Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs

Of the 139 patients with ≥1 prior second-generation ALK TKI (EXP3B-5), 28 received one prior second-generation ALK TKI (EXP3B), 65 two prior ALK TKIs (EXP4), and 46 three prior ALK TKIs (EXP5). In EXP3B-5, the objective response rate (ORR) [95% confidence intervals] was 39.6% (31.4-48.2), intracranial ORR (IC-ORR) was 56.1% (42.4-69.3), extracranial ORR (EC-ORR) was 36.7% (28.7-45.3), median duration of response (DOR) was 9.6 months [5.6-16.7; IC-DOR, 12.4 (6.0-37.1); EC-DOR, 9.7 (6.1-33.3)], median progression-free survival was 6.6 (5.4-7.4) months, and median overall survival was 20.7 months (16.1-30.3). In EXP3B, the ORR was 42.9% (24.5-62.8), the IC-ORR was 66.7% (29.9-92.5), and the EC-ORR was 32.1% (15.9-52.4). In EXP4 and EXP5, the ORR was 38.7% (29.6-48.5), the IC-ORR was 54.2% (39.2-68.6), and the EC-ORR was 37.8% (28.8-47.5). Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post-second-generation ALK TKI setting, with elevated intra..... READ ARTICLE

Annals of Oncology DOI: 10.1016/j.annonc.2021.02.012

Authors: E. Felip, A. T. Shaw, A. Bearz, D. R. Camidge, B. J. Solomon, J. R. Bauman, T. M. Bauer, S. Peters, F. Toffalorio, A. Abbattista, H. Thurm, G. Peltz, R. Wiltshire, B. Besse

Real-World OutcomesKirk SmithJanuary 1, 2021ALK, NSCLC, lorlatinib

Immunotherapy Treatment Patterns and Outcomes Among ALK-Positive Patients With Non–Small-Cell Lung Cancer

Real-world effectiveness (rwPFS) of ICIs in ALK-positive NSCLC patients, whether provided before or after TKIs, was limited, underscoring the relative lack of efficacy of ICI in this patient population, particularly compared to approved ALK TKIs. READ ARTICLE

Clinical Lung Cancer DOI: 10.1016/j.cllc.2020.08.003

Authors: Mohammad Jahanzeb, Huamao M.Lin, Xiaoyun Pan, Yu Yin, Pia Baumann, Corey J. Langer

Neoadjuvant treatment of stage IIIA-N2 in EGFR-Mutant/ ALK-rearranged non-small cell lung cancer

Discusses risks and benefits of adjuvant therapy for treatment of earlier stage and locoregional lung cancer; advocates genome sequencing of earlier stage lung cancer. READ ARTICLE

Translational Lung Cancer Research DOI: 33569340

Authors: Reyes, Roxana, Reguart, Noemi

Real-World OutcomesKirk SmithJanuary 1, 2021Early stage, neoadjuvant therapy, targeted therapy, ALK, EGFR, NSCLC

ALK ligand ALKAL2 potentiates MYCN‐driven neuroblastoma in the absence of ALK mutation

Neuroblastoma is a childhood disease that has 8-10% ALK positive and may be higher in the replapse population. Overexpression of ALKAL2 (ligand for ALK) located on chromosome 2p with neutral MYC oncogene can drive neuroblastoma in the absense of ALK mutation. READ ARTICLE

European Molecular Biology Organization (EMBO) DOI: 10.15252/embj.2020105784

Authors: Marcus Borenäs,Ganesh Umapathy,Wei-Yun Lai,Dan E Lind,Barbara Witek,Jikui Guan, Patricia Mendoza-Garcia,Tafheem Masudi,Arne Claeys,Tzu-Po Chuang,Abeer El Wakil, Badrul Arefin,Susanne Fransson,Jan Koster,Mathias Johansson,Jennie Gaarder,Jimmy Van den Eynden, Bengt Hallberg, Ruth H Palmer

Clinical TrialsKirk SmithJanuary 1, 2021ALK receptor, neuroblastoma, neural MYC, MYCN, oncogene, ALKAL2 ligand

Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation

Here, we report that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, is crucial for the tau-mediated AD pathology. ALK caused abnormal accumulation of highly phosphorylated tau in the somatodendritic region of neurons through its tyrosine kinase activity. ALK-induced LC3-positive axon swelling and loss of spine density, leading to tau-dependent neuronal degeneration. We propose that aberrantly activated ALK is a bona fide mediator of tau proteinopathy that disrupts autophagosome maturation and causes tau accumulation and aggregation, leading to neuronal dysfunction in AD. READ ARTICLE

Molecular Psychiatry DOI: 10.1038/s41380-020-01003-y

Authors: Jisu Park, Hyunwoo Choi, Young Doo Kim, Seo-Hyun Kim, Youbin Kim, Youngdae Gwon, Dong Young Lee, Sung-Hye Park, Won Do Heo & Yong-Keun Jung

Pre-ClinicalKirk SmithJanuary 1, 2021ALK, tau, Alzheimer's disease, AD

Upfront Management of ALK-Rearranged Metastatic Non-small Cell Lung Cancer: One Inhibitor Fits All?

During the past 10 years, multiple ALKi have been developed, and four different compounds are currently available as upfront options for ALK+ NSCLC patients: crizotinib, ceritinib, alectinib, and brigatinib. Second-generation (2G) ALKi demonstrated superior clinical activity in terms of median progression-free survival (mPFS), objective response rate (ORR), intracranial disease control, and duration of response (DOR) when compared with crizotinib. 2G ALKi represent the current gold-standard first-line treatment for ALK-rearranged metastatic NSCLC. Among all available options, in our opinion, alectinib has likely the best profile of clinical activity and safety, thus emerging as the best upfront therapy. More insights will come from ongoing trials and analysis of biomarkers. READ ARTICLE

Current Oncology Reports DOI: 10.1007/s11912-020-00989-6

Authors: Febrizio Tabbò, Francesco Passiglia, Silvia Novello

Review PaperKirk SmithJanuary 1, 2021ALK, NSCLC, TKIs, biomarkers

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

The efficacy of lorlatinib in a lung adenocarcinoma patient with a novel ALK G1202L mutation: a case report

Report reveals the efficacy of lorlatinib in targeting ALK G1202L and can serve as an option for the clinical management of patients with ALK-rearranged lung adenocarcinoma after acquiring G1202L-mediated resistance from prior ALK inhibitor therapy. Furthermore, it demonstrates the sequential use of crizotinib, brigatinib, and lorlatinib in a patient with advanced ALK-rearranged lung adenocarcinoma with an overall progression-free survival of 33.3 months for the sequential ALK inhibitor regimens. His overall survival was 41.5 months inclusive of all regimens. READ ARTICLE

Cancer Biology & Therapy DOI: 10.1080/15384047.2020.1836947

Authors: Zhaoting Meng, Ting Li, Pei Wang, Analyn Lizaso, Dingzhi Huang

Case StudyKirk SmithDecember 30, 2020TKI Resistance, Lorlatinib, ALK-rearranged NSCLC, ALK G1202L, sequential, ALK inhibitor

Real-World Evidence of Diagnostic Testing for Driver Oncogene Mutations in Lung Cancer in Japan

This descriptive, retrospective observational study used the Japan Medical Data Vision Co., Ltd. (MDV), database (June 2017–November 2018) and covered data for EGFR, ALK, ROS1, and PD-L1; records on BRAF testing were not yet available. This real-world evidence revealed variations in diagnostic testing patterns, which could affect time to treatment in Japan. Variations are likely influenced by individual biomarker prioritization considering limited tissue samples in clinical practice. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtocrr.2020.100136

Authors: Yasushi Yatabe, Yasumasa Yoshiki, MPH, Koichi Matsumura, Kanae Togo, MSc, Hironori Kikkawa, Laura Iadeluca, MPH, Benjamin Li, Kazuto Nishio,

Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer: Implications for Oncogene-Driven Lung Cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, commonly defined by genetic alterations in oncogenic drivers. Targeted therapies have transformed the management of oncogene-driven lung cancers, with targeted agents now approved in the United States for 7 distinct molecular alterations. Nonetheless, acquired resistance remains an ongoing challenge, underscoring the need for alternative therapeutic approaches. Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) axis have emerged as important therapies in the management of advanced NSCLC, but the role of these agents in patients with oncogenic driver mutations remains unclear. Here, we focus on epidermal growth factor receptor-mutant and anaplastic lymphoma kinase-rearranged NSCLC as paradigms to explore the role of immune checkpoint inhibitors in oncogene-driven NSCLC. We provide an overview of the clinical data examining programmed death ligand 1 (PD-L1) inhibitor monotherapy, PD-(L)1 inhibitors, and tyrosine kinase inhibitor combinations, as well as combinations of PD-(L)1 inhibitors and chemotherapy. READ ARTICLE

The Cancer Journal DOI: 10.1097/PPO.0000000000000491

Authors: Gavralidis A, Gainor JF.

Review PaperKirk SmithDecember 26, 2020EGFR, ALK, combinations, Targeted therapy

Food–Drug Interactions with Fruit Juices

Fruit juices contain a large number of phytochemicals that, in combination with certain drugs, can cause food–drug interactions that can be clinically significant and lead to adverse events. The mechanisms behind such interactions are in most cases related to phytochemical interference with the activity of cytochrome P450 metabolizing enzymes (CYPs) or drug transporters. Moreover, alterations in their activity can have a clinical relevance if systemic exposure to the drug is decreased or increased, meaning that the pharmacological drug effects are suboptimal, or the drug will cause toxicity. In general, the common pharmacokinetic parameters found to be altered in food–drug interactions regarding fruit juices are the area under the concentration–time curve, bioavailability, and maximum plasma concentration. In most cases, the results from the drug interaction studies with fruit juices provide only limited information due to the small number of subjects, which are also healthy volunteers. Moreover, drug interactions with fruit juices are challenging to predict due to the unknown amounts of the specific phytochemicals responsible for the interaction, as well as due to the inter-individual variability of drug metabolism, among others. Therefore, this work aims to raise awareness about possible pharmacological interactions with fruit juices. READ ARTICLE

Foods DOI: 10.3390/foods10010033

Authors: Zvonimir Petric, Irena Žuntar, Predrag Putnik and Danijela Bursać Kovačević

Review PaperKirk SmithDecember 24, 2020fruit juice, interaction, drug, phytochemical, pharmacokinetics

The Prevalence of the EML4-ALK Fusion Gene in Cytology Specimens from Patients with Lung Adenocarcinoma

qRT-PCR successfully identified EML4-ALK fusion rearrangement in direct smear preparations of lung adenocarcinoma. Direct smear samples can be used for EML4-ALK rearrangement detection using qRT-PCR. The EML4-ALK rearrangement gene has high prevalence in selected lung adenocarcinoma and EGFR mutation-negative populations. ALK inhibitors in lung cancer can be openly considered for use in Indonesian patients to improve the outcome of this subset of patients. READ ARTICLE

Pulmonary Medicine DOI:10.1155/2020/3578748

Authors: Didik S. Heriyanto, Ika Trisnawati, Evan G. Kumara, Vincent Laiman, Fara S. Yuliani, Auliya S. B. Sumpono, Rita Cempaka, Marcellus, Eko Budiono

Real-World OutcomesKirk SmithDecember 23, 2020qRT-PCR, EML4-ALK fusion rearrangement

Treatment of anaplastic lymphoma kinase-positive lung adenocarcinoma with pemetrexed and carboplatin after crizotinib failure and significant liver dysfunction; a case report

Tyrosine kinase inhibitors are the first-line treatment for Anaplastic Lymphoma Kinase-positive lung adenocarcinomas. However, chemotherapy is still an option in patients who are unresponsive or intolerant of tyrosine kinase inhibitors. There is a high likelihood of brain metastasis in patient with lung adenocarcinomas with Anaplastic Lymphoma Kinase rearrangement. Surveillance brain imaging may have a role in clinical follow up. Brigatinib and lorlatinib are two tyrosine kinase inhibitors with excellent intracranial penetrance. READ ARTICLE

Cancer Treatment and Research Communications DOI:10.1016/j.ctarc.2020.100291

Authors: Oranus Mohammadi, Kayla Haines, Mohammad Jahanzeb,

Heterogeneous Tumor-Immune Microenvironments between Primary and Metastatic Tumors in a Patient with ALK Rearrangement-Positive Large Cell Neuroendocrine Carcinoma

We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions. READ ARTICLE

International Journal of Molecular Science DOI: 10.3390/ijms21249705

Authors: Tashiro T, Imamura K, Tomita Y, Tamanoi D, Takaki A, Sugahara K, Sato R, Saruwatari K, Sakata S, Inaba M, Ushijima S, Hirata N, Sakagami T

Identification of a novel ALK variant intrinsically resistant to crizotinib

The knowledge of oncogene addiction in non small cell lung carcinoma (NSCLC) involving EGFR, ALK and ROS1 genes has changed the therapeutic and prognostic landscape of NSCLC. ALK rearranged NSCLC accounts for 10% of these cases, and with the development and approval of ALK TKIs (tyrosine kinase inhibitors) like crizotinib, it is imperative to detect the same. Various ALK variants are known to occur resulting in differential sensitivities to TKIs because of different protein stabilities. The precise characterization hence is important which can be achieved only by high throughput next generation sequencing (NGS) based assays. Immunohistochemistry and FISH (fluorescence in situ hybridization) although considered gold standards cannot define the breakpoints and length of the fusion transcripts. We herein report a novel EML4-ALK variant in a case of advanced NSCLC which plausibly is inherently resistant to crizotinib because of the breakpoints involved. READ ARTICLE

Current Problems in Cancer DOI:doi.org/10.1016/j.cpccr.2020.100040

Authors: Ullas Batra, Shrinidhi Nathany, Mansi Sharma, Satyajeet Soni, Parveen Jain, Sunil Pasricha, Abhishek Bansal, Anurag Mehta

Case StudyKirk SmithDecember 15, 2020ALK rearranged, NSCLC, Crizotinib resistance, Novel variant

Risk of thromboembolism in patients with ALK- and EGFR-mutant lung cancer: A cohort study

Patients with ALK-mutant advanced lung adenocarcinoma have the highest rate of TE. TE is associated with worse survival across molecular subtypes. These findings should be taken into consideration in decision-making regarding thromboprophylaxis. READ ARTICLE

Journal of Thrombosis and Haemostasis DOI:doi.org/10.1111/jth.15215

Authors: Joanna Roopkumar,Shyam K. Poudel,Lorenzo Gervaso,Chandana A. Reddy,Vamsidhar Velcheti,Nathan A. Pennell,Keith R. McCrae,Alok A. Khorana

The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer

Review providing a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized. READ ARTICLE

Pharmaceuticals (Basel) DOI: 10.3390/ph13120474

Authors: Valerio Gristina, Maria La Mantia, Federica Iacono, Antonio Galvano, Antonio Russo, Viviana Bazan

Review PaperKirk SmithDecember 13, 2020ALK inhibitor, NSCLC, TKI, alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib

Complex ALK Fusions Are Associated With Better Prognosis in Advanced Non-Small Cell Lung Cancer

The objective response rate and median progression-free survival to crizotinib treatment tended to be better in complex ALK fusion patients.
Notably, patients with complex ALK fusions had significantly improved overall survival after crizotinib treatment especially when compared with the pure canonical EML4-ALK fusion group.
The complex ALK fusion group also tended to respond better to next-generation ALK TKIs, which were used as later-line therapies.
Most identified non-canonical ALK fusions were likely to be expressed in tumors, and some of them formed canonical EML4-ALK transcripts during mRNA maturation.
Diagnosis using CGP is of great value to identify novel ALK fusions and predict prognosis. READ ARTICLE

Frontiers in Oncology DOI: 10.3389/fonc.2020.596937

Authors: Jin Kang,Xu-Chao Zhang,Hua-Jun Chen, Wen-Zhao Zhong, Yang Xu, Jian Su, Qing Zhou, Hai-Yan Tu, Zhen Wang, Chong-Rui Xu, Xue-Ning Yang, Zhi-Hong Chen, Xue Wu, Xian Zhang, Yang Shao, Yi-Long Wu, Jin-Ji Yang

Early serum tumor marker levels after fourteen days of tyrosine kinase inhibitor targeted therapy predicts outcomes in patients with advanced lung adenocarcinoma

In conclusion, image evaluation strategy with RECIST for patients with lung cancer has difficulty in obtaining the appropriate quantity of diffuse lung nodules, pleural effusions, and bone metastases. The type of 4-TMpc after 14 days TKI targeted therapy is associated with image response and PFS without accounting for mutation status in advanced lung adenocarcinoma patients. Our study results could help early therapeutic decision making by identifying patients who may benefit from gefitinib, erlotinib, afatinib, crizotinib, or ceritinib 14 days after TKI targeted therapy.status, in patients with advanced lung adenocarcinoma. READ ARTICLE

PLOS ONE DOI: 10.1371/journal.pone.0240736

Authors: Chen H-J, Tu C-Y, Huang K-Y, Chien C-R, Hsia T-C

Real-World OutcomesKirk SmithDecember 11, 2020serum tumor marker, TKI

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development p..... READ ARTICLE

Journal of Hematology and Oncology DOI: 10.1186/s13045-020-01007-9

Authors: rnold Bolomsky, Meike Vogler, Murat Cem Köse, Caroline A. Heckman, Grégory Ehx, Heinz Ludwig, Jo Caers

Review PaperKirk SmithDecember 11, 2020MCL-1, Resistance