Comparative Efficacy of Systemic Agents for Brain Metastases From Non-Small-Cell Lung Cancer With an EGFR Mutation/ALK Rearrangement: A Systematic Review and Network Meta-Analysis

In patients with NSCLC BMs and EGFR/ALK mutations, targeted TKIs improve intracranial and overall PFS compared to conventional modalities such as chemotherapy, with greater efficacy seen using newer generations of TKIs. This data is important for treatment selection and patient counseling, and highlights areas for future RCT research. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.739765

Authors: Taslimi, S., Brar, K., Ellenbogen, Y., Deng, J., Hou, W., Moraes, F. Y., Glantz, M., Zacharia, B. E., Tan, A., Ahluwalia, M. S., Khasraw, M., Zadeh, G., & Mansouri, A.

Comparative Efficacy of Systemic Agents for Brain Metastases From Non-Small-Cell Lung Cancer With an EGFR Mutation/ALK Rearrangement: A Systematic Review and Network Meta-Analysis

Brain metastases (BM) from non-small-cell lung cancer (NSCLC) are frequent and carry significant morbidity, and current management options include varying local and systemic therapies. Here, we performed a systematic review and network meta-analysis to determine the ideal treatment regimen for NSCLC BMs with targetable EGFR-mutations/ALK-rearrangements.</sec><sec>MethodsWe searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published from inception until June 2020. Comparative RCTs including ≥10 patients were selected. We used a frequentist random-effects model for network meta-analysis (NMA) and assessed the certainty of evidence using the GRADE approach. Our primary outcome of interest was intracranial progression-free survival (iPFS).</sec><sec>ResultsWe included 24 studies representing 19 trials with 1623 total patients. Targeted tyrosine kinase inhibitors (TKIs) significantly improved iPFS, wit..... READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.739765

Authors: Taslimi Shervin, Brar Karanbir, Ellenbogen Yosef, Deng Jiawen, Hou Winston, Moraes Fabio Y., Glantz Michael, Zacharia Brad E., Tan Aaron, Ahluwalia Manmeet S., Khasraw Mustafa, Zadeh Gelareh, Mansouri Alireza

1356P Cumulative incidence and baseline imaging patterns of brain metastases in advanced EGFR and ALK positive non-small cell lung cancer (NSCLC)

Background: Up to 40% of NSCLC patients develop brain metastases (mets) during the course of their disease. We explored the impact of histology and EGFR and ALK mutations on cumulative incidence rates of brain mets and influence of brain imaging patterns. Conclusions: Our real-world data confirm a higher cumulative incidence of brain metastases in EGFR+/ALK+ adenocarcinoma compared to WT or SCC and more brain imaging at baseline. Future analyses will focus on treatment-based outcomes (tyrosine kinase inhibitors, different radiation modalities) in EGFR+/ALK+ patients compared to WT adenocarcinoma and SCC. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2021.08.1956

Authors: M.T. Chowdhury, M. García Pardo de Santayana, S. Schmid, S. Cheng, L.J. Zhan, M.C. Brown, K. Khan, P. Walia, A. Sabouhanian, E. Strom, J. Herman, N. Leighl, P. Bradbury, F.A. Shepherd, A. Sacher, W. Xu, G. Liu, D. Shultz

Treatment Strategy of Lung Adenocarcinoma with Concomitant EGFR Mutation and ALK Rearrangement

The incidence of synchronous mutations of Epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) was low. Now clinical experience is still insufficient. Simultaneously the treatment of brain metastasis hemorrhage in the acute phase with lung cancer is still controversial. We described the clinical treatment strategy of a patient with synchronous mutations of EGFR and ALK.We found that the tumor was well controlled. Progression-free survival (PFS)1 was 4 months, PFS2 was 3 months, PFS3 was 5 months, PFS4 was 5 months, and PFS5 was 9 months. At present, the patient still maintains partial response (PR) status. READ ARTICLE

Research Square DOI:10.21203/rs.3.rs-718876/v1

Authors: Li Li , Wei Liu , Chunhua Xu, Jue Zou

Treatment of brain metastases in ALK-positive Non-Small Cell Lung Cancer

Brain metastases are quite frequent in patients with ALK-translocated non-small cell lung cancer (NSCLC): they are often not amenable to surgical resection and are generally treated with radiotherapy (RT). This however causes severe late toxic side effects that may become invalidating considering the relatively long survival provided by recent medical treatment with target therapies. Several clinical trials have demonstrated that ALK-inhibitors (crizotinib, alectinib, brigatinib) show excellent activity also against brain metastases. It is therefore reasonable, in asymptomatic patients, to start treatment with specific inhibitors: RT will be used at the time of tumor progression or when symptoms appear. This sequence provides the best quality of life for patients. READ ARTICLE

Critical Reviews in Oncology/Hematology DOI: 10.1016/j.critrevonc.2021.103400

Authors: Serena Ceddia and Giovanni Codacci-Pisanelli

Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer

Highlights: Upfront LT delay intracranial progression, but do not prolong OS in oncogene-driven NSCLC. Use of stereotactic versus whole-brain radiotherapy and primary tumor TP53 status do not significantly affect brain control. Non-del19 EGFR mutations and ‘short’ EML4-ALK fusions are independent predictors of earlier intracranial failure. Results: Median overall survival (OS) was 49.1 months for ALK+ and 19.5 months for EGFR+ patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and ‘short’ EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial..... READ ARTICLE

ESMO Open DOI:10.1016/j.esmoop.2021.100161

Authors: R.A. El Shafie, K. Seidensaal, F. Bozorgmehr, D. Kazdal, T. Eichkorn, M. Elshiaty, D. Weber, M. Allgäuer, L. König, K. Lang, T. Forster, N. Arians, S. Rieken, C.-P. Heussel, F.J. Herth, M. Thomas, A. Stenzinger, J. Debus, P. Christopoulos.

Outcomes of first, second, and third-generation anaplastic lymphoma kinase (ALK) inhibitors in non-small cell lung cancer brain metastases (NSCLCBM)

Background: Non-small cell lung cancer (NSCLC) is the most common cause of brain metastases. ALK, which codes for tyrosine kinase receptors, is rearranged in 4-7% of NSCLC. First-generation ALK inhibitors have restricted efficacy due to poor blood-brain barrier (BBB) penetration and ALK-resistant tumor mutations. Second-generation ALK inhibitors have shown better BBB penetration, while third-generation ALK inhibitors were efficacious even against ALK-resistant mutations. In this retrospective study, we investigated the overall survival (OS) and progression-free survival (PFS) in NSCLCBM patients treated with first, second, and third-generation ALK inhibitors. Conclusions: Newer generations of targeted therapies in NSCLCBM have improved BBB penetration and effectiveness against resistant mutations. We determined that there was a significant 5-year OS benefit in patients who received second and third-generation ALK inhibitors compared to first-generation ALK inhibitors, and a respective..... READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.2034

Authors: Vineeth Tatineni, Patrick Joseph O'Shea, Yasmeen Rauf, Xuefei Jia, Erin Sennett Murphy, Samuel T. Chao, John H. Suh, David M. Peereboom, Manmeet Singh Ahluwalia

Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program

Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis. READ ARTICLE

Therapeutic advances in Medical Oncology DOI: 10.1177/1758835920980558

Authors: Nikolaj Frost, Petros Christopoulos, Diego Kauffmann-Guerrero, Jan Stratmann, Richard Riedel, Monica Schaefer, Jürgen Alt, Sylvia Gütz, Daniel C Christoph, Eckart Laack, Martin Faehling, Richard Fischer, Klaus Fenchel, Sebastian Haen, Lukas Heukamp, Christian Schulz and Frank Griesinger

Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program

We report on the results of the German early access program (EAP) with the
third-generation ALK- and ROS1-inhibitor lorlatinib. Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis. READ ARTICLE

Therapeutic advances in Medical Oncology DOI: 10.1177/1758835920980558

Authors: Nikolaj Frost, Petros Christopoulos, Diego Kauffmann-Guerrero, Jan Stratmann, Richard Riedel, Monica Schaefer, Jürgen Alt, Sylvia Gütz, Daniel C. Christoph, Eckart Laack, Martin Faehling, Richard Fischer, Klaus Fenchel, Sebastian Haen, Lukas Heukamp, Christian Schulz, Frank Griesinger

Real-World OutcomesKirk SmithFebruary 1, 2021ALK, brain metastases, early access program, NSCLC, ROS1, TP53, lorlatinib

Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma

Lung cancer is one of the most common malignant neoplasms. As a result of the disease’s progression, patients may develop metastases to the central nervous system. The prognosis in this location is unfavorable; untreated metastatic lesions may lead to death within one to two months. Existing therapies—neurosurgery and radiation therapy—do not improve the prognosis for every patient. The discovery of Epidermal Growth Factor Receptor (EGFR)—activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes ..... READ ARTICLE

International Journal of Molecular Science DOI:10.3390/ijms22020593

Authors: Agnieszka Rybarczyk-Kasiuchnicz, Rodryg Ramlau, and Katarzyna Stencel

392P Clinical data from the real world: Efficacy analysis of ceritinib (450mg) in ALK-positive non-small cell lung cancer patients with brain metastases in China

The real-world intracranial efficacy data of ceritinib at a dose of 450mg QD are still unavailable, thus this study aims to analyze the intracranial efficacy of ceritinib (450mg QD) in ALK-rearrangement NSCLC patients in China. Conclusion Ceritinib administered at a dose of 450mg QD to ALK-rearrangement NSCLC patients with BM in China demonstrates superior ORR and DCR, as well as PFS and EFP that are expected to be improved. Especially the estimated 12-month EFP of intracranial lesions was improved in patients with prior brain radiotherapy. READ ARTICLE

European Society for Medical Oncology. DOI:10.1016/j.annonc.2020.10.386

Authors: Z. Qiu, , K. Wang, M. Huang, M. Yu, C. Liu, X. Xian

Real-World OutcomesKirk SmithDecember 31, 2020ceritinib, brain metastases

Optimal Timing And Technique Of Local Therapy For Brain Metastases From Non-Small Cell Lung Cancer With Driver Mutations

Objective(s): Brain metastases (BM) are frequent in non-small cell lung cancer patients with driver mutations (dm-NSCLC). Since the availability of brain-penetrating tyrosine kinase inhibitors (TKI), the role of local therapy (LT) for BM from dm-NSCLC is frequently discussed. This analysis examines prognostic factors, particularly the effect of LT timing and technique, in patients with BM from dm-NSCLC. Conclusion: In this analysis, early LT improved icPFS but not OS in TKI-naive patients with BM from dm-NSCLC, compared to upfront TKI treatment. No benefit was shown for WBRT over SRS regarding either icPFS or OS. In light of the toxicities of WBRT, the choice of RT technique should be considered carefully in the context of overall prognosis and quality of life. Especially patients presenting initially with multiple BM may benefit from delaying RT or from individualized approaches like the SRS of multiple or only selected BM instead of WBRT. READ ARTICLE

International Journal of Radiation Oncology DOI:10.1016/j.ijrobp.2020.07.096

Authors: R. El Shafie, T. Eichkorn, D. Weber, F. Bozorgmehr, L. König, S. Rieken, M. Thomas, J. Debus, P. Christopoulos

Outcomes Based On Brain Metastases Characteristics And Treatment Modality For Patients With EGFR-Mutated And ALK-Rearranged Non-Small Cell Lung Cancer (NSCLC)

Purpose/objective(s): Lung cancer patients with driver mutations and brain metastases can be managed with various modalities given intracranial penetrance of available tyrosine kinase inhibitors (TKIs). We sought to determine these patient’s outcomes based on brain metastases characteristics and the upfront treatment modalities utilized, including stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT). Conclusion: For patients with EGFR-mutated or ALK-rearranged NSCLC and brain metastases, there was no difference in IC-PFS based on number or volume of brain metastases. Those treated with TKI alone experienced similar IC-PFS and risk of neurologic death as those also treated with radiotherapy. Further studies are needed to evaluate optimal treatment strategies for these patients, particularly for those with larger or symptomatic brain metastases when radiation is typically recommended. READ ARTICLE

International Journal of Radiation Oncology DOI:10.1016/j.ijrobp.2020.07.2048

Authors: S.W. Dutta, M.L. Mack, K.A. Ward, E. Aliotta, R. Hall, R.D. Gentzler, J.P. Sheehan

ALK Inhibitors in ALK-positive NSCLC with Central Nervous System Metastases

In anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer, brain metastases occur in 22–33% of cases at diagnosis and could reach up to 70% after crizotinib failure. Next-generation ALK inhibitors (ngALKi) have superior intracranial activity and prolonged responses compared with crizotinib and chemotherapy, as was shown in treatment-naïve or crizotinib pre-treated patients, irrespective of prior brain irradiation. Nevertheless, central nervous system relapse is also seen with ngALKi. Tailored treatment is necessary to obtain long-term survival without detrimental effects on cognition. Possible options include profiling secondary mutations to select sequential ngALKi, stereotactic radiotherapy and/or surgery, with the aim to avoid/deter whole brain irradiation. READ ARTICLE

touchONCOLOGY DOI:10.17925/EOH.2020.16.1.18

Authors: Mihaela Aldea, Benjamin Besse, Lizza EL Hendriks

Adverse Events of Concurrent Radiotherapy and ALK Inhibitors for Brain Metastases of ALK-Rearranged Lung Adenocarcinoma

Background: We investigated acute adverse events in patients with brain metastases (BMs) of anaplastic lymphoma kinase-rearranged (ALKr) non-small cell lung cancer (NSCLC) treated with both cranial radiotherapy and tyrosine kinase inhibitors (TKIs) of ALK. Patients and Methods: Acute AEs were retrospectively investigated in patients with BMs of ALKr-NSCLC who received both whole-brain radiotherapy (WBRT) and ALK-TKI. For comparison, they were also assessed in patients with epidermal growth factor receptor (EGFR)-mutated NSCLC and wild-type with neither ALK rearrangement nor EGFR mutation treated with WBRT. Results: Two ALKr cases were consequently eligible. Grade 3 otitis media unexpectedly occurred in both cases, while there was one case out of 11 and one case out of 18 of grade 2 otitis media among the EGFR-mutated cases and wild-type cases (p=0.013), respectively. Conclusion: Concurrent treatment with WBRT and ALK-TKI may be associated with acute severe ear toxicity in patients with BMs of ALKr-NSCLC. READ ARTICLE

In Vivo DOI:10.21873/invivo.11767

Authors: TAKAAKI NAKASHIMA, TAKESHI NONOSHITA, HIDENARI HIRATA, KOUJI INOUE, AKIRA NAGASHIMA, TADAMASA YOSHITAKE, KAORI ASAI and YOSHIYUKI SHIOYAMA

Case StudyKirk SmithJanuary 1, 2020ALK-TKI, radio therapy, adverse events, lung adenocarcinoma, brain metastases

Efficacy of Alectinib in Patients with ALK-Positive NSCLC and Symptomatic or Large CNS Metastases

Central nervous system (CNS) metastases represent a significant source of morbidity and mortality for patients with ALK tyrosine kinase gene (ALK)-positive NSCLC. Alectinib has demonstrated robust CNS activity in both crizotinib-naive and crizotinib-resistant settings. However, the CNS efficacy of alectinib has not been established in patients with untreated symptomatic, large CNS metastases.
In this retrospective study, patients were eligible if they had advanced ALK-positive NSCLC with large (defined as ≥1 cm) or symptomatic CNS metastases and received alectinib. Medical records and radiographic imaging were reviewed to determine treatment outcomes. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1.
Alectinib demonstrated meaningful CNS efficacy in patients with ALK-positive NSCLC with untreated symptomatic or large brain metastases. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.12.002

Authors: Jessica J Lin, Ginger Y Jiang, Nencyben Joshipura, Jennifer Ackil, Subba R Digumarthy, Sandra P Rincon, Beow Y Yeap, Justin F Gainor, Alice T Shaw