Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors

Abstract

PURPOSE Anaplastic lymphoma kinase ( ALK) rearrangement is a well-known driver oncogene in non–small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare ALK-rearranged tumors. PATIENTS AND METHODS Between April 2012 and April 2019, clinical outcomes and characteristics of patients with ALK-rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression. RESULTS We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-ALK and ITSN2-ALK, were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib. CONCLUSION This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK-rearranged nonlung solid tumors.

Crizotinib in Sarcomatous Malignancies Harboring ALK Fusion With a Definitive Partner(s): Response and Efficacy

“…Ten cases had no response or progressed on crizotinib treatment ( 11 , 13 , 15 , 23 , 24 , 28 , 30 , 32 ). Nine of them received next-generation ALK inhibitors (ceritinib, brigatinib, alectinib, or lorlatinib) with 77.8% (7/9) achieving ORR ( 11 , 13 , 23 , 24 , 28 , 30 , 32 ), and the remaining two cases resistant to ceritinib or alectinib died within one year after their progression on crizotinib ( 23 , 30 ). One case with radical surgery followed by alectinib adjuvant treatment was still alive without evidence of disease ( 15 ).…”

“…One case with radical surgery followed by alectinib adjuvant treatment was still alive without evidence of disease ( 15 ). Two cases showed no response to alectinib but achieved tumor shrinkage following subsequent ceritinib treatment ( 24 , 30 ).…”

“…Second generation of ALK TKIs, including ceritinib, brigatinib, alectinib, were usually effective in later lines ( 13 , 32 ), similar to their current indications in NSCLC. Interestingly, 2 cases that progressed on alectinib following crizotinib resistance showed response to subsequent ceritinib ( 24 , 30 ). Different ALK inhibitors bind slightly differently within the ATP-binding pocket of the ALK kinase domain, and thus coax different resistance mutation patterns.…”

CD73 Severed as a Potential Prognostic Marker and Promote Lung Cancer Cells Migration via Enhancing EMT Progression

“…Currently, lung cancer is the first leading cause of cancer-related death worldwide. Although there are several target drug have been used in clinical therapy of lung cancer or is in clinical trials, such as EGFR-target TKI (Tyrosine Kinase Inhibitor), ALK-target TKI and VEGF-target Bevacizumab, etc ( Fang et al, 2021 ; Takeyasu et al, 2021 ; Yu et al, 2021 ) However, because of the strong heterogeneity, drug resistance and prone to metastasis of lung cancer, the mortality of lung cancer remain high. There is still an urgent need to identify novel therapeutic target and prognostic markers for lung cancer patients.…”

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“…Currently, lung cancer is the first leading cause of cancer-related death worldwide. Although there are several target drug have been used in clinical therapy of lung cancer or is in clinical trials, such as EGFR-target TKI (Tyrosine Kinase Inhibitor), ALKtarget TKI and VEGF-target Bevacizumab, etc (Fang et al, 2021;Takeyasu et al, 2021;Yu et al, 2021) However, because of the strong heterogeneity, drug resistance and prone to metastasis of lung cancer, the mortality of lung cancer remain high. There is still an urgent need to identify novel therapeutic target and prognostic markers for lung cancer patients.…”