALK TKI, cohort B enrolled patients with disease progression after first-line therapy with alectinib, and cohort C enrolled patients who experienced disease progression on standard dose brigatinib. Brigatinib treatment was 90 mg daily for seven days and then escalated to 180 mg daily in cohorts A and B, and 240 mg daily in cohort C. The primary endpoint was objective response rate (ORR), and a 2-stage design was used. The intended enrollment was 20 patients in stage 1, and 20 patients in stage 2. ResultsThe study was closed due to slow accrual. Between March 2017 and June 2020, 32 patients received study therapy; three patients in cohort A moved to cohort C after initial progression for a total of 35 study subjects. Of the 32 patients, 16 (50%) were male, the median age was 55 years (range 32–76), and patients received a median number of 2 prior ALK TKI’s (range 1–3). Cohort A enrolled 27 patients, cohort B enrolled four patients, and cohort C enrolled four patients. The ORR in cohorts A, B, and C was 33% (95% confidence interval (CI: 16% to 54%), 25% (95% CI: 0.63% to 81%), and 0%, respectively. ConclusionBrigatinib has activity in ALK positive NSCLC patients with disease progression after second generation ALK TKIs.

P45.04 Phase II Study of Brigatinib in ROS1 Positive Non-Small Cell Lung Cancer (NSCLC) Patients Previously Treated with Crizotinib: Barossa Cohort 2

Brigatinib is a next-generation tyrosine kinase inhibitor targeting ALK and ROS1. Crizotinib is the first drug approved for the treatment of ROS1 fusion-positive NSCLC. Standard treatment for crizotinib-resistant ROS1 positive NSCLC is not established. Barossa is a multicenter, phase II basket study of brigatinib in patients with ROS1 positive solid tumors. This study is composed of three cohorts. ROS1 inhibitor-naïve ROS1 positive NSCLC patients were enrolled in the cohort 1, and ROS1 positive NSCLC patients previously treated with crizotinib were enrolled in the cohort 2.

Brigatinib Versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial

IntroductionIn the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor–naive advanced ALK-positive NSCLC, brigatinib exhibited superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results. MethodsPatients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. ResultsA total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed. ConclusionsIn the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study.

PCN68 Brigatinib Compared with Crizotinib and Alectinib in Patients with ALK-Positive Non-Small Cell Lung Cancer (NSCLC) with Brain Metastases at Diagnosis: A Cost-Effectiveness Analysis from the Perspective of the Brazilian Private Health Care System

Second generation ALK-inhibitors have shown improvement in brain disease control compared with Crizotinib in patients with metastatic ALK+ NSCLC. However, Crizotinib is the only treatment covered by the Brazilian private health care system (BHCS) so far. The objective of this study was to evaluate the cost-effectiveness of first-line Brigatinib in patients with ALK+ NSCLC and brain metastases at diagnosis, in comparison with Crizotinib and Alectinib, according to BHCS perspective.

Real-world treatment outcomes with brigatinib in patients with pretreated ALK+ metastatic non-small cell lung cancer

BackgroundThe next-generation ALK inhibitor brigatinib is approved for use in patients with ALK inhibitor-naïve ALK-positive advanced NSCLC and in patients previously treated with crizotinib. A phase II trial showed that brigatinib is active in patients with ALK-positive metastatic NSCLC (mNSCLC) who had progressed on prior crizotinib (response rate 56 %, median PFS 16.7 months, median OS 34.1 months). We report final data from the UVEA-Brig study of brigatinib in ALK inhibitor-pretreated ALK-positive mNSCLC in clinical practice. MethodsUVEA-Brig was a retrospective chart review of patients treated with brigatinib in Italy, Norway, Spain and the UK in an expanded access program. Adults with ALK-positive mNSCLC, including those with brain lesions, resistant to or intolerant of ≥1 prior ALK inhibitor and ECOG performance status ≤3 were eligible. Patients received brigatinib 180 mg once daily with a 7-day lead-in at 90 mg. The objectives were to describe patient characteristics, clinical disease presentation, treatment regimens used and clinical outcomes. ResultsData for 104 patients (male: 43 %; median age: 53 [29–80] years; ECOG performance status 0/1/2/3: 41/41/10/5 %; brain/CNS metastases: 63 %) were analyzed. Patients had received a median of 2 (1–6) lines of systemic therapy prior to brigatinib (37.5 % received ≥3) and a median of 1 (1–5) lines of prior ALK inhibitor-containing therapy (crizotinib 83.6 %; ceritinib 50.0 %; alectinib 6.7 %; lorlatinib 4.8 %). At the time of analysis, 77 patients had discontinued brigatinib. Overall, the response rate was 39.8 %, median PFS was 11.3 (95 % CI:8.6–12.9) months and median OS was 23.3 (95 % CI: 16.0–NR) months. Four patients discontinued brigatinib treatment due to adverse events. 53 patients received systemic therapy after brigatinib, 42 with an ALK inhibitor (lorlatinib, n = 34). ConclusionsThese real-world data indicate the activity and tolerability of brigatinib in patients with ALK-positive mNSCLC who were more heavily pretreated than patients included in clinical trials.

Phase II study of brigatinib in ROS1 positive non-small cell lung cancer (NSCLC) patients previously treated with crizotinib: Barossa cohort 2.

9040 Background: Brigatinib is a next-generation tyrosine kinase inhibitor targeting ALK and ROS1. Crizotinib is the first drug approved for the treatment of ROS1 fusion-positive NSCLC. Standard treatment for crizotinib-resistant ROS1 positive NSCLC is not established. Barossa is a multicenter, phase II basket, study of brigatinib in patients with ROS1 positive solid tumors. This study is composed of three cohorts. ROS1 inhibitor-naïve ROS1 positive NSCLC patients were enrolled in the cohort 1, and ROS1 positive NSCLC patients previously treated with crizotinib were enrolled in the cohort 2. Patients with ROS 1 positive solid tumors other than NSCLC were enrolled in the cohort 3. This time we report the cohort 2 results. Methods: Patients with advanced, previously treated with crizotinib, ROS1 positive NSCLC received brigatinib at a dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary end point was objective response rate (ORR; RECIST 1.1) by independent review. Key secondary endpoint was PFS, OS, and safety. The sample size was set at 19 patients, with a one-sided alpha of 0.05, beta of 0.2, and threshold and expected values for primary endpoint of 20% and 50%, respectively. Results: From July 2019 and Jan 2020, 19 patients were enrolled from 9 institutions. Baseline characteristics as follows: median age (range): 60 (31-75) years; women, n = 10 (53%); ECOG PS of 0 to 1, n = 18 (95%); never smoker, n = 11 (58%); tumor histopathological type: adenocarcinoma, n = 18 (95%). Five and 6 patients achieved PR and SD, respectively at data cutoff date of 30 Oct 2020. The ORR was 26.3% (90%CI, 11.0-47.6), and the disease control rate was 57.9% (95%CI, 33.5-79.7). The median duration of follow-up for PFS was 12.0 months. The median PFS was 7.3 months (95% CI, 1.3-9.3), and the 1-year PFS rate was 26.9% (95%CI, 9.2-48.6). Grade ≥3 TRAEs were CPK increased (21.1%), infection (5.3%), AST and/or ALT increased (5.3%), hypercalcemia (5.3%), anorexia (5.3%), hypoxia (5.3%), erythema (5.3%), hypertension (5.3%). Pneumonitis was observed in one patient (5.3%, Grade 2). No treatment-related death was observed. Conclusions: Brigatinib has modest activity for ROS1 positive NSCLC patients previously treated with crizotinib. The safety profile of brigatinib was consistent with previous studies. Enrollment of the cohort 1 for ROS1 inhibitor-naïve NSCLC patients is ongoing, and the data will be presented at a future congress. Clinical trial information: JapicCTI-194851.

Effect of severe renal impairment on the pharmacokinetics of brigatinib

SummaryBackground Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, targets activated, mutant forms of ALK and overcomes mechanisms of resistance to the ALK inhibitors crizotinib, ceritinib, and alectinib. Brigatinib is approved in multiple countries for treatment of patients with ALK-positive non–small cell lung cancer. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. Methods An open-label, single-dose study was conducted to evaluate the PK of brigatinib (90 mg) in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2; n = 8) and matched healthy volunteers with normal renal function (estimated glomerular filtration rate ≥ 90 mL/min/1.73 m2; n = 8). Plasma and urine were collected for the determination of plasma protein binding and estimation of plasma and urine PK parameters. Results Plasma protein binding of brigatinib was similar between patients with severe renal impairment (92 % bound) and matched healthy volunteers with normal renal function (91 % bound). Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment.Trial registry: Not applicable.