Background: Brigatinib is an ALK inhibitor with demonstrated activity against ALK resistance mutations. To evaluate efficacy and safety in Japanese patients with ALK-positive non-small cell lung cancer (NSCLC), a prospective, single-arm, phase 2 study was conducted. We report the efficacy and safety of brigatinib in patients who have progressed on alectinib with or without prior crizotinib and of those who previously received up to two ALK tyrosine kinase inhibitors (TKIs) with or without prior chemotherapy... Conclusions: Brigatinib showed clinically meaningful efficacy in Japanese patients refractory to prior alectinib (first line or post crizotinib), regardless of prior chemotherapy. The safety profile of brigatinib was consistent with prior studies and no new safety findings were identified. Clinical trial information: NCT03410108 READ ARTICLE
Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9537
Authors: Tatsuya Yoshida, Makoto Nishio, Toru Kumagai, Toyoaki Hida, Ryo Toyozawa, Tadasuke Shimokawaji, Koichi Goto, Kazuhiko Nakagawa, Yuichiro Ohe, Nobuyuki Yamamoto, Kentarou Kudou, Takayuki Asato, Pingkuan Zhang, Takashi Seto
Background: Brigatinib is a next-generation ALK tyrosine kinase inhibitor (TKI) with differential activity by dose (90 mg vs 180 mg [with a 7-day lead-in at 90 mg] qd) in the phase 2 post-crizotinib ALTA trial (NCT02094573). Herein, we describe results from population PK and exposure-response analyses of the efficacy and safety of brigatinib 180 mg qd (with a 7-day lead-in at 90 mg) from data in the first-line phase 3 ALTA-1L study (NCT02737501)... Conclusions: These results support a favorable benefit/risk profile of the proposed 180 mg qd brigatinib dose (with a 7-day lead-in at 90 mg) for the front-line treatment of patients with ALK+ NSCLC. Clinical trial information: NCT02737501. READ ARTICLE
Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.e21725
Authors: Neeraj Gupta, Karen L. Reckamp, D. Ross Camidge, Huub Jan Kleijn, Aziz Ouerdani, Francesco Bellanti, John Maringwa, Michael J. Hanley, Shining Wang, Pingkuan Zhang, Karthik Venkatakrishnan
Background: Efficacy of ALK TKIs in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) varies. We evaluated the impact of EML4-ALK fusion variants and other baseline (BL) molecular and clinical variables on clinical efficacy of brigatinib (BRG) vs crizotinib (CRZ) as first ALK TKI therapy in pts with ALK+ NSCLC in the phase 3 ALTA-1L (NCT02737501) trial... Conclusions: EML4-ALK fusion variant 3 and TP53 mutation were identified as poor prognosis biomarkers in ALK+ NSCLC. BRG demonstrated better efficacy than CRZ as first-line therapy in pts regardless of EML4-ALK fusion variant and TP53 mutation status. These findings may help define areas of greatest unmet need. Clinical trial information: NCT02737501 READ ARTICLE
Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9517
Authors: D. Ross Camidge, Huifeng Niu, Hye Ryun Kim, James Chih-Hsin Yang, Myung-Ju Ahn, Jacky Yu-Chung Li, Maximilian Hochmair, Angelo Delmonte, Alexander I. Spira, Rosario Garcia Campelo, Fabrice Barlesi, Geoffrey Liu, Marcello Tiseo, Cong Li, Miguel Williams, Hyunjin Shin, Pingkuan Zhang, Sanjay Popat
Background: Lorlatinib, a third-generation tyrosine kinase inhibitor targeting ALK and ROS1, has been made available in France starting October 2015 through an EAP for advanced, refractory, ALK+ NSCLC after the failure of chemotherapy and TKIs. Besides the landmark, multi-cohort phase II trial that assessed lorlatinib in ALK+ NSCLC, real-life evidence regarding the efficacy and safety, as well as treatment sequences including lorlatinib, is lacking. Methods: We report the cohort of consecutive patients with advanced, refractory, ALK or ROS1+ NSCLC enrolled in the French EAP of lorlatinib from October 2015 to October 2019. Data were collected from medical records by French Cooperative Thoracic Intergroup (IFCT) research study assistants on site. Primary endpoint was progression-free survival... Conclusions: These real-life results confirmed lorlatinib as a major treatment option for patients with advanced refractory ALK or ROS1+ NSCLC. READ ARTICLE
Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9615
Authors: Simon Baldacci, Virginie Avrillon, Benjamin Besse, Bertrand Mennecier, Michael Duruisseaux, Julien Mazieres, Renaud Descourt, Helene Doubre, Pascale Dubray-Longeras, Jacques Cadranel, Denis Moro-Sibilot, Charles Ricordel, Sigolène Galland-Girodet, Isabelle Monnet, Josiane Otto, Sophie Schneider, Pascale Missy, Franck Morin, Virginie Westeel, Nicolas Girard
Background: Lorlatinib is a 3rd-generation ALK tyrosine kinase inhibitor (TKI) developed to penetrate the central nervous system (CNS) and overcome resistance to 2nd-generation (2nd-gen) ALK TKIs. In a phase II study, lorlatinib demonstrated significant intracranial (IC) activity after failure of 2nd-gen TKIs. As treatment discontinuation for extracranial (EC) progression can confound assessment of durability of IC response, we performed a phase II study (NCT02927340) to selectively evaluate lorlatinib activity in ALK+ pts with CNS-only disease... Conclusions: Lorlatinib induces durable intracranial responses in pts with CNS-only progression on 2nd-gen ALK TKIs, suggesting that CNS-specific relapses are primarily driven by ALK-dependent mechanisms. Further studies are needed to characterize the molecular basis of sensitivity to lorlatinib in this unique subgroup of pts with ALK+ lung cancer. Clinical trial information: NCT02927340 READ ARTICLE
Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9595
Authors: Ibiayi Dagogo-Jack, Geoffrey R. Oxnard, Jessica Fink, Gianluca Diubaldi, Caitlyn Helms, Justin F. Gainor, Michael S. Rabin, Rebecca Suk Heist, Jessica Jiyeong Lin, Jennifer Ackil, Alona Muzikansky, Alice Tsang Shaw
As the use of up-front osimertinib for advanced epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer is increasing, it is important to understand the resistance pathways to the drug and subsequent treatment. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2020.05.016
Authors: Ullas Batra, Mansi Sharma, B.P. Amrith, Anurag Mehta, Parveen Jain
Purpose: Anaplastic lymphoma kinase (ALK) inhibitors have transformed the management of non-small-cell lung cancer (NSCLC) patients with ALK gene rearrangement. This paper reports a new resistance mechanism to a second-generation ALK inhibitor, brigatinib. Case Report: A 43-year-old woman who had no history of smoking was diagnosed with stage IVa (T2bN2M1b) lung adenocarcinoma. After the first-line chemotherapy failed, the patient received crizotinib due to the presence of EML4-ALK fusion by next-generation sequencing (NGS). The patient had disease progression after 8 months on crizotinib, and a second NGS identified the ALK G1202R resistance mutation. Therefore, she was switched to brigatinib. After only 53 days of treatment with brigatinib, the patient developed a new 1.6× 1.2 cm lesion in the mediastinal lymph node. A third NGS testing revealed a new form of NTRK rearrangement (LIPI-NTRK1). The patient died 16 months after diagnosis.Conclusion: This paper provides new insights into ..... READ ARTICLE
OncoTargets and Therapy DOI:10.2147/OTT.S249652
Authors: Xiao Z, Huang X, Xie B, Xie W, Huang M, Lin L.
Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes. Additionally, we found that during this adaptation tumor cells might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting the potential for new therapeutic interventions, directed against evolving resistance. READ ARTICLE
Nature Communications DOI:10.1038/s41467-020-16212-w
Authors: Robert Vander Velde, Nara Yoon, Viktoriya Marusyk, Arda Durmaz, Andrew Dhawan, Daria Miroshnychenko, Diego Lozano-Peral, Bina Desai, Olena Balynska, Jan Poleszhuk, Liu Kenian, Mingxiang Teng, Mohamed Abazeed, Omar Mian, Aik Choon Tan, Eric Haura, Jacob Scott & Andriy Marusyk
Anaplastic lymphoma kinase (ALK) fusion is present in approximately 2–7% of patients with lung adenocarcinoma. ALK fusion-positive patients can benefit from targeted therapy. We herein report a 53-year-old Chinese male patient diagnosed as lung adenocarcinoma with a smoking history. Next-generation sequencing was performed to detect somatic mutations of oncogenic drivers and tumor suppressor genes in plasma-derived circulating tumor DNA using an ultra-deep 160-gene panel. A novel HPCAL1-ALK fusion variant was identified in the patient responding to ALK inhibitor treatments, and the fusion variant was also confirmed by fluorescence in situ hybridization and immunohistochemical. Our study expands the mutational spectrum of ALK fusion variants and provides options for the precise treatment of such patients. READ ARTICLE
OncoTargets and therapy DOI:10.2147/OTT.S252210
Authors: Wang R, Qin J, Fan Y, Li Z, Chen C, Su W.
Background. Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)- positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiv- ing crizotinib.
Materials and Methods. PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments.
Results. A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants
were identified in 32 patients, and those with ..... READ ARTICLE
The Oncologist DOI:10.1634/theoncologist.2020-0088
Authors: CHING-YAO YANG, WEI-YU LIAO, CHAO-CHI HO, KUAN-YU CHEN, TZU-HSIU TSAI, CHIA-LIN HSU, YI-NAN LIU, KANG-YI SU, YIH-LEONG CHANG, CHEN-TU WU, BIN-CHI LIAO, CHIA-CHI HSU, WEI-HSUN HSU, JIH-HSIANG LEE, CHIA-CHI LIN, JIN-YUAN SHIH, JAMES CHIH-HSIN YANG, CHONG-JEN YU
In time-to-event analyses controlling for thrombosis risk factors, the ALK rearrangement conferred a fourfold increase in VTE risk and a threefold increase in arterial thrombosis risk in NSCLC. These patients may benefit from pharmacologic thromboprophylaxis. READ ARTICLE
Journal of Thoracic Oncology DOI: 10.1016/j.jtho.2020.04.033
Authors: Hanny Al-Samkari, Orly Leiva, Ibiayi Dagogo-Jack, Alice Shaw, Jochen Lennerz, Anthony J Iafrate, Pavan K Bendapudi, Jean M Connors
Read MoreEML4–ALK is an oncogenic fusion present in ∼5% of non-small cell lung cancers. However, alternative breakpoints in the EML4 gene lead to distinct variants of EML4–ALK with different patient outcomes. Here, we show that, in cell models, EML4–ALK variant 3 (V3), which is linked to accelerated metastatic spread, causes microtubule stabilization, formation of extended cytoplasmic protrusions and increased cell migration. EML4–ALK V3 also recruits the NEK9 and NEK7 kinases to microtubules via the N-terminal EML4 microtubule-binding region. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates migration in a microtubule-dependent manner that requires the downstream kinase NEK7 but does not require ALK activity. Strikingly, elevated NEK9 expression is associated with reduced progression-free survival in EML4–ALK patients. Hence, we propose that EML4–ALK V3 promotes microtubule stabilization through NEK9 and NEK7, leading to..... READ ARTICLE
Journal of Cell Science DOI:10.1242/jcs.241505
Authors: Laura O'Regan, Giancarlo Barone, Rozita Adib, Chang Gok Woo, Hui Jeong Jeong, Emily L. Richardson, Mark W. Richards, Patricia A. J. Muller, Spencer J. Collis, Dean A. Fennell, Jene Choi, Richard Bayliss, Andrew M. Fry
Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. * Investigator-assessed PFS data in the ALEX study are now mature (53% of events in the alectinib arm). * Alectinib significantly prolonged PFS vs crizotinib (stratified HR 0.43, 95% CI 0.32–0.58; median 34.8 vs 10.9 months). * OS data are immature (37% of events); median NR alectinib vs 57.4 months crizotinib (stratified HR 0.67, 95% CI 0.46–0.98). * 5-year OS rate of 62.5% with alectinib and 45.5% with crizotinib. * Median treatment duration was longer with alectinib (28.1 vs 10.8 months crizotinib), with no new safety signals seen. READ ARTICLE
Annals of Oncology DOI: 10.1016/j.annonc.2020.04.478
Authors: T. Mok, D. R. Camidge, S. M. Gadgeel, R. Rosell, R. Dziadziuszko, D.-W. Kim, M. Pérol, S.-H. I. Ou, J. S. Ahn, A. T. Shaw, W. Bordogna, V. Smoljanovi, M. Hilton, T. Ruf, J. Noé, S. Peters
Read MoreMature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. * Investigator-assessed PFS data in the ALEX study are now mature (53% of events in the alectinib arm). * Alectinib significantly prolonged PFS vs crizotinib (stratified HR 0.43, 95% CI 0.32–0.58; median 34.8 vs 10.9 months). * OS data are immature (37% of events); median NR alectinib vs 57.4 months crizotinib (stratified HR 0.67, 95% CI 0.46–0.98). * 5-year OS rate of 62.5% with alectinib and 45.5% with crizotinib. * Median treatment duration was longer with alectinib (28.1 vs 10.8 months crizotinib), with no new safety signals seen. READ ARTICLE
Annals of Oncology DOI: 10.1016/j.annonc.2020.04.478
Authors: T. Mok, D. R. Camidge, S. M. Gadgeel, R. Rosell, R. Dziadziuszko, D.-W. Kim, M. Pérol, S.-H. I. Ou, J. S. Ahn, A. T. Shaw, W. Bordogna, V. Smoljanovi, M. Hilton, T. Ruf, J. Noé, S. Peters
Read MoreAnaplastic lymphoma kinase (ALK) fusion events account for ~3–7% genetic alterations in patients with non-small cell lung cancer (NSCLC). In this study, we identified the ALK fusion patterns and a novel ALK fusion partner in 44 ALK positive NSCLC patients using a customized HapOncoCDx panel, and identified ALK fusion partners. The most common partner is EML4, forming the variant 1 (v1, E13:A20, 18/44), variant 2 (v2, E20:A20, 5/44), and variant 3 (v3, E6:A20, 13/44). Moreover, we detected a new ALK fusion partner HMBOX1. At the mutation level, TP53 is the most frequently mutated gene (24%), followed by ALK (12%) and STED2 (12%). The median tumor mutation burden (TMB) of these samples is 2.29 mutations/Mb, ranging from 0.76 mut/Mb to 16.79 muts/Mb. We further elaborately portrayed the TP53 mutation sites on the peptide sequence of the encoded protein by lollipop. The mutational signature and copy number alterations (CNAs) of the samples were also analyzed. The CNA events were found in 1..... READ ARTICLE
Frontiers in oncology DOI:10.3389/fonc.2020.00726
Authors: Shaokun Liu, Tanxiao Huang, Ming Liu, Wenlong He, YingShen Zhao, Lizhen Yang, Yingjiao Long, Dandan Zong, Huihui Zeng, Yuanyuan Liu, Wenting Liao, Jingxian Duan, Subo Gong and Shifu Chen
Anaplastic lymphoma kinase (ALK) inhibitors have been used in patients with non-small cell lung cancer (NSCLC) harboring EML4-ALK fusion gene.1 Severe skeletal muscle adverse events of ALK inhibitors, such as muscle weakness, have seldom been reported.2,3 Herein, we describe a patient who showed a severe skeletal muscle deficit after the administration of the ALK inhibitor, alectinib, and was successfully treated by corticosteroids without withdrawal from the cancer therapy READ ARTICLE
Neurology: Neuroimmunology & Neuroinflammation DOI:10.1212/NXI.0000000000000735
Authors: Akinori Uruha, Stefan Kliesch, Simone Schmid, Carsten Dittmayer, Hans-Hilmar Goebel, Alexander Dressel, Werner Stenzel, Robert Handreka
Background The prevalence of EGFR/ALK co-alterations in patients with NSCLC was low. The several previous studies focused on the simultaneous occurrence of EGFR mutations and ALK rearrangements in a unifocal lung cancer. However, the incidence of multifocal pulmonary adenocarcinomas was increasingly encountered in clinical practice, due to the increased availability and improvement of the thoracic imaging. The clinical relevance of EGFR/ALK co-alterations in multifocal adenocarcinomas required detailed investigation as well. ConclusionsThe status of the oncogenic mutations in lymph node metastasis may provide some effective hints for metastasis lesion in other organ or tissue. Therefore, it is recommended to fully evaluate the driver genes in lymph node metastasis after radical resection. READ ARTICLE
Diagnostic Pathology DOI:10.1186/s13000-020-00969-1
Authors: Fan, J., Wu, J., Huang, B. et al.
Anaplastic lymphoma kinase (ALK) fusion is an important molecular subtype of non–small-cell lung cancer, and patients who have ALK fusion can be highly sensitive to ALK tyrosine kinase inhibitors. Different ALK fusions showed different sensitivities to ALK tyrosine kinase inhibitors. EML4-ALK (E6; A18) fusion showed resistance to crizotinib in a 48-year-old male patient with lung adenocarcinoma. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2020.04.014
Authors: Xiaofeng Chen, Guohong Zhao, Peilin Zhong, Min Zhang, Rongrong Chen, Derong Zhang
What is known and objective: Ceritinib is a new, oral, potent and selective second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the Food and Drug Administration of the United States in April 2014. It is active in crizotinib-resistant patients, especially in patients with non-small cell lung cancer (NSCLC) and brain metastasis. The aim of this study was to analyse the effects and side effects of ceritinib in ALK-rearranged NSCLC. What is new and conclusion: Ceritinib is effective in the treatment of patients with ALK-rearranged NSCLC with crizotinib resistance. The DCR was up to 76%, and PFS was extended to 7.6 months. The AEs were acceptable. READ ARTICLE
Journal of Clinical Pharmacy and Therapeutics DOI:10.1111/jcpt.13157
Authors: Tian, W, Zhang, P, Yuan, Y, Deng, X-H, Yue, R, Ge, X-Z.
EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has ..... READ ARTICLE
European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2020.112190
Authors: Ning Sun, Chaowei Ren, Ying Kong, Hui Zhong, Jinju Chen, Yan Li, Jianshui Zhang, Yuedong Zhou, Xing Qiu, Haifan Lin, Xiaoling Song, Xiaobao Yang, Biao Jiang