Real-world patterns of biomarker testing and targeted therapy in metastatic non-small cell lung cancer (mNSCLC) in the community oncology setting

Background: National guidelines recommend biomarker testing in mNSCLC, and targeted therapy is associated with improved outcomes. The aim of this study was to understand the real-world biomarker testing and treatment patterns in the community setting. Conclusions: Despite availability of promising biomarker-based therapies, the lack of adequate testing in the community oncology setting means that not all eligible patients are receiving the most effective therapies upfront. Nearly 61% of patients had no DM test reported before 1L treatment in this mNSCLC cohort (all histologies), and some were determined to be DM positive at a later time, highlighting a missed opportunity to employ the most effective biomarker-directed front-line treatment. Next steps in this study will include assessing patterns by histology. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.9079

Authors: Eric S. Nadler, Anupama Vasudevan, Kalatu Davies, Yunfei Wang, Ravindra Gupta, Sarika Ogale

Patient-derived lung cancer organoids for the selection of therapeutic options in an ALK-rearranged tumor

Background: ALK rearrangements are key targets in non-small-cell lung cancer (NSCLC). Unfortunately, the optimal sequential strategy of ALK-tyrosine kinase inhibitors (TKI) remains to be defined. Testing drug sensitivity in patient derived organoids (PDOs) could support a rational drug selection in this setting. Conclusions: We present clinical evidence that PDOs are an alternative tool in oncogenic addicted tumors helping to guide treatment decisions and increasing a more personalized sequential treatment approach. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.e21014

Authors: Beatriz Jimenez Munarriz, Zahra Dantes, Javier De Castro, Paloma Navarro, Monica Yagüe, Arantzazu Barquin, Juan Francisco Rodriguez-Moreno, Elena Sevillano, Sergio Ruiz, Anabel del Barrio, Gema García Ledo, Miriam Dorta, Ana Collazo Lorduy, Emiliano Calvo, Jesús García-Donas, Sandra Serrano, Apoorva Manjunath, Luciana Ferreira, Barbara Hefel, Jordi Remon

Impact of rapid multigene assays with short turnaround time (TAT) on the development of precision medicine for non-small cell lung cancer (NSCLC)

Background: A variety of oncogene drivers have been identified in NSCLC and molecularly-stratified precision medicine has led to improved survival in advanced NSCLC. Next-generation sequencing (NGS)-based testing is utilized to detect actionable gene alterations; however, the TAT of NGS is often too long to translate into clinical decision making. Thus, rapid multi-gene testing alternatives are needed. Conclusions: Both the 9-in-1 test and Genexus/OPA had short TATs (3−4 days), high success rates (96−98%) and good concordance (95−98%) compared with another NGS assay (OCA). These rapid multi-gene assays highly contributed to enabling precision medicine and the development of targeted therapies for advanced NSCLC. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.9094

Authors: Shingo Matsumoto, Takaya Ikeda, Kiyotaka Yoh, Akira Sugimoto, Terufumi Kato, Kei Kunimasa, Atsushi Nakamura, Ichiro Nakachi, Shoichi Kuyama, Jun Sakakibara-Konishi, Haruko Daga, Eiji Iwama, Kageaki Taima, Naoki Furuya, Kaname Nosaki, Hiroki Izumi, Yoshitaka Zenke, Koichi Goto

Brigatinib in Japanese patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC): First results from the J-ALTA

Background: Brigatinib is a next-generation ALK inhibitor with demonstrated activity against ALK mutations. We report primary analysis results with brigatinib in Japanese patients with ALK-positive NSCLC who have not previously been treated with an ALK TKI in the phase 2 J-ALTA study (NCT03410108). Conclusions: In the J-ALTA TKI-naive cohort, brigatinib demonstrated substantial efficacy and manageable safety in the Japanese patient population. Brigatinib remains one of the treatment options in Japanese patients. Clinical trial information: NCT03410108. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.9042

Authors: Masashi Kondo, Shunichi Sugawara, Toshihide Yokoyama, Toru Kumagai, Makoto Nishio, Koichi Goto, Yuichiro Ohe, Takashi Seto, Nobuyuki Yamamoto, Kentarou Kudou, Takayuki Asato, Pingkuan Zhang, Kazuhiko Nakagawa

Biomarker tissue journey among patients (pts) with untreated metastatic non-small cell lung cancer (mNSCLC) in the U.S. Oncology Network community practices

Background: Given the importance of molecular testing and targeted therapy for mNSCLC, the MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) consortium pragmatic study assessed real-world biomarker testing rates and turnaround times (TAT) within The US Oncology Network of over 1,000 providers across the United States. Conclusions: This real-world study showed that most pts received at least one biomarker test prior to 1L, but <50% received all 5 tests. NGS testing occurred in <50% of pts but increased over the periods examined. Median time from dx to 1L therapy was about 5 weeks and TAT from orders to results about 2 weeks. Analyses by histology and other trends will be reported. These data will be compared to the next phase of the MYLUNG study, which will evaluate contemporary ordering practices and TATs prospectively. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.9004

Authors: Nicholas J. Robert, Esmond D. Nwokeji, Janet L. Espirito, Liwei Chen, Mandar Karhade, Makenzi Colleen Evangelist, Alexander I. Spira, Marcus A. Neubauer, Susie A. Bullock, Robert L. Coleman, on behalf of MYLUNG Consortium Collaborators: The U.S. Oncology Network and sponsors

Outcomes of KRAS mutated, EGFR mutated, ALK mutated and wildtype patients in non-small cell lung cancer brain metastases

Background: Non-small cell lung cancer (NSCLC) is the most common primary tumor leading to brain metastases. Multiple genetic markers have been profiled in NSCLC patients for potential targeted therapies. EGFR is mutated in up 50% of NSCLCs, while ALK is mutated in around 4-7%. KRAS is the most commonly overexpressed marker, seen in up to 85% of all lung cancers. In this retrospective study, we evaluated the overall survival (OS) and progression-free survival (PFS) between NSCLCBM patients with KRAS mutations, ALK mutations, EGFR mutations, and wildtype. Conclusions: Molecular mutations serve as both prognostic predictors and alternative targeted therapies for NSCLCBM treatment. Our retrospective study showed improved mOS and mPFS in NSCLCBM patients with ALK rearrangements when compared to patients with EGFR mutations, KRAS mutations, and the wildtype. While these results looked at patient outcomes with specific tumor markers, further investigation needs to be done regarding outcomes..... READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.e21028

Authors: Yasmeen Rauf, Vineeth Tatineni, Patrick joseph Oshea, Xuefei Jia, David M. Peereboom, Manmeet Singh Ahluwalia

Conference PaperKirk SmithMay 28, 2021non-small cell lung cancer (NSCLC), mutations, PFS

Impact of prior ALK-tyrosine kinase inhibitor on pemetrexed-based chemotherapy in patients with advanced ALK positive non-small cell lung cancer

Background: In phase Ⅲ trial comparing crizotinib with chemotherapy in patients with ALK-positive non-small-cell lung cancer (NSCLC) patients, it suggests that pemetrexed is highly effective against ALK-positive NSCLC. However, it is unclear that pemetrexed-based chemotherapy is effective in patients previously treated with ALK-tyrosine kinase inhibitor (ALK-TKI) as well as ALK-TKI naïve patients. Therefore, we investigated the impact of prior ALK-TKI therapy on pemetrexed-based chemotherapy. Conclusions: Pemetrexed-based chemotherapy might be less effective in ALK-positive NSCLC patients previously treated with ALK-TKI. This retrospective study results suggested that ALK-TKI sequence can be a better treatment option in ALK-positive NSCLC patients. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.e21113

Authors: Michitoshi Yabe, Hirotsugu Kenmotsu, Hiroaki Kodama, Naoya Nishioka, Eriko Miyawaki, Taichi Miyawaki, Nobuaki Mamesaya, Haruki Kobayashi, Shota Omori, Kazushige Wakuda, Akira Ono, Tateaki Naito, Haruyasu Murakami, Toshiaki Takahashi

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

ALKtALK: Ed Speigel and Mariah Balestracci from PEER Medical, a private company

Ed Speigel and Mariah Balestracci present how to empower patients through shared data with Peer Medical. ALK Positive patients and caregivers ask questions and engage with the Peer Medical team. SEE VIDEO

ALK Positive Inc.

Authors: Ed Speigel and Mariah Balestracci

VideoKirk SmithMay 23, 2021ALKtALK

A Novel Nonreciprocal/Reciprocal ALK Translocation Cause ALK+ in NSCLC

The development and clinical application of ALK inhibitors have made a great breakthrough in recent years. It is of great clinical significance to identify the target population suitable for ALK inhibitors by using appropriate ALK detection methods. 5’ALK fusions currently draw the most attention. Nonreciprocal/reciprocal ALK translocations were often thought of nonfunctional or neglected. Here, we identified a rare patient with lung adenocarcinoma in pT1N2M0 stage IIIA. Tumor tissue of the patient harbored a novel nonreciprocal/reciprocal ALK translocation which did not form a 5’ALK fusion. But Tumor tissue did express ALK protein, which is normally not expressed in the lungs. READ ARTICLE

Lung Cancer DOI: 10.1016/j.lungcan.2021.05.020

Authors: Xianguo Chen, Bo Xu, Fangni Fu, Ke Cai and Zhaonan Yu

Case StudyKirk SmithMay 20, 2021ALK, Nonreciprocal/reciprocal Translocation, NSCLC, inhibitors

Successful Alectinib Treatment for Carcinoma of Unknown Primary with EML4-ALK Fusion Gene: A Case Report

Gene alteration in anaplastic lymphoma kinase (ALK) is rare, and the efficacy of ALK inhibitors in the treatment of carcinoma of unknown primary (CUP) with ALK alteration remains unclear. The patient was a 56-year-old woman who presented with cervical lymph node swelling. Computed tomography revealed paraaortic, perigastric, and cervical lymph node swelling; ascites; a liver lesion; and a left adrenal mass. A cervical lymph node biopsy was performed, and pathological diagnosis of an undifferentiated malignant tumor was conducted. Finally, the patient was diagnosed with CUP and treated with chemotherapy. To evaluate actionable mutations, we performed a multigene analysis, using a next-generation sequencer (FoundationOne® CDx). It revealed that the tumor harbored an echinoderm microtubule-associated protein-like 4 (EML4) and ALK fusion gene. Additionally, immunohistochemistry confirmed ALK protein expression. Alectinib, a potent ALK inhibitor, was recommended for the patient at a molecular oncology conference at our institution. Accordingly, alectinib (600 mg/day) was administered, and the multiple lesions and symptoms rapidly diminished without apparent toxicity. The administration of alectinib continued for a period of 10 months without disease progression. Thus, ALK-tyrosine kinase inhibitors should be considered in patients with CUP harboring the EML4-ALK fusion gene. READ ARTICLE

Current Oncology DOI: 10.3390/curroncol28030180

Authors: Sugiyama K., Izumika A., Iwakoshi A., Nishibori R., Sato M., Shiraishi K., Hattori H., Nishimura R. and Kitagawa C.

Genetic Analysis and Operative Outcomes in Patients with Oncogene-Driven Advanced NSCLC Treated with Cytoreductive Surgery as a Component of Local Consolidative Therapy

Most patients with oncogene-driven advanced non-small cell lung cancer (NSCLC) demonstrate recurrence because of the developing targeted therapy resistance. In this retrospective study, we assessed the efficacy of surgical local consolidative treatment by analyzing the operative outcomes and genetic data in 44 patients who underwent pulmonary resection for stage IIIB/C-IV NSCLC after targeted therapy. The initial mutations were in the EGFR (n = 32), ALK (n = 11), and ROS1 (n = 1) genes. The median interval from the initiation of tyrosine kinase inhibitor (TKI) therapy immediately before the surgery to the actual operation was 9.8 months. Operative mortality was absent. Four patients showed complete remission. The median follow-up period after TKI therapy initiation was 23.1 months. The Kaplan-Meier survival analysis showed that the 2-year failure-free survival and overall survival rates from the initiation of TKI were 70.8% and 95.0%, respectively. During the follow-up period, two patients died and 15 suffered from disease progression. Among the 32 patients with EGFR mutations, 12 showed additional mutations, and targeted agents were replaced in nine patients after the operation. We conclude that pulmonary resection for advanced NSCLC after targeted therapy is feasible, and the surgical specimens could be used for planning further targeted therapy. READ ARTICLE

Cancers DOI: 10.3390/cancers13112549

Authors: Byung Jo Park , Hyo Sup Shim , Chang Young Lee , Jin Gu Lee , Hye Ryun Kim , Sang Hoon Lee , Min Hee Hong and Seong Yong Park

Targeting EML4-ALK gene fusion variant 3 in thyroid cancer

Finding targetable gene fusions can expand the limited treatment options in radioactive iodine-refractory (RAI-r) thyroid cancer. To that end, we established a novel cell line ‘JVE404’ derived from an advanced RAI-r papillary thyroid cancer (PTC) patient, harboring an EML4-ALK gene fusion variant 3 (v3). Different EML4-ALK gene fusions can have different clinical repercussions. JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient’s treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use). In vitro treatment with crizotinib or ceritinib decreased viability in JVE404, but most potently and significantly only with lorlatinib. Western blot analysis showed a near total decrease of 99% and 89%, respectively, in pALK and pERK expression levels in JVE404 cells with lorlatinib, in contrast to remaining sig..... READ ARTICLE

Endocrine-Related Cancer DOI:10.1530/ERC-20-0436

Authors: Mehtap Derya Aydemirli, Jaap D H van Eendenburg, Tom van Wezel, Jan Oosting, Willem E Corver , Ellen Kapiteijn and Hans Morreau

Efficacy and Safety of Intrathecal Pemetrexed Combined With Dexamethasone for Treating Tyrosine Kinase Inhibitor-Failed Leptomeningeal Metastases From EGFR-Mutant NSCLC

We aimed to evaluate the efficacy and safety of intrathecal pemetrexed (IP) for treating EGFR-mutant leptomeningeal metastases (LMs) from EGFR-mutant NSCLC. The RD observed in the phase 1 study was 50 mg pemetrexed. A total of 30 cases of LM-NSCLC were enrolled in the phase 2 study, including 14 males and 16 females. Four patients did not survive for 4 weeks and could not be evaluated for efficacy. The clinical response rate was 84.6% (22 of 26). The median overall survival of all patients was 9.0 months (n = 30, 95% confidence interval: 6.6–11.4 mo). Most AEs were mild, and the most frequent AE of any grade was myelosuppression (n = 9, 30%), which returned to normal after symptomatic treatment. This study revealed that 50 mg pemetrexed is the RD which results in few AEs and a good response rate. IP is an effective treatment for patients with EGFR-mutant NSCLC-LM who had failed on tyrosine kinase inhibitor...... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/J.JTHO.2021.04.018

Authors: Chengjuan Fan, Qiuyu Zhao, Li Li, Weixi Shen, Yang Du, Chong Teng, Feng Gao, Xiaowei Song, Qiuying Jiang, Dayong Huang, Yinghua Jin, Yanju Lv, Lingxiao Wei, Tengfei Shi, Xue Zhao, Naisheng Gao, Zhengjun Jiang, Tao Xin

EML4-ALK fusion variant.3 and co-occurrent PIK3CA E542K mutation exhibiting primary resistance to three generations of ALK inhibitors

The ALK inhibitors are promising therapeutic agents against lung cancer harboring ALK fusion genes and are currently under development up to the third generation. However, its therapeutic effects are reported to be affected by differences in ALK variants and co-occurrent mutations. Materials and Methods; We experienced an autopsy case of an ALK-positive lung cancer patient who showed primary resistance to three generations of ALK inhibitors. The poor survival time of the case was 14 months. To reveal the mechanism of primary resistance to three generations of ALK inhibitors, we performed next generation sequencing for 12 specimes obtained from an autopsy with covering whole exons of 53 significantly mutated, lung cancer-associated genes and amplicon-based target RNA sequenceing for the ALK fusion gene. The NGS analysis revealed a rare variant.3 of ALK fusion, in which 30 bp of base was inserted at the end of ALK intron.19 and was associated with EML exon.6 [E6_ins30A20] and a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. Structural analysis of the fusion protein ALK [E6_ins30A20] showed no interferance with the binding of ALK inhibitors to the kinase domain. The NGS analysis of primary and metastatic lesions obtained from an autopsy revealed a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. The constitutive activation of PI3K-Akt signal by PIK3CA E542K mutation occurred downstream of ALK signaling pathway, could lead to primary resistance to ALK inhibitors in all generations. READ ARTICLE

Cancer Genetics DOI: 10.1016/j.cancergen.2021.05.010

Authors: Kei Kunimasa, Yosuke Hirotsu, Yoji Kukita, Yumi Ueda, Yoshiharu Sato, Madoka Kimura, Tomoyuki Otsuka, Yuichiro Hamamoto, Motohiro Tamiya, Takako Inoue, Takahisa Kawamura, Kazumi Nishino, Kenji Amemiya, Taichiro Goto, Hitoshi Mochizuki, Keiichiro Honma, Masao Omata and Toru Kumagai

Primary resistance to alectinib in a patient with STRN-ALK-positive non-small cell lung cancer: A case report

naplastic lymphoma kinase (ALK) rearrangements are drivers of a subset of non-small cell lung cancer (NSCLC). The rapid progression of ALK inhibitors has significantly prolonged the progression-free survival of patients with ALK gene-sensitive mutations. However, the response of patients with rare ALK rearrangements to tyrosine kinase inhibitors remains unknown. Here, we report a rare case of striatin (STRN)-ALK-positive NSCLC showing primary resistance to first-line therapy alectinib and limited clinical activity of crizotinib in the alectinib-resistant setting. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13983

Authors: Kunyan Sun,Ligong Nie,Lin Nong and Yuan Cheng

Case StudyKirk SmithMay 7, 2021STRN-ALK, NSCLC, alectinib, crizotinib

Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors

We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-ALK and ITSN2-ALK, were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib. This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK-rearranged nonlung solid tumors. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1200/PO.20.00383 JCO

Authors: Yuki Takeyasu, Hitomi S. Okuma, Yuki Kojima, Tadaaki Nishikawa, Maki Tanioka, Kazuki Sudo, Tatsunori Shimoi, Emi Noguchi, Ayumu Arakawa, Taisuke Mori, Kuniko Sunami, Takashi Kubo, Takashi Kohno, Yoshida Akihiko, Noboru Yamamoto and Kan Yonemori

Characteristics of central nervous system progression in non-small cell lung cancer treated with crizotinib or alectinib

Aims: We compared the clinical-radiographic characteristics of CNS metastases among patients undergoing crizotinib and alectinib treatment for ALK-positive NSCLCs. Conclusion: We observed no significant difference in the clinical-radiographic characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including stereotactic radiosurgery, for CNS progression may be suitable and important following alectinib and crizotinib treatment. READ ARTICLE

Cancer Reports DOI:doi.org/10.1002/cnr2.1414

Authors: Hiroaki Sakamoto, Noriko Yanagitani, Ryo Manabe, Ryosuke Tsugitomi, Shinsuke Ogusu, Takehiro Tozuka, Hiroshi Yoshida, Yoshiaki Amino, Ryo Ariyasu, Ken Uchibori, Satoru Kitazono, Sadatomo Tasaka, Makoto Nishio

Circulating tumor DNA to investigate resistance mechanism and clone evolution of ALK TKI treated lung adenocarcinoma.

Genotyping of sequential post-progression plasma specimens reveals that treatment with sequential first-, second-, and third-generation ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance. READ ARTICLE

Journal of Clinical Oncology DOI: 10.1200/JCO.2021.39.15_suppl.3011

Authors: Gang Hua, Xiaoxi Chen, Ruoying Yu, Hua Bao, Xue Wu and Yang Shao

Case StudyKirk SmithMay 6, 2021ALK, ctDNA

Phase separation of EML4–ALK in firing downstream signaling and promoting lung tumorigenesis

Using two genetically engineered mouse models (GEMMs), we find that EML4–ALK variant 1 can drive lung tumorigenesis and these murine tumors, as well as primary tumor-derived organoids, clearly show the condensates of EML4–ALK protein, further supporting the findings from in vitro study. Mutation of multiple aromatic residues in EML4 region significantly impairs the phase separation of EML4–ALK and dampens the activation of the downstream signaling pathways, especially the STAT3 phosphorylation. Importantly, it also significantly decreases cancer malignant transformation and tumor formation. These data together highlight an important role of phase separation in orchestrating EML4–ALK signaling and promoting tumorigenesis, which might provide new clues for the development of clinical therapeutic strategies in treating lung cancer patients with the EML4–ALK fusion. READ ARTICLE

Cell Discovery DOI: 10.1038/s41421-021-00270-5

Authors: Zhen Qin, Honghua Sun, Meiting Yue, Xinwen Pan, Liang Chen, Xinhua Feng, Xiumin Yan, Xueliang Zhu, Hongbin Ji

Pre-ClinicalKirk SmithMay 5, 2021EML4-ALK fusion, variant 1, STAT3