Treatment Optimization for Brain Metastasis from Anaplastic Lymphoma Kinase Rearrangement Non-Small-Cell Lung Cancer.

Brain metastasis is common in non-small-cell lung cancer (NSCLC) with driver gene mutations. Anaplastic lymphoma kinase (ALK) gene rearrangement is one of the common driver mutations in NSCLC. Tyrosine kinase inhibitor (TKI) has been the research hotspot at present. However, there are relatively few studies specified on the treatment of brain metastasis from ALK gene rearrangement NSCLC. The prognosis of these patients, the role of ALK-TKI, and the proper combination model of ALK-TKI with radiotherapy are worth further exploring. This review focuses on new data on the prognosis of ALK-TKI and the proper combination model of ALK-TKI with radiotherapy. According to some retrospective trials, for ALKi-naïve ALK rearrangement NSCLC patients with brain metastasis, crizotinib together with radiotherapy seem to improve intracranial control rate, progression-free survival, and very likely improve overall survival; next-generation ALK-TKIs are now replacing crizotinib as first-line treatment. For patients with central nervous system progression during crizotinib application, combining radiotherapy could improve the local control rate while continuing crizotinib to control systemic disease. Second-/third-generation ALK inhibitors had higher intracranial ORR and DCR even after crizotinib-refractory situations, and they alone had a strong efficacy against intracranial tumors, in which situation radiotherapy might be omitted. Stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT) were both local treatment options for brain metastasis, and the preferred choice was hard to make. ALK resistance is complicated with a wide range of molecular changes, and future studies are needed to solve these problems. Anyway, further and larger prospective studied are worth exploring to offer a confirmed preferred choice of drugs and radiation. Key Messages: Next-generation ALK-TKIs are now replacing crizotinib as first-line treatment in ALKi-naïve ALK rearrangement NSCLC patients with brain metastasis, and they alone might have a strong efficacy against intracranial tumors in crizotinib-refractory situations in which occasion radiotherapy might be omitted. SRS and WBRT are both local treatment options for brain metastasis.

Wang W ，Sun X ，Hui Z 《-》

Optimal timing and clinical value of radiotherapy in advanced ALK-rearranged non-small cell lung cancer with or without baseline brain metastases: implications from pattern of failure analyses.

Ni J ，Li G ，Yang X ，Chu L ，Wang J ，Li Y ，Zou L ，Li Y ，Xie C ，Zhu Z ... -  《Radiation Oncology》

Management of Central Nervous System Metastases in Patients With Advanced Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer During Crizotinib Treatment.

Central nervous system (CNS) progression is a common manifestation of acquired resistance to crizotinib in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). However, an optimal tailored treatment approach has not been established in patients with CNS failure during crizotinib treatment. Patients with ALK-rearranged NSCLC with CNS progression during crizotinib treatment between January 2013 and December 2016 were included for analysis. Clinical data for different treatments after CNS failure during crizotinib treatment were retrospectively collected. Among the 44 patients who had CNS progression during crizotinib treatment, 19, 15, 8, and 2 patients received crizotinib treatment beyond progressive disease (CBPD), a second ALK tyrosine kinase inhibitor (TKI), chemotherapy, and best supportive care, respectively. Post progression survival offered by treatment with a second ALK TKI was significantly more favorable than that of chemotherapy (P < .001) or CBPD (P = .045). In addition, patients who received sequential treatment with a second ALK TKI had significantly longer intracranial time to progression (IC-TTP) compared with those treated with chemotherapy (P < .01) or CBPD after radiotherapy (P = .003). In the 7 patients who received brigatinib, the median IC-TTP was 21.8 months (95% confidence interval, 11.7-32.0). The additional use of CNS radiotherapy in patients treated with a second ALK TKI showed no significance in terms of IC-TTP (P = .54). Although CBPD is an option in patients with isolated CNS progression during crizotinib treatment, sequential treatment with a second ALK TKI, particularly brigatinib, might be preferable. The newly approved TKI, brigatinib, showed promise in the control of brain metastases, even without radiotherapy.

Zhao Y ，Zhang B ，Wang S ，Qiao R ，Xu J ，Zhang L ，Zhang Y ，Han B ... -  《-》

Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastasis.

We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and brain metastasis. A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling. Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001). Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease.

Johung KL ，Yeh N ，Desai NB ，Williams TM ，Lautenschlaeger T ，Arvold ND ，Ning MS ，Attia A ，Lovly CM ，Goldberg S ，Beal K ，Yu JB ，Kavanagh BD ，Chiang VL ，Camidge DR ，Contessa JN ... -  《-》

Clinical observation of crizotinib in the treatment of ALK-positive advanced non-small cell lung cancer.

ALK is a prognostic and predictive tumor marker in non-small cell lung carcinoma (NSCLC), and is more often found in lung adenocarcinomas. The clinical and pathological data of 87 patients confirmed to have NSCLC by pathology or cytology were selected from April 2014 to January 2017 at the Tumor Hospital of Hebei Province. Of the 87 ALK-positive-patients, 47 patients were treated with oral administration of crizotinib. The objective response rate (ORR) was 61.7%, the disease control rate (DCR) was 93.6%, and the mPFS was 19 months. In an analysis of the number of metastatic sites, the patients who had more than three metastatic sites, the ORR, DCR, and mPFS were 63.9%, 94.5%, and 19 months, compared with the 45.5%, 91%, and 11 months in the patients with less sites (P = 0.040). For patients of 60 years or older, ORR and DCR were 40% and 100%, the other group was 71.9% and 90.6%, respectively(P = 0.036). The timing of treatment was analyzed. At the first application of crizotinib, ORR and DCR were 78.2% and 100% corresponding 45.8% and 87.5% at the second and final application of crizotinib group (P = 0.022). Baseline brain metastases were present in 25.5% (12/47) of patients in this study. 9 of the patients who developed disease progression during crizotinib treatment had new brain metastases or increased preexisting cranial foci. Most of them took the treatment strategy of continuing crizotinib or replacing the second/third generation ALK-TKI treatment combined with local radiotherapy for brain metastases. The efficacy of crizotinib in patients with advanced NSCLC is related to the number of metastatic organs, age and timing of treatment. The use of crizotinib is prone to intracranial progression, and progression of simple brain metastases is not an indication that crizotinib is discontinued. Patients will continue to benefit from combination of local radiotherapy.

Deng H ，Li B ，Li L ，Peng J ，Lv T ，Liu Y ，Ding C ... -  《-》