Brigatinib in Japanese patients with tyrosine kinase inhibitor-naive ALK-positive non-small cell lung cancer: first results from the phase 2 J-ALTA study

Background We evaluated the safety and efficacy of the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) brigatinib in Japanese patients with TKI-naive ALK-positive non-small cell lung cancer (NSCLC) from the phase 2, open-label, single-arm, multicenter J-ALTA study. Methods In the TKI-naive cohort of J-ALTA, the primary end point was independent review committee (IRC)-assessed 12-month progression-free survival (PFS). Secondary end points included objective response rate (ORR), intracranial response, overall survival (OS), and safety. Results The data were cut approximately 12 months after last patient enrollment. Thirty-two patients with ALK TKI-naive ALK-positive NSCLC were enrolled (median age [range], 60.5 [29–85] years; median duration of follow-up, 14.2 [3.2–19.3] months; median treatment duration, 13.8 [0.4–19.3] months). IRC-assessed 12-month PFS was 93.0% (90% confidence interval (CI) 79.2–97.8%); ORR, 96.9% (95% CI 83.8–99.9%), 12-month OS, 96.9% (95% CI 79.8–99.6%), and median OS was not reached. Of five patients with measurable baseline CNS metastases, two had partial intracranial response. The most common treatment-emergent adverse events were increased blood creatine phosphokinase (81%), hypertension (59%), and diarrhea (47%). Grade ≥ 3 adverse events occurred in 91% of patients; pneumonitis was reported in 3 (9%) patients. Conclusions In the J-ALTA TKI-naive cohort, brigatinib demonstrated clinically meaningful efficacy consistent with the international phase 3 study. The safety profile in Japanese patients was consistent with previous studies. Brigatinib is an important first-line option for Japanese patients with ALK-positive NSCLC. Clinical registration NCT03410108 Supplementary Information The online version contains supplementary material available at 10.1007/s10147-022-02232-7.

The phase 2 J-ALTA trial (NCT03410108), which evaluated the efficacy and safety of brigatinib in Japanese patients with ALK-positive NSCLC who were refractory to alectinib or other ALK TKIs, also included a cohort of patients who had not received any previous ALK TKI treatment [12]. Results from the TKI-refractory cohorts of J-ALTA demonstrated that brigatinib has clinically meaningful efficacy in patients previously treated with alectinib [12]. We report here the results from the TKI-naive cohort of J-ALTA.

Study design
J-ALTA was a single-arm, multicenter, phase 2, open-label study of the ALK TKI brigatinib in Japanese patients with ALK-positive NSCLC. The trial started with a safety leadin stage (Part 1) followed by an expansion stage (Parts 2 and 3). Part 2 consisted of two cohorts of patients with ALK-positive NSCLC refractory to ALK TKI, one cohort previously treated with alectinib and one previously treated with any ALK TKI, while patients enrolled in Part 3 had no previous TKI therapy (Fig. 1). Results for patients with TKI-refractory ALK-positive NSCLC (Part 2) have been previously reported [12]. This manuscript reports the efficacy and safety results from Part 3 of this study.
The study was conducted in compliance with the ethical principles from the Declaration of Helsinki, the International Council for Harmonisation guideline for Good Clinical Practice, and all applicable local regulations. All informed consent and protocol documents were approved by the local institutional review board or ethics committee at each study site. All patients provided informed written consent prior to screening.

Patients and treatment
Eligible patients were ≥ 20 years of age with histologically or cytologically confirmed stage IIIB, stage IIIC (locally advanced or recurrent and not a candidate for definitive multimodality therapy), or stage IV NSCLC. Patients were required to 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 intercalated antibody-enhanced polymer (iAEP) Kit, or the Ventana ALK (D5F3) CDx Assay prior to enrollment and required to submit sufficient tumor tissue for central Patients were excluded from the Part 3 expansion cohort if they had received any prior TKIs, including ALK inhibitors and vascular endothelial growth factor receptor (VEGFR) inhibitors; received more than one systemic anticancer therapy regimen for locally advanced or metastatic disease; had a history or presence of interstitial lung disease (ILD); had current spinal cord compression; or had symptomatic CNS metastases or asymptomatic CNS metastases requiring an increasing dose of corticosteroids. Patients with asymptomatic leptomeningeal disease without cord compression were permitted. Online Resource 1 lists the complete inclusion and exclusion criteria.

Procedures
Patients received brigatinib orally at a dose of 90 mg once daily (qd) for the first seven days followed by 180 mg qd (ie, 180 mg qd with 7-day lead-in at 90 mg) and continued treatment until they experienced disease progression or intolerable toxicity, withdrew consent, or discontinued for another reason. Disease was assessed by computed tomography or magnetic resonance imaging scans of the chest, abdomen, pelvis, and brain performed at screening, every two cycles (8 weeks) from Day 1 of Cycle 3 (± seven days) through Day 1 of Cycle 15, every three cycles until the end of therapy, and at the end of treatment if more than four weeks had passed since the last scan.
All radiographic images were assessed by an independent review committee (IRC) according to RECIST version 1.1 [13]. Complete responses (CR) or partial responses (PR) were confirmed at least four weeks after the initial response. Stable disease was evaluated at least 6 weeks after initiation of brigatinib. Patients were followed for survival every 12 weeks after treatment discontinuation.
Adverse events (AEs), including laboratory abnormalities, were categorized using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. An independent data monitoring committee (IDMC) evaluated cases of ILD and pneumonitis, which were reported as serious AEs, and made recommendations as needed.

End points
The primary end point was PFS rate at 12 months as assessed by an IRC per RECIST version 1.1 [13]. Secondary end points included IRC-assessed confirmed objective response rate (ORR), PFS, duration of response (DoR), disease control rate, and time to response; intracranial PFS (iPFS by IRC); intracranial ORR (iORR by IRC); overall survival (OS); and safety.

Statistical analysis
A sample size of 32 patients was determined to allow approximately 80% power to rule out the threshold rate of 42.6% (estimated 12-month PFS rate in Kaplan-Meier [KM] plots observed in the ALTA-1L crizotinib arm) when the true 12-month PFS rate is expected to be ≥ 66.5% (estimated 12-month PFS rate in KM plots observed in the ALTA-1L brigatinib arm) with a one-sided alpha of 0.05 [10]. Twelvemonth PFS rate and CIs were based on the complementary log-log transformation. This primary analysis was performed at approximately ten months after enrollment of the last patient in the cohort. Summary tabulations with number of observations, mean, standard deviation, median, and minimum and maximum are reported for continuous variables and number and percentage per category for categorical data. KM survival curves are used to report timeto-event data. For secondary end points, statistical inference was performed at a one-sided 0.025 level of significance or a two-sided 0.05 level of significance, as appropriate, to preserve a one-sided overall type I error rate at or below 0.025 or two-sided overall type I error rate at or below 0.05. Statistical analyses were performed using SAS version 9.4.

Patients and treatment
Between January 2018 and November 2019, 32 Japanese patients with ALK TKI-naive ALK-positive NSCLC were enrolled. The data cutoff of September 29, 2020, was selected so that all enrolled patients could be followed for 12 months. Demographic and baseline characteristics are summarized in Table 1. The median age was 60.5 (range, 29-85) years, and 25% of patients had received prior chemotherapy or checkpoint inhibitor. As of data cutoff, 27 patients (84%) remained on treatment (Fig. 2), with a median duration of follow-up of 14.2 months (range, 3.2-19.3 months). The median treatment duration was 13.8 months (range, 0.4-19.3).

Primary end point: IRC-assessed progression-free survival
For the primary end point of IRC-assessed PFS rate at 12 months, 93.0% of patients with TKI-naive ALK-positive NSCLC did not have progression or death at 12 months (90% CI 79.2-97.8%) (Fig. 3a)

Secondary end points
Thirty-one patients responded to treatment, with an IRCassessed confirmed ORR of 96.9% (95% CI 83.8-99.9%), including two confirmed CRs (6%) and 29 PRs (91%)  Figure 3b shows responses over time for all 32 patients in this cohort. Because the treatment decision was made by investigator instead of IRC and there were some inconsistencies in response evaluation between IRC assessment and investigator assessment, one patient continued treatment after progressive disease by IRC, and three patients discontinued treatment before progressive disease by IRC. All three patients had been assessed with progression by investigators before discontinuation. Changes from baseline in target lesions for patients who had confirmed responses are represented in Fig. 3c. One of the 32 patients did not have an IRC-assessed target lesion at baseline and was therefore excluded from the plot. The median best regression in target lesions was − 72%. Among the 31 patients with confirmed response by IRC, median time to response was 1.8 months (range, 0.95-12.9). KM estimated median DoR was not reached (95% CI 13.9-not reached) in patients who had confirmed responses. At data cutoff, one patient had died due to disease progression. OS for this cohort at 12 months was 96.9% (95% CI 79.8-99.6%). Median OS was not reached (Fig. 3d).

ILD and pneumonitis
Pneumonitis was reported in 3 (9.4%) patients. All cases were reviewed and confirmed by the IDMC. Chest computed tomography showed patterns of faint infiltration/acute hypersensitivity pneumonitis in two patients (days 29 and 223) and cryptogenic organizing pneumonia/chronic eosinophilic pneumonia (day 386) in one patient. All events were grade 1. Following interruption of brigatinib treatment, one case resolved in 12 days, and two cases resolved in 28 days. All patients resumed brigatinib without dose reduction after resolution of pneumonitis (two patients resumed at 90 mg qd and escalated to 180 mg qd since the dose interruption periods were longer than 14 days, per protocol) and have had no recurrence.

Discussion
This study is the first prospective clinical trial in Japanese patients to evaluate brigatinib efficacy and safety in patients with ALK-positive NSCLC who had not received ALK TKI treatment. The predefined primary end point, in which the . c Best percentage change from baseline in the sum of the longest diameters of target lesions per IRC assessment for patients who had a measurable lesion at baseline and at least one postbaseline assessment (n = 31). The line at − 30% indicates the threshold for partial response according to RECIST, version 1.1. One patient had investigator-assessed baseline measurable disease and therefore satisfied entry criteria. However, the tumor was located in a nontarget region. Since the IRC review found no measurable lesion in the target region at baseline, the patient was necessarily excluded from the plot. The best overall response in this patient was CR by the IRC and PR by the investigator. SD for ≥ 6 weeks from the first dose could be evaluated as an IRC-assessed SD case. However, one of the 31 responders discontinued treatment due to disease progression (by investigator assessment) prior to being evaluated as IRCassessed SD, and therefore was not evaluable.  Fig. 3e) despite the inclusion of seven patients with brain metastases at baseline. Based on these results, it would be expected that brigatinib suppresses disease progression in the brain.
As in previous brigatinib studies, the most common AEs in this J-ALTA cohort included elevated CPK, hypertension, elevated amylase, elevated lipase, hepatic enzyme abnormalities, and gastrointestinal AEs. Elevated CPK levels were not associated with clinically meaningful muscle-associated AEs. In an ALTA-1L study subanalysis, safety profiles were similar in Asian and non-Asian patients. However, the Asian patients showed higher rates of AST and ALT elevations compared with these rates in non-Asian patients [16]. Consistent with the ALTA-1L subanalysis, there was a tendency in J-ALTA for a higher incidence of laboratory abnormalities. This trend should be explored further in larger studies, such as real-word evidence studies of Japanese patients. A higher proportion of patients in the TKI-naive cohort of J-ALTA compared with the overall ALTA-1L population had AEs that required dose interruption (94% vs 72%) or dose reduction (66% vs 44%) [11]. Grade ≥ 3 AEs were also higher in the TKI-naive cohort of J-ALTA (91%) compared with ALTA-1L (70%). AEs were manageable, and no treatment discontinuations were required. There were no earlyonset pulmonary AEs reported. Three patients had pneumonitis; all events were grade 1 and occurred after day 15 of brigatinib treatment. All cases resolved within 28 days or fewer, and patients resumed brigatinib without dose reduction after resolution of pneumonitis, with no recurrence. In ALTA-1L, early-onset ILD/pneumonitis were reported in 4 of 136 patients (3%) in the brigatinib arm and 1 of 61 patients (2%) who crossed over from crizotinib to brigatinib [17]. No new safety signals were identified.
This study has two limitations. First, J-ALTA was a singlearm trial with limited sample size; 32 patients were ultimately enrolled in this expansion cohort out of 104 total patients enrolled in J-ALTA. Second, while immunohistochemistry was the primary method of ALK rearrangement detection at the time when the patients were enrolled, ALK status was obtained in a substantial proportion of patients by FISH-based testing in this study. However, the results presented here provide support for the efficacy and safety of first-line brigatinib already established in the ALTA-1L study.
In the J-ALTA TKI-naive expansion cohort, brigatinib demonstrated clinically meaningful efficacy. The safety profile in Japanese patients was consistent with that in previous studies in other populations, and AEs were manageable. Brigatinib is an important first-line option for Japanese patients with ALK-positive NSCLC.
Acknowledgments The authors would like to thank the patients, their families, and their caregivers; the J-ALTA investigators and their team  All authors had full access to all of the data in the study, participated in the analysis and interpretation of the data, contributed to the writing and critical revision of all drafts, and agreed to submit the paper for publication.

Data availability
The data sets, including the redacted study protocol, redacted statistical analysis plan, and individual participant data supporting the results reported in this article, will be made available within 3 months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after deidentification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.

Declarations
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