Clinical Benefit From a Combination of Brigatinib and Camrelizumab in Sarcomatoid Transformation of ALK-Rearranged Squamous Cell Lung Cancer Resistant to Crizotinib

A 27-year-old nonsmoking Chinese man was referred to the hospital owing to chest pain in May 2015. He had a diagnosis of stage IV lung squamous cell carcinoma (SCC), (cT2aN3M1b). Computed tomography displayed a 3-cm dense mass in the left superior lung (Fig. 1A, baseline), and immunohistochemistry (IHC) staining of the tumor biopsy reported positive for pulmonary SCC marker p40 (Fig. 1B, baseline). READ ARTICLE

JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100009

Authors: Wei Jiang, Ruting Guan, Yang W. Shao, Bo Wang, Yina Wang

Efficacy and safety of ALK inhibitors in ALK-rearranged non-small cell lung cancer: A systematic review and meta-analysis

Objectives: No overall survival (OS) benefit has been reported from a mature randomized trial with the use of ALK inhibitors. We conducted a systematic review and meta-analysis to assess the efficacy of ALK inhibitors compared to chemotherapy (ALK vs. chemo) and 2nd generation ALK inhibitors compared to 1 st generation ALK inhibitors (ALK-2 G vs. ALK-1 G)... Conclusions: This meta-analysis is the first, to our knowledge, to report an OS and PFS benefit with the use of ALK inhibitors compared to chemotherapy from randomized trial data. A trend toward a better OS was also seen with ALK-2 G vs. ALK-1 G and this is likely because of crossover effects and limited OS follow-up. Longer follow up and further research are warranted to directly compare ALK inhibitor sequences and to understand the outcomes of second generation ALK inhibitors as initial therapy. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.04.011

Authors: Daniel Breadner, Phillip Blanchette, Sumugan Shanmuganathan, Ronald Gabriel Boldt, Jacques Raphael

HDAC inhibition synergizes with ALK inhibitors to overcome resistance in a novel ALK mutated lung adenocarcinoma model

Objectives: Somatic chromosomal rearrangements resulting in ALK fusion oncogenes are observed in 3–7 % of lung adenocarcinomas. ALK tyrosine kinase inhibitors (ALKi) induce initially response, however, various resistance mechanisms limit their efficacy. Novel therapeutic approaches are of utmost importance to tailor these targeted therapies... Conclusion: Using a patient-derived ALKi resistant lung cancer model we demonstrated the synergism of HDAC and ALK inhibition. Furthermore, our findings provide strong evidence for intratumoral heterogeneity under targeted therapy and highlight the importance of site-specific mutational analysis. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.04.002

Authors: Paul Stockhammer, Cassandra Su Lyn Ho, Luca Hegedus, Gabor Lotz, Eszter Molnár, Agnes Bankfalvi, Thomas Herold, Stavros Kalbourtzis, Till Ploenes, Wilfried E. E. Eberhardt, Martin Schuler, Clemens Aigner, Alexander Schramm, Balazs Hegedus

Advances in Treatment of Locally Advanced or Metastatic Non–Small Cell Lung Cancer: Targeted Therapy

KEY POINTS:
Most epidermal growth factor receptor (EGFR)-mutated NSCLC (exon 19 del and L858R) should be
initially treated with osimertinib.
Anaplastic lymphoma kinase (ALK) fusion-positive NSCLC should be initially treated with alectinib,
brigatinib, or ceritinib; however, tolerability issues limit the use of ceritinib.
ROS1 fusion-positive NSCLC should be initially treated with entrectinib over crizotinib given central
nervous system activity.
BRAF V600E-mutated NSCLC should be initially treated with dabrafenib plus trametinib.
Neurotrophic tropomyosin receptor kinase fusion-positive NSCLC should be initially treated with
entrectinib or larotrectinib.
Patients with HER2 or EGFR exon 20 insertions, RET fusions, NRG1 fusions, MET amplification and
exon 14 skipping mutations, and KRAS G12C mutations should be initially treated with standard-ofcare chemoimmunotherapy; however, there are targeted therapies under investigation showing
promise. READ ARTICLE

Clinics in Chest Medicine DOI:10.1016/j.ccm.2020.02.003

Authors: Nicholas P. Giustini, Ah-Reum Jeong, James Buturla, Lyudmila Bazhenova

Feasibility and Safety of Neoadjuvant Alectinib in a Patient With ALK-Positive Locally Advanced NSCLC

A 46-year-old man, a nonsmoker, was hospitalized owing to complaints of repeated cough and hemoptysis. Enhanced computed tomography scan revealed a large mass with a diameter of 66 mm located in the left lower lobe. Enlarged mediastinal lymph nodes were also identified with bulky station 7... Herein, we have first reported a clinically successful case involving neoadjuvant alectinib... Collectively, neoadjuvant alectinib may be clinically feasible and a registered real-world study will be set to further assess its clinical implication. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.12.133

Authors: Chao Zhang, Li-Xu Yan, Ben-Yuan Jiang, Yi-Long Wu, Wen-Zhao Zhong

Case StudyKirk SmithJune 1, 2020Neoadjuvant, Alectinib, ALK, NSCLC

Radiomic prediction of mutation status based on MR imaging of lung cancer brain metastases

Lung cancer metastases comprise most of all brain metastases in adults and most brain metastases are diagnosed by magnetic resonance (MR) scans. The purpose of this study was to conduct an MR imaging-based radiomic analysis of brain metastatic lesions from patients with primary lung cancer to classify mutational status of the metastatic disease. We retrospectively identified lung cancer patients with brain metastases treated at our institution between 2009 and 2017 who underwent genotype testing of their primary lung cancer. Brain MR Images were used for segmentation of enhancing tumors and peritumoral edema, and for radiomic feature extraction. The most relevant radiomic features were identified and used with clinical data to train random forest classifiers to classify the mutation status. Of 110 patients in the study cohort (mean age 57.51 ± 12.32 years; M: F = 37:73), 75 had an EGFR mutation, 21 had an ALK translocation, and 15 had a KRAS mutation. One patient had both ALK transloca..... READ ARTICLE

Magnetic Resonance Imaging DOI:10.1016/j.mri.2020.03.002

Authors: Bihong T. Chen, Taihao Jin, Ningrong Ye, Isa Mambetsariev, Ebenezer Daniel, Tao Wang, Chi Wah Wong, Russell C. Rockne, Rivka Colen, Andrei

A Novel Linc00308/D21S2088E Intergenic Region ALK Fusion and Its Enduring Clinical Responses to Crizotinib

... Herein we report a novel ALK fusion partner, the Linc00308/D21S2088E intergenic region, that conferred responsiveness to crizotinib in a patient with lung adenocarcinoma (LUAD)... Thus, we have provided proof that patients with advanced NSCLC harboring a Linc00308/D21S2088E intergenic region ALK may benefit from crizotinib, expanding the spectrum of ALK fusion variants to optimize treated strategy. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.03.009

Authors: Jian Zhang, Chang Zou, Chenzhi Zhou, Yifeng Luo, Qiong He, Yu Sun, Jianwen Zhou, Zunfu Ke

Case StudyKirk SmithJune 1, 2020Linc00308/D21S2088E, Intergenic Region, ALK Fusion, Crizotinib

Comprehensive analyses of immunodynamics and immunoreactivity in response to treatment in ALK-positive non-small-cell lung cancer

ALK-positive tumors progressing on ceritinib is not immunogenic enough to respond to immune checkpoint inhibitors. READ ARTICLE

Journal for ImmunoTherapy of Cancer DOI: 10.1136/jitc-2020-000970

Authors: Kyoung-Ho Pyo, Sun Min Lim, Chae-Won Park, Ha-Ni Jo, Jae Hwan Kim, Mi-Ran Yun, Dohee Kim, Chun-Feng Xin, Wongeun Lee, Bianca Gheorghiu, Min Hee Hong, Hye Ryun Kim, Hyo Sup Shim, Mi Jang, Sung Sook Lee, Byoung Chul Cho

Pre-ClinicalKirk SmithJune 1, 2020Pd-1 inhibitor, ceritinib

Successful alectinib desensitization in a patient with anaplastic lymphoma kinase-positive adenocarcinoma of the lung and alectinib-induced drug rash

Alectinib is currently recommended as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase gene rearrangement-positive NSCLC due to improved progression-free survival when compared to crizotinib. The development of skin toxicity can lead to early discontinuation of alectinib treatment, forcing providers and patients to select alternative, potentially less effective options. This case report provides evidence that patients who have experienced severe skin toxicity due to alectinib may be able to continue this first-line treatment option by rechallenging them using a desensitization procedure. READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220918644

Authors: Anderson BE, Luczak TS, Ries LM, Hoefs GE, Silva-Benedict AC.

Case StudyKirk SmithMay 31, 2020Alectinib, desensitization, hypersensitivity, ALK-positive

Treatment Sequencing in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer in Japan: A Real-World Observational Study

Introduction The anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) alectinib was approved in Japan in 2014 for the treatment of ALK fusion gene-positive advanced non-small cell lung cancer (NSCLC). With the approvals of crizotinib in 2012 and ceritinib in 2017, Japan became the first country with multiple ALK TKIs available for first-line or later use in patients with ALK-positive advanced NSCLC. Here, we collected and evaluated real-world data on ALK TKI clinical usage patterns and sequencing in patients with ALK-positive NSCLC in Japan. Results A total of 378 patients met the inclusion criteria and were evaluated in mutually exclusive groups of patients receiving one, two, or three ALK TKIs. The initial ALK TKI prescribed was crizotinib for 52.1% of patients and alectinib for 47.9% of patients; however, the proportion of patients receiving alectinib as the initial ALK TKI increased over time following the Japanese approval of alectinib in 2014. Of the 117 patients who ..... READ ARTICLE

Advances in Therapy DOI:10.1007/s12325-020-01392-0

Authors: Yasushi Goto, Nobuyuki Yamamoto, Elizabeth T. Masters, Hironori Kikkawa, Jack Mardekian, Robin Wiltshire, Kanae Togo and Yuichiro Ohe

Anaplastic lymphoma kinase (ALK) partners identified by next-generation sequencing in Chinese patients with solid tumors

Background: Anaplastic lymphoma kinase (ALK) rearrangement is a validated therapeutic driver gene in non-small cell lung cancer (NSCLC). More than 30 different fusion partner genes of ALK in NSCLC have been reportedand most of these ALK fusions respond well to ALK inhibitors crizotinib. With the development of next-generation sequencing (NGS), more novel partners for ALK rearrangement have been identified. Here, we aimed to report the landscape of ALK rearrangement in Chinese patients with solid tumors... Conclusions: Novel ALK fusions are detected in patients with not only NSCLC but also other solid tumors. NGS fusion assay is an optional method for screening novel fusions. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.3555

Authors: Sheng Yang, Fuyu Gong, Guoqiang Wang, Xiaohui He

Surviving metastatic non-small cell lung cancer (mNSCLC): The lived experience and supportive care needs of patients (pts) receiving immunotherapy (IT) or targeted therapy (TT)

Background: IT and TT have improved survival for many pts with mNSCLC. However, the lived experience of these pts is under-studied. We conducted a single centre, qualitative study to understand concerns and supportive care needs of this novel survivor population... Conclusions: Longer term survivors of mNSCLC report significant physical, psychological and functional concerns and unmet needs. Self-management strategies for chronic toxicities, professional psychological services to manage FCP and scan-related anxiety, and tailored information regarding work and financial planning may mitigate these concerns. Future work should examine these issues in a larger population. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.e24185

Authors: Julia Elizabeth Lai-Kwon, Sarah Heynemann, Jacinthe Flore, Mary Duffy, Renata Kokanovic, Michael Jefford

Trends in ALK inhibitors for non-small cell lung cancer

Background: Rearrangements in the gene encoding anaplastic lymphocyte kinase (ALK) are found in 3%–5% of patients. Treatment options have significantly expanded with ALK inhibitor drug approvals including crizotinib in 2011, ceritinib in 2014, alectinib in 2015, brigatinib in 2017 and lorlatinib in 2018. We sought to better understand the real-world treatment utilization and cost of ALK inhibitors in lung cancer (LCA) over the most recent period for which adjudicated claims are available, October 2017-September 2018... Conclusions: Our analyses demonstrate alectinib is the preferred first-line ALK inhibitor in the last twelve months of available data. Furthermore, the increased ER and in-patient costs may substantiate the findings of the ALEX trial, notably higher liver toxicity and more nausea, vomiting, and diarrhea for crizotinib. There is not yet sufficient data on the newer ALK inhibitors, brigatinib and lorlatinib in the real-world. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.e14046

Authors: Denise Meade, Marie Ng, S Alford

Real-World OutcomesKirk SmithMay 25, 2020ALK, inhibitor, non-small cell lung cancer

SAF-189s in previously treated patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC): Results from the dose-finding portion in a single-arm, first-in-human phase I/II study

Background: Patients(pts) with ALK-rearranged non-small cell lung cancer (NSCLC) are sensitive but progress in 8–11 months with treatment of ALK inhibitor crizotinib, with leading progression in brain metastasis. SAF-189s is a novel and selective ALK inhibitor, can penetrate through blood brain barrier, and overcome multiple resistance mutation. This study aimed to explore the safety, efficacy, and pharmacokinetic properties of SAF-189s in patients with advanced ALK-rearranged NSCLC... Conclusions: In the dose-escalation portion of this study, SAF-189s was safe, very tolerable, and demonstrated both systemic and intracranial activity in pts with advanced ALK-positive NSCLC who had failed to at least 1 prior systemic therapy. Therefore, this study warrants further investigation to prove SAF-189s as an effective therapeutic option for pts who have ALK+ NSCLC. Clinical trial information: NCT04237805. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.e21689

Authors: Jin-Ji Yang, Jianying Zhou, Nong Yang, Zhuli Wu, Juan Sun, Ai-Min Hui, Yi-Long Wu

Clinical TrialsKirk SmithMay 25, 2020SAF-189s, ALK, non-small cell lung cancer (NSCLC)

A phase I study to evaluate safety, tolerability, pharmacokinetics, and preliminary antitumor activity of TQ-B3101

Background: TQ-B3101 is a novel compound, which deacetylated metabolite targets to receptor tyrosine kinases including ALK, ROS1 and MET. Preclinical studies showed TQ-B3101 had a better Inhibition activity and duration compared with equimolar crizotinib... Conclusions: TQ-B3101 was well tolerated and showed preliminary antitumor activity in ALK+, ROS1+ and MET amplification pts. Recommended phase II dose (RP2D) might be 300mg BID according longtime safety data. Further anti-tumor research in pts with ROS1+ is under going as multicenter clinical study in China. (NCT03972189). Clinical trial information: NCT03019276. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.e21705

Authors: Yong Fang, Hongming Pan, Shun Lu, Hong Hu, Qin Lu

A phase I, dose-escalation and expansion study of TQ-B3139, a novel ALK TKI, in Chinese ALK or ROS1 positive advanced non-small cell lung cancer (NSCLC)

Background: TQ-B3139 is a novel ALK inhibitor with activity 3-7 folds higher than Crizotinib against a broad range of ALK mutations. This phase I study (NCT03099330) is to investigate the safety, and determine the recommended phase II dose (RP2D), and pharmacokinetic (PK), clinical efficacy of TQ-B3139 in Chinese NSCLC patients... Background: TQ-B3139 is a novel ALK inhibitor with activity 3-7 folds higher than Crizotinib against a broad range of ALK mutations. This phase I study (NCT03099330) is to investigate the safety, and determine the recommended phase II dose (RP2D), and pharmacokinetic (PK), clinical efficacy of TQ-B3139 in Chinese NSCLC patients. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9585

Authors: Yuxiang Ma, Nong Yang, Su Li, Hongyun Zhao, Liu Li, Haiyan Yang, Wenfeng Fang, Yang Zhang, Shaodong Hong, Yi Xiong, Chunhua Zhou, Yongchang Zhang, Liang Zeng, Li Zhang

Clinical TrialsKirk SmithMay 25, 2020TQ-B3139, ALK, TKI, ROS1, non-small cell lung cancer (NSCLC)

3rd-line anaplastic lymphoma kinase (ALK) inhibitors (ALKi) in advanced non-small cell lung cancer (aNSCLC): Real-world comparison to non-ALKi therapy

Background: ALKi represent the standard 1st- and 2nd -line treatment (Tx) for ALK+ aNSCLC patients (pts). The value of ALKi in the 3rd-line setting is unclear. We retrospectively assessed the real-world impact of a 3rd -line ALKi vs. non-ALKi Tx in ALK+ aNSCLC pts... Conclusions: Following progression on a 2ndALKi, OS and TNT were numerically higher for pts receiving a 3rd ALKi, but statistically NS. Extensive exposure of pts in the non-ALKi Tx Gr to an ALKi at a later stage might have impacted these results. Further studies are required to identify patients likely to benefit from ALKi after progressing on 2 or more ALKi Tx lines. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.e21685

Authors: Natalie Maimon, Elizabeth Dudnik, Yakir Rottenberg, Noa Popovits-Hadari, Noam Asna, Mira Wollner, Alona Zer, Maya Gottfried, Moshe Mishaeli, Yulia Rovitsky-Gelis, Anastasiya Lobachov, Amir Onn, Damien Urban, Mor Tal Moskovitz, Jair Bar, Israel Lung Cancer Group

A multicenter real-world study of tumor-derived DNA from pleural effusion supernatant in genomic profiling of advanced lung cancer

Background: Pleural effusion (PE) is commonly observed in advanced lung cancer. Researches have suggested molecular profiling of PE represents a minimally invasive approach of detecting tumor driver mutations for clinical decision making. The objective of this study is to investigate the efficacy and precision of detecting gene alterations in PE samples in the real world setting... Conclusions: This real world large cohort study verified that genomic profiling of PE-supernatant has higher actionable mutation detection sensitivity than plasma. It offers an alternative approach in assessing tumor genomics in advanced lung cancer when tumor tissue is not available. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.e21584

Authors: Renhua Guo, Likun Chen, Chengzhi Zhou, Xinghao Ai, Jun Zhao, Rongrong Chen, Xuefeng Xia

Longitudinal monitoring by next generation sequencing of plasma cell-free DNA in ALK-rearranged non-small cell lung cancer (NSCLC) patients treated with ALK tyrosine kinase inhibitors

Background: Patients with anaplastic lymphoma kinase-rearranged (ALK+) NSCLC inevitably acquire resistance to ALK inhibitors. We hypothesized that longitudinal monitoring of cell-free plasma DNA (cfDNA) next generation sequencing (NGS) could predict the response and resistance of TKI therapy in ALK+NSCLC... Conclusions: NGS of cell-free plasma DNA is useful not only for the detection of ALK fusions and resistance mutations but also for assessing prognosis and monitoring the dynamic changes of genomic alterations in ALK+ NSCLC treated with ALK TKI. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9603

Authors: Minsuk Kwon, Bo Mi Ku, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn

Clinical impact of targetable gene alterations on therapeutic outcomes in stage II/III locally advanced non-small cell lung cancer patients

Background: The clinical significance of genetic alterations in stage II/III non-small cell lung cancer (NSCLC) patients has not yet been clarified. We have prospectively analyzed NSCLC patients for cancer-related gene alterations and have followed up clinical course of the patients, establishing a large-scale clinico-genomic database in our nationwide genome screening project (LC-SCRUM-Japan)... Conclusions: In stage II/III NSCLC, the total frequency of targetable gene alterations was similar to that previously evaluated in our stage IV cohort (45%), and the current standard therapies showed early progression in the targetable gene-altered patients. A novel effective multimodality treatment in combination with targeted therapies is needed for this population. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9038

Authors: Yoshitaka Zenke, Shingo Matsumoto, Terufumi Kato, Shingo Miyamoto, Takuma Imakita, Tetsuya Mitsudomi, Hiromi Aono, Ryota Ushio, Naoki Furuya, Kazumi Nishino, Saori Takata, Mika Nakao, Satoshi Hara, Motoko Tachihara, Akimasa Sekine, Jun Sakakibara-Konishi, Ryo Toyozawa, Kiyotaka Yoh, Koichi Goto

Review PaperKirk SmithMay 25, 2020Gene alterations, non-small cell lung cancer