Short progression‐free survival of ALK inhibitors sensitive to secondary mutations in ALK‐positive NSCLC patients

Haratake, Naoki; Seto, Takashi; Takamori, Shinkichi; Toyozawa, Ryo; Nosaki, Kaname; Miura, Naruhisa; Ohba, Taro; Toyokawa, Gouji; Taguchi, Kenichi; Yamaguchi, Masafumi; Shimokawa, Mototsugu; Takenoyama, Mitsuhiro

doi:10.1111/1759-7714.13143

Cited by 7 publications

(5 citation statements)

References 29 publications

(58 reference statements)

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“…Consistent with the results of previous studies, [22][23][24][25][26] secondary ALK alterations were adversely associated with PFS, both in the univariate and multivariate analyses, and could identify patients at high risk for early progression in the Kaplan-Meier analysis. As in previous studies, 16,22 secondary ALK mutations were more common in V3; however, they were not statistically significant in this study because of the small number of patients.…”

Section: Discussionsupporting

confidence: 89%

Association of anaplastic lymphoma kinase variants and alterations with ensartinib response duration in non‐small cell lung cancer

et al. 2021

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Background: Here, we aimed to assess the association of ALK variants and alterations with ensartinib response duration in NSCLC, and explore the potential value of computed tomography (CT) radiomic features in predicting progression-free survival (PFS). Methods: We enrolled 88 patients with identified ALK variant NSCLC in a multicenter phase 2 trial, and assessed the impact of ALK variants and secondary ALK alterations on the clinical outcome (response duration) of patients receiving ensartinib. We also established a multifactorial model of clinicopathological and quantitative CT radiomic features to predict PFS and risk stratification. Kaplan-Meier analysis was conducted to identify risk factors for tumor progression. Results: Univariate analysis indicated a statistical difference (p = 0.035) in PFS among ALK variants in three classifications (V1, V3, and other variants). Secondary ALK alterations were adversely associated with PFS both in univariate (p = 0.008) and multivariate (p = 0.04) analyses and could identify patients at high risk for early progression in the Kaplan-Meier analysis (p = 0.002). Additionally, response duration to crizotinib <1 year and liver metastasis were adversely associated with PFS. The combined model, composed of clinicopathological signature and CT radiomic signature, showed good prediction ability with the area under the receiver operating characteristic curve being 0.85, and 0.89 in the training and validation dataset respectively. Conclusions: Our study showed that secondary ALK alterations were adversely associated with ensartinib efficacy, and that ALK variants might not correlate with PFS.

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Section: Discussionsupporting

confidence: 89%

Association of anaplastic lymphoma kinase variants and alterations with ensartinib response duration in non‐small cell lung cancer

et al. 2021

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“…However, performing a rebiopsy at relapse can provide important prognostic information and help physicians to determine the next course of treatment. In a study by Haratake et al, 2019, 33 patients who failed an ALK inhibitor and were given a subsequent ALK inhibitor based on rebiopsy results had a higher objective response rate.…”

Section: Discussionmentioning

confidence: 98%

Real-World Treatment and Outcomes of ALK-Positive Metastatic Non–Small Cell Lung Cancer in a Southeast Asian Country

Poh

How

et al. 2023

CMAR

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Purpose Anaplastic lymphoma kinase (ALK) inhibitors are associated with good overall survival (OS) for ALK-positive metastatic non–small cell lung cancer (NSCLC). However, these treatments can be unavailable or limited by financial constraints in developing countries. Using data from a nationwide lung cancer registry, the present study aimed to identify treatment patterns and clinical outcomes of ALK-positive NSCLC in Malaysia. Methods This retrospective study examined data of patients with ALK-positive NSCLC from 18 major hospitals (public, private, or university teaching hospitals) throughout Malaysia between January 1, 2015 and December 31, 2020 from the National Cardiovascular and Thoracic Surgical Database (NCTSD). Data on baseline characteristics, treatments, radiological findings, and pathological findings were collected. Overall survival (OS) and time on treatment (TOT) were calculated using the Kaplan–Meier method. Results There were 1581 NSCLC patients in the NCTSD. Based on ALK gene-rearrangement test results, only 65 patients (4.1%) had ALK-positive advanced NSCLC. Of these 65 patients, 59 received standard-of-care treatment and were included in the analysis. Crizotinib was the most commonly prescribed ALK inhibitor, followed by alectinib and ceritinib. Patients on ALK inhibitors had better median OS (62 months for first-generation inhibitors, not reached at time of analysis for second-generation inhibitors) compared to chemotherapy (27 months), but this was not statistically significant ( P =0.835) due to sample-size limitations. Patients who received ALK inhibitors as first-line therapy had significantly longer TOT (median of 11 months for first-generation inhibitors, not reached for second-generation inhibitors at the time of analysis) compared to chemotherapy (median of 2 months; P <0.01). Conclusion Patients on ALK inhibitors had longer median OS and significantly longer TOT compared to chemotherapy, suggesting long-term benefit.

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“…However, as observed in melanoma patients treated with BRAF and MEK inhibitors, the treatment of ALK-TKI-mutated NSCLC with crizotinib eventually leads to the acquisition of resistance through the development of secondary mutations in, for example, ALK-TKI or alternative pathways. In addition, despite second-generation ALK-TKI-targeting inhibitors, such as alectinib, ceritinib and lorlatinib, having been developed to circumvent these secondary mutations in ALK-TKI, it is expected that they or similar mutations will appear upon the treatment of neuroblastoma with these same inhibitors [ 13 , 29 ]. To overcome these problems and fill the current lack of therapeutic options, new alternatives need to be developed that can be used as single drugs or in combination with other therapies, namely immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Small-Molecule Kinase Modulators for the Treatment of Neuroblastoma

Serra-Roma

Shakhova

2020

Oncol Ther

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Neuroblastoma represents 8-10% of all childhood cancer cases and is responsible for 15% of all cancer-related deaths in infants. Even though patients with low-and intermediate-risk disease have a good prognosis, the 5-year survival rate of the vast majority of patients with high-risk neuroblastoma is 50%. Despite extensive research efforts to find a cure for neuroblastoma, current treatment options are still limited. The aim of our study was to identify novel therapeutic compounds using highthroughput drug screening of a small molecule kinase inhibitor library containing 960 compounds. This screening resulted in the identification of two compounds, ST013381 and ST022328, that showed pronounced cytotoxic effects in six human neuroblastoma cell lines in vitro while having reduced effects in the BJ-5ta control cell line. These effects were observed in both MYCN-amplified and -nonamplified cells, indicating that these compounds can affect a wide range of neuroblastomas. Our experiments also revealed that several signaling pathways underlie the selective elimination of neuroblastoma cells by the ST013381 and ST022328 compounds. In summary, we have identified two novel compounds with a strong cytotoxic effect in vitro as promising agents for the treatment of neuroblastoma. Key Summary PointsWhy carry out this study?Neuroblastoma, although representing 8-10% of all childhood cancer cases, accounts for 15% of all cancer-related deaths in infants.No treatment options other than chemotherapy exist for high-risk neuroblastoma, even though the 5-year survival rate is 50%.We searched for novel therapeutic compounds using high-throughput drug screening of a small-molecule kinase inhibitor library containing 960 compounds.What was learned from the study?We identified a group of compounds with cytotoxic effects in six neuroblastoma cell lines.Data from validation studies on two of the identified compounds suggest that the cytotoxic effects are attained through modulation of the PKA, PKC, ATM/ATR, AMPK, Akt and MAPK/CDK signalling pathways.

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Short progression‐free survival of ALK inhibitors sensitive to secondary mutations in ALK‐positive NSCLC patients

Cited by 7 publications

References 29 publications

Association of anaplastic lymphoma kinase variants and alterations with ensartinib response duration in non‐small cell lung cancer

Association of anaplastic lymphoma kinase variants and alterations with ensartinib response duration in non‐small cell lung cancer

Real-World Treatment and Outcomes of ALK-Positive Metastatic Non–Small Cell Lung Cancer in a Southeast Asian Country

Identification of Novel Small-Molecule Kinase Modulators for the Treatment of Neuroblastoma

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