Alunbrig (brigatinib)

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.

Victim drugs brigatinib and lorlatinib were evaluated with the new approach in combination with the perpetrator drugs itraconazole and rifampicin. The model was able to adequately describe the inhibition of CYP3A4 metabolism and the subsequent magnitude of change in exposure. However, it was unable to accurately predict the magnitude of change in exposure of victim drugs in combination with an inducer.

P2, N=103, Completed, Ariad Pharmaceuticals | Active, not recruiting --> Completed

P2, N=45, Not yet recruiting, Groupe Francais De Pneumo-Cancerologie

Compared with chemotherapy, alectinib, lorlatinib, brigatinib and ceritinib, crizotinib significantly increased the risk of TE and VTE.

P3; Active, not recruiting --> Completed

P2, N=90, Recruiting, Hunan Province Tumor Hospital | Phase classification: P --> P2

Eight studies, involving 1,477 Asian patients and seven treatments (crizotinib, alectinib, brigatinib, ensartinib, envonalkib, iruplinalkib, and lorlatinib), were included in the NMA. Next-generation ALK inhibitors had better efficacy than crizotinib in the treatment of Asian patients with ALK inhibitor-naïve advanced ALK-positive NSCLC. Iruplinalkib may have more favorable PFS benefit than other ALK inhibitors for Asians.

Lorlatinib was estimated to have superior efficacy over first- and second-generation ALK-TKIs, but a higher rate of Grade ≥3 AEs compared to alectinib. These data support the use of lorlatinib as a first-line treatment for ALK+ advanced/metastatic NSCLC.

P=N/A, N=1, Completed, Pfizer | Recruiting --> Completed | N=20605 --> 1 | Trial completion date: Feb 2025 --> Jan 2024 | Trial primary completion date: Feb 2025 --> Jan 2024

In this large real-world study, TTD2 and the total time on sequential ALK TKIs was approximately 2.5 years. The high attrition rate from 1L to 2L and the longest clinical benefit observed with 1L therapy support using the drug with the longest 1L effectiveness up front in patients with ALK-positive advanced NSCLC.

Second- and third-generation ALK inhibitors (alectinib, brigatinib, and lorlatinib) offer to NSCLC patients a clinically meaningful prolongment of survival with a very good quality of life profile...Very recently, alectinib has been demonstrated to improve efficacy outcomes compared with chemotherapy also in resected stage IB-IIIA ALK-rearranged NSCLC, extending the clinical benefit offered by ALK inhibitors also to the adjuvant setting. Future development of ALK inhibitors in NSCLC treatment includes the search for optimal management of acquired resistance to first-line treatments and the extension of use of ALK inhibitors also to neoadjuvant and preferably to perioperative setting.

P3; Trial primary completion date: Aug 2024 --> Feb 2024

P=N/A, N=80, Recruiting, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

P=N/A, N=108, Recruiting, Fondazione Policlinico Universitario Agostino Gemelli IRCCS | Trial primary completion date: Mar 2024 --> Mar 2026

The patient remained disease-free during a 13-month follow-up period. This case report provides compelling evidence of pCR following brigatinib therapy in ALK-positive NSCLC, suggesting that surgery after neoadjuvant therapy with brigatinib may offer a safe and effective approach for patients with ALK-positive NSCLC.

P2, N=168, Not yet recruiting, M.D. Anderson Cancer Center

Yet, to our knowledge, we present herein the first case of ALK + NSCLC rapidly progressing on 1 st line Brigatinib treatment due to de novo MET- amplification. The recognition of this mechanism of ALK-TKI resistance by FISH, especially in NGS-negative cases, should be considered before initiating 1 st line treatment. This is of clinical importance, as effective combined therapy with ALK-TKI and MET-inhibitor is feasible.

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.

Detection rate by ctDNA profiling is higher compared with RNA-based approaches and it is of prognostic significance.

High ctDNA VAF, EML4-ALK v3, and TP53mt were associated with early discontinuation of first-line ALK TKIs.

Brigatinib was effective in TKI-naive patients with ROS1-rearranged NSCLC. The safety profile of brigatinib was consistent with that reported from previous studies.

P=N/A, N=500, Recruiting, Takeda | Trial completion date: May 2026 --> Nov 2027 | Trial primary completion date: May 2026 --> Nov 2027

For one patient who maintained original baseline ALK rearrangement positive without acquired mutation after progression of ceritinib resistance, lung cancer-like organ culture with sequential brigatinib and lorlatinib led to a PFS of 3.2 and 1.9 months, respectively, which aligned with the corresponding drug susceptibility testing results for this patient. NGS testing of patients' blood or tissue samples after disease progression may provide insight into the etiology of alectinib resistance. Patient-sourced drug sensitivity testing of lung cancer-like organs selects drug-sensitive medications based on NGS results and provides a reference for subsequent drug therapy for patients after drug resistance, particularly those who remain ALK rearrangement-positive at baseline.

Our approach demonstrates preclinical, in silico, and clinical evidence of a novel crizotinib resistance mutation in ALK as well as sensitivity toward brigatinib and potentially lorlatinib. In future cases, this procedure represents an important contribution to functional diagnostics in the context of molecular tumor boards.

Taken together, we speculate that the low CNS penetration rate of brigatinib confers CNS progression. Further studies are warranted to reveal the resistance mechanism and propose a treatment strategy for CNS progression in ALK-positive patients.

Brigatinib 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.).

P3; Trial completion date: May 2024 --> Sep 2024 | Trial primary completion date: Apr 2024 --> Aug 2024

However, the emergence of intrinsic and acquired resistance inevitably occurs with ALK TKI use. This review describes the molecular mechanisms of ALK TKI resistance and discusses management strategies to overcome therapeutic resistance.

P2, N=6000, Recruiting, Hunan Province Tumor Hospital | Phase classification: P --> P2 | N=100 --> 6000 | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2026

This study sought to assess the cost-effectiveness of 6 tyrosine kinase inhibitors (TKIs)-crizotinib, alectinib, ceritinib, brigatinib, ensartinib, and lorlatinib-as first-line treatments for ALK-positive NSCLC from the perspective of the Chinese health care system. Under a willingness-to-pay threshold of $38 223/QALY, ceritinib and brigatinib were cost-effective compared with ensartinib, while lorlatinib and alectinib were not cost-effective when compared with ensartinib. Overall, brigatinib emerged as the most cost-effective treatment among all the options considered.

To our knowledge, this is the first report to evaluate the relationship between ALK inhibitors and seizures using post-marketing surveillance data. These results suggest that ceritinib, alectinib, brigatinib, and lorlatinib, which are highly brain-migrating drugs, are associated with seizures.