The Dramatic and Long-lasting Effect of Alectinib Against Crizotinib-resistant Leptomeningeal Carcinomatosis in a Patient with ALK-positive Lung Cancer
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Abstract:
背景．ALK融合遺伝子陽性非小細胞癌に対しALK阻害薬は有効な薬剤であるが，多くは耐性化する．また癌性髄膜症は治療抵抗性であり致死的転帰を辿る重篤な病態である．今回我々は，クリゾチニブ耐性髄膜症にアレクチニブが劇的に奏効し，その後も持続奏効した1例を経験したため報告する．症例．45歳女性．ALK融合遺伝子陽性肺腺癌（cT3N2M1b，OSS，stage IV）と診断し，カルボプラチン，ペメトレキセド，ベバシズマブ併用療法後のペメトレキセド，ベバシズマブ継続維持療法で部分奏効を得た．その後再発を認めクリゾチニブにより部分奏効を得たが，癌性髄膜症および肝転移の増大で病勢進行（progressive disease：PD）を認めた．アレクチニブにより両病変とも速やかな奏効を得たが，後に肝転移および原発巣は徐々に増悪し，Trousseau症候群による多発脳梗塞で死亡した．しかし，治療経過中，癌性髄膜症は死亡までの8ヶ月間再燃を認めなかった．結論．ALK陽性肺癌の癌性髄膜症においてアレクチニブは選択すべき薬剤であり，さらに他病変がPDでもbeyond PDとしてアレクチニブ継続投与が癌性髄膜症再燃の抑制に有益となる可能性がある．Keywords:
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The treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the discovery of genetic driver mutations and associated targeted therapies. Anaplastic lymphoma kinase (ALK) mutations are present in about 5% of NSCLC cases, and treatment with the first-generation ALK inhibitor crizotinib has shown better progression-free survival (PFS) and response rate compared to traditional chemotherapy. However, eventually, ALK-mutated NSCLC develops resistance to treatment with crizotinib, and second-generation ALK inhibitors such as ceritinib, brigatinib, and alectinib have been shown to be effective in the second-line setting after progression on crizotinib. In the second-line setting, alectinib showed an objective response rate (ORR) of 45% and PFS of 8 to 12 months. Brigatinib showed an ORR of 45% to 54% with a PFS of 9.2 to 12.9 months in the second-line setting. A more recent trial compared alectinib to crizotinib in the treatment-naive setting and showed a significant PFS benefit to treatment with alectinib. The second-generation ALK inihibitors brigatinib and alectinib offer new options for the treatment of ALK mutation-positive NSCLC.
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Alectinib and crizotinib have been approved as first-line therapies for advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) gene fusion. However, the therapeutic efficacy and side effects are still largely unknown of patients who switched to next-generation ALK tyrosine kinase inhibitors (ALK-TKIs), such as alectinib, after experiencing no disease progression with initial crizotinib treatment.This prospective real-world study enrolled patients who were treated with alectinib after experiencing no disease progression with initial crizotinib treatment. The patients' baseline characteristics, objective response rate (ORR) of crizotinib and alectinib, size change of target tumor lesions, treatment regimen and adverse events (AEs) were collected and analyzed.The study included 53 patients, the majority of whom (96.2%) had non-squamous NSCLC. The median age was 51 (range, 31-80) years old. The ORR of first-line crizotinib was 54.7%. The ORR of sequential alectinib was 73.6%, and 90.5% of patients showed further tumor shrinkage after the alectinib treatment. The median progression-free survival was not reached, and 90.5% of patients were still enrolled in the study at the last follow-up. Among them, 34.0% of patients switched to alectinib treatment due to the toxicity. Crizotinib was associated with a higher frequency of AEs of grades 3 and 4 than alectinib (15.1% vs. 0%). Neither group had any AEs resulting in death.Switching to alectinib might be an option for patients who do not experience disease progression with initial crizotinib therapy, and may promote better treatment compliance.
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Alectinib is a highly selective second-generation ALK inhibitor that is active against most crizotinib ALK resistance mutations, with a good penetration in CNS and a good safety profile. Thanks to the positive results of Phase II trials, alectinib was approved in Japan and by the US FDA for ALK-positive non-small-cell lung cancer (NSCLC) patients pretreated with crizotinib. Recently, the Phase III J-ALEX study demonstrated superiority of alectinib over crizotinib in crizotinib naive ALK-positive NSCLC, with an impressive improvement of progression-free survival. From the results and those expected of Phase III ALEX study, alectinib might become the frontline treatment of ALK-positive NSCLC. This article summarizes the therapeutic options in ALK-positive advanced NSCLC, and the chemical, pharmacodynamics, pharmacokinetics, metabolism and clinical efficacy of alectinib.
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Crizotinib was the first clinically available anaplastic lymphoma kinase (ALK) inhibitor, showing remarkable activity against ALK-rearranged non-small-cell lung cancer (NSCLC). Despite initial responses, acquired resistance to crizotinib inevitably develops, with the brain being a common site of relapse. Alectinib is a highly selective, next-generation ALK inhibitor with potent inhibitory activity also against ALK mutations conferring resistance to crizotinib, including the gatekeeper L1196M substitution. In a Phase I/II study from Japan, alectinib was found to be highly active and safe in crizotinib-naïve, ALK-rearranged NSCLC patients. Alectinib also demonstrated promising antitumor activity in crizotinib-resistant patients, including those with CNS metastases. Based on these data, the drug received Breakthrough Therapy Designation by the US FDA and has been recently approved in Japan for the treatment of ALK-positive, advanced NSCLC patients. However, patients may eventually develop resistance to alectinib, highlighting the need for novel therapeutic strategies to further improve the management of ALK-rearranged NSCLC.
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