Alunbrig (brigatinib)

In this retrospective study, we compare the efficacy of crizotinib, brigatinib, and alectinib in NSCLC patients with different clinical courses of the disease. Second-generation ALK inhibitors are more effective than crizotinib in ALK-rearranged patients. Liver metastases, but not brain metastases, are the main clinical factors shortening PFS and OS in NSCLC patients treated with ALK inhibitors.

While our model slightly favors brigatinib at a $150,000/QALY willingness-to-pay threshold, substantial uncertainty precludes definitive cost-effectiveness conclusions among the three first-line therapies.

P2, N=33, Active, not recruiting, Fundación GECP | Trial completion date: Apr 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Nov 2025

The most common first-line regimen was alectinib (n = 97, 49.0%) followed by crizotinib (n = 84, 42.4%); only four and one patient received lorlatinib and brigatinib first line, respectively. Despite approval of all ALK TKIs for first-line use since 2021, alectinib is largely the favored agent in BC. Further real-world investigations can refine treatment strategies and shape policies around ALK TKIs for patients with ALK+ NSCLC.

We retrospectively analyzed 86 plasma samples from 33 patients enrolled in the BRIGHTSTAR clinical trial assessing local consolidative therapy (LCT) and brigatinib in patients with stage IV or recurrent NSCLC and confirmed ALK rearrangement (NCT03707938) using a targeted next-generation sequencing assay that analyzes ctDNA to detect gene rearrangements and mutations in 80 genes and ctRNA to detect gene arrangements in 36 genes...Plasma cell-free DNA concentrations for patients with detectable ALK rearrangements at baseline were significantly higher than for those without detectable gene fusions (12.3 ng/mL versus 20.2 ng/mL, p = 0.0046). The inclusion of ctRNA in liquid biopsies increased detection of ALK rearrangements and detection at baseline was associated with significantly worse progression-free survival highlighting the added benefit of ctRNA.

This is the first report demonstrating the efficacy of brigatinib after alectinib failure in a patient with duodenal carcinoma harboring ALK fusion. Furthermore, this case suggests that ctDNA sequencing can detect specific acquired mutations and help expand optimal treatment options for patients.

P=N/A, N=154, Active, not recruiting, Takeda | Recruiting --> Active, not recruiting | Trial completion date: Dec 2029 --> Dec 2028 | Trial primary completion date: Mar 2025 --> Mar 2028

P=N/A, N=18, Completed, University of Colorado, Denver | Active, not recruiting --> Completed

In this study, we evaluated the direct activation of inflammasomes by brigatinib and other ALK TKI (crizotinib, alectinib, ceritinib) in differentiated THP-1 cells. These findings suggest that brigatinib induces the release of DAMPs from hepatocytes, which subsequently activate inflammasomes. This mechanism may be essential for brigatinib-induced immune system activation and the development of immune-related adverse events.

Brigatinib may represent an interesting therapeutic option for patients who have progressed after standard treatments.

The median ToT in first line (1L) for EGFR+ patients was 11 months for osimertinib (CI: 10.1-NA) and 9 months (CI: 8.2-11.2) for afatinib, dacomitinib, erlotinib and gefitinib. For ALK+ patients, median ToT in 1L was 20 months (CI: 14.7-23.7for alectinib, 11 months (CI: 4.7-NA) for brigatinib, and 7 months (CI: 2.9-21.6) for crizotinib...ToT for targeted therapies was shorter than progression-free survival in clinical trials. However, patients eligible for targeted therapy still had a survival improvement during the study period.

In addition, we demonstrated that brigatinib reduced the protein expression of amphiregulin, epiregulin, TGFA, PI3K, AKT and phosphorylated AKT (p-AKT). This study confirms the inhibition of HaCaT cells growth and progression by brigatinib and highlights the potential value of the PI3K/AKT pathway as a therapeutic target for brigatinib-induced dermal toxicities.

Importantly, 5d also demonstrated superior anti-tumor activity in vivo and was superior to the positive control Brigatinib. We concluded that cyclopropylsulfonamide 5d derivatives induce cell cycle arrest, apoptosis, and DNA damage by regulating tumor-related genes, thereby inhibiting the proliferation of C797S mutated lung cancer cells.

Brigatinib was demonstrated to be a safe and effective treatment option for ALK-positive metastatic non-small cell lung cancer in routine clinical practice in Argentina.

Early recognition and prompt intervention are crucial to mitigate renal complications and optimize patient outcomes. Brigatinib may serve as a suitable alternative for patients intolerant to alectinib.

A multifunctional covalent organic framework (COF) nanoplatform for GSH consumption, AXL inhibition, and co-delivery of the AXL inhibitor (Brigatinib) and Osi is creatively constructed to confirm whether Osi sensitivity improves by simultaneously targeting GSH-AXL resistance mechanisms. The engineered multifunctional antiresistance-specific nanovesicles effectively inhibited the GSH-AXL axis, induced apoptosis in Osi-resistant cells both in vitro and in vivo, and delayed the progression of Osi-resistant tumors. Overall, these findings provide a novel strategy to overcome the Osi-acquired resistance caused by high AXL levels in NSCLC.

Alectinib and brigatinib demonstrated comparable efficacy in ALK-positive advanced NSCLC. Undergoing crizotinib followed by a second-generation TKI was not significantly different from initiating a second-generation TKI without prior crizotinib in terms of outcomes.

Brigatinib demonstrated clinically meaningful systemic and intracranial efficacy in patients with ALK TKI-naive ALK+ NSCLC. Safety results were consistent with the known profile for brigatinib.

In addition to reporting the identification of a novel ALK fusion, XPO1-ALK (intergenic), and the sensitivity and safety of brigatinib treatment for lung cancer, this study increased the list of known ALK fusion partners in ALK-positive NSCLC. This case report has a significant clinical reference.

P2, N=25, Not yet recruiting, University Health Network, Toronto

Following rapid clinical recovery and radiographic resolution of the opacities, the patient was started with brigatinib, with no recurrence of the clinical symptoms or radiographic findings of pneumonitis. While further descriptions are needed, our experience suggests that switching to a second ALK-TKI may be a safe therapeutic option in some patients who develop drug-induced pneumonitis on ALK TKIs.

P=N/A, N=257, Recruiting, Takeda | N=616 --> 257

P2, N=168, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Dec 2025 --> Dec 2024

In this context, we endeavored to develop ALK degraders utilizing FDA-approved ALK inhibitors-crizotinib, ceritinib, brigatinib, and alectinib-as ALK binders, along with 4-methoxyphenylfumarate as a covalent handle to bind to RNF126 E3 ligase. However, the enhanced anti-proliferative activity of dALK-3 was found to be independent of RNF126, a presumed potential E3 ligase, suggesting the need for investigation of other components within the ubiquitin-proteasome system. Our findings further support the potential application of the fumarate moiety as a binder for E3 ligases in targeted protein degradation.

The study suggests that hybrid scaffolds combining key pharmacophoric features from Osimertinib and Brigatinib along with Lys745 targeting warheads, could enhance selectivity and potency. Fourth-generation TKIs targeting Lys745 offer a novel therapeutic avenue, potentially overcoming mutation-induced resistance and improving NSCLC treatment outcomes. This approach represents a critical advancement toward durable clinical responses in patients with drug-resistant cancer.

While first-line treatment options include alectinib, brigatinib, and lorlatinib per National Comprehensive Cancer Network (NCCN) guidelines, therapeutic challenges arise in cases of disease progression. Direct comparison of second and third-generation ALK inhibitors is essential to elucidate their comparative efficacy and adverse event profiles, which could refine current management guidelines. Furthermore, if lorlatinib proves superior in terms of progression-free survival, it may offer the potential to delay or obviate the need for radiation therapy, thus mitigating the risk of neurotoxic adverse events associated with these modalities.

P1, N=5, Active, not recruiting, City of Hope Medical Center | Trial completion date: Nov 2024 --> Jun 2025 | Trial primary completion date: Nov 2024 --> Jun 2025

P=N/A, N=200, Recruiting, Takeda | Trial completion date: Dec 2026 --> Dec 2029

P=N/A, N=200, Recruiting, Takeda | Trial primary completion date: Dec 2024 --> Mar 2025

Between January 2020 and February 2024, we identified four patients with either EML4-ALK fusions (2/4) or EGFR mutations (2/4) who underwent treatment with brigatinib or osimertinib before surgery. This case series highlights the potential of targeted therapies for resectable NSCLC in the neoadjuvant setting. Further research is required to confirm their benefits, assess their safety and efficacy, and determine optimal timing and sequencing.

P2, N=100, Active, not recruiting, Scott R. Plotkin, MD, PhD | Recruiting --> Active, not recruiting

In further analysis, lorlatinib revealed superior intracranial efficacy and prolonged time to intracranial progression compared with crizotinib. Herein, we report a case of ALK-positive NSCLC with leptomeningeal metastasis that was successfully treated with lorlatinib after progression to brigatinib and alectinib. This case demonstrates the potential of lorlatinib in managing leptomeningeal metastasis in ALK-positive NSCLC. The case suggests a paradigm shift in therapeutic approaches for CNS metastasis, including brain and leptomeningeal metastases.

A 43-year-old, female diagnosed with T4N3M1c NSCLC harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variant 1 (EML4-ALK v.1) and TP53 co-mutation, displayed only mixed response after three months and highly symptomatic progression after 6 months of first-line brigatinib treatment. The latter may represent a mechanism of intrinsic ALK-TKI resistance and its recognition by FISH, in NGS-negative cases, may be considered before initiating first-line treatment. This recognition is clinically important as combined therapy with ALK-TKI and MET-inhibitor should be the preferred first-line treatment.

P=N/A, N=18, Active, not recruiting, Academic Thoracic Oncology Medical Investigators Consortium | Trial completion date: Aug 2024 --> Aug 2025

P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

P2, N=110, Active, not recruiting, Intergroupe Francophone de Cancerologie Thoracique | Recruiting --> Active, not recruiting

Aim: We conducted network meta-analysis to assess cardiovascular toxicity of anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs).Materials & Eleven articles involving 2855 patients and six interventions including crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and chemotherapy were analyzed. No significant difference was observed in overall cardiovascular risk among ALK-TKIs. For vascular toxicity, crizotinib and ceritinib had a higher risk of thrombotic events than brigatinib. Crizotinib and lorlatinib were more likely to cause blood pressure abnormalities. Clinicians should carefully monitoring cardiovascular events when ALK-TKIs used in NSCLCs patients with baseline cardiovascular diseases.

The results of the in vitro stability experiment showed that the selected mixed micelle (F6) was stable at both room temperature and 4 °C, with only minor changes in size and PDI. Our results indicate great potential for the developed Soluplus-TPGS mixed micelles as a delivery system for BGT.

Based on the genomic analysis, we treated the patient with brigatinib, an ALK inhibitor. We describe here a patient with LCNEC who responded significantly to brigatinib without serious adverse events.

For patients with ALK+ NSCLC, treatments including next-generation ALK-TKIs were independently associated with longer survival outcomes.

P2, N=0, Withdrawn, ETOP IBCSG Partners Foundation | N=44 --> 0 | Trial completion date: Apr 2029 --> Sep 2024 | Recruiting --> Withdrawn | Trial primary completion date: Apr 2027 --> Sep 2024

Our NMA analysis adds to existing findings and supplements data gaps from other published NMAs. Findings from eight published NMAs consistently supported lorlatinib as a clinically effective 1L treatment for ALK + advanced NSCLC patients compared to other TKIs.