Hypoxia in Lung Cancer Management: A Translational Approach

Hypoxia is a common feature of lung cancers. Nonetheless, no guidelines have been established to integrate hypoxia-associated biomarkers in patient management. Here, we discuss the current knowledge and provide translational novel considerations regarding its clinical detection and targeting to improve the outcome of patients with non-small-cell lung carcinoma of all stages. READ ARTICLE

Cancers DOI: 10.3390/cancers13143421

Authors: Ancel J, Perotin J-M, Dewolf M, Launois C, Mulette P, Nawrocki-Raby B, Dalstein V, Gilles C, Deslée G, Polette M and Dormoy V.

Review Paper, group4Kirk SmithJuly 8, 2021NSCLC, hypoxia, HIF, angiogenesis, oxygen sensing, lung cancer management

Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibition agents

Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. Here we synthesized and evaluated sixteen new 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibitors. The optimal compound 9e exhibited excellent antiproliferative activity against non-small cell lung cancer NCI-H2228 cells, which is better than that of Brigatinib and similar to Ceritinib. Mechanism study revealed that the optimal compound 9e decreased the mitochondrial membrane potential and arrested NCI-H2228 cells in the G0/G1 phase, finally resulting in cellular apoptosis. It is interesting that 9e could effectively inhibit the migration of NCI-H2228 cells and may be a promising leading compound for chemotherapy of metastatic cancer. READ ARTICLE

Bioorganic & Medicinal Chemistry Letters DOI:10.1016/j.bmcl.2021.128253

Authors: Feng Wu, Han Yao, Wei Li, Niuniu Zhang, Yangyang Fan, Albert S.C. Chan, Xingshu Li, Baijiao An

Targeted therapy in advanced non-small cell lung cancer: current advances and future trends

Lung cancer remains the leading cause of cancer-related mortality in both men and women in the US and worldwide. Non-small cell lung cancer is the most common variety accounting for 84% of the cases. For a subset of patients with actionable mutations, targeted therapy continues to provide durable responses. Advances in molecular and immunohistochemical techniques have made it possible to usher lung cancer into the era of personalized medicine, with the patient getting individualized treatment based on these markers. This review summarizes the recent advances in advanced NSCLC targeted therapy, focusing on first-in-human and early phase I/II clinical trials in patients with advanced disease. We have divided our discussion into different topics based on these agents' mechanisms of action. This article is aimed to be the most current review of available and upcoming targeted NSCLC treatment options. We will also summarize the currently available phase I/II clinical trial for NSCLC patient..... READ ARTICLE

Journal of Hematology & Oncology DOI:10.1186/s13045-021-01121-2

Authors: Umair Majeed, Rami Manochakian, Yujie Zhao & Yanyan Lou

SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy

The screening of non-small cell lung cancer (NSCLC) tumors for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is important because of the dramatically favorable therapy response to ALK inhibitor. However, the exact mechanism of poor survival in ALK fusion lung cancer patients without receiving targeted therapy is unclear. In this study, total of 521 tumor specimens from Chinese patients with lung cancer were screened for ALK fusion by immunohistochemistry (IHC) and confirmed by fluorescence in situ hybridization (FISH). As results, there were no cases of coexisting EGFR and ALK mutations identified. Fourteen cases (2.7%) harbored ALK fusion, including eight solid adenocarcinomas with signet ring cell features, four acinar adenocarcinomas with cribriform pattern containing mucin, one adenosquamous carcinoma and one micropapillary adenocarcinoma with mucin. Six (42.9%) of fourteen patients with ALK-positive lung cancer had stage IV disease, and five ALK-positive patients treated with platinum-based chemotherapy had poor outcome (all patients were dead and the mean survival time was 12 months), compared to 72 months for patients with ALK inhibitor therapy. Furthermore, Five ALK-positive cases were analyzed by whole exome sequencing (WES) and via direct transcript counting using a digital probe-base (NanoString) to explore the driver genes. Deregulation of PI3K/AKT signaling pathway in ALK-positive lung cancer was demonstrated by WES analysis, and significantly increased mRNA of ALK, ROS1, MET, SPP1 and PI3K signaling pathway was identified by NanoString assay. The concordance between NanoString, IHC and FISH methodologies for detecting ALK fusion was 100%. Significant overexpression of SPP1 protein in ALK-positive lung cancer was confirmed by IHC compared to paired adjacent normal tissues and ALK-negative cancers. Thus we concluded that SPP1 overexpression is associated with poor outcomes for patients with ALK fusion lung cancer without receiving targeted therapy and PI3K/AKT/SPP1 pathway may become the promising targets in patients with aggressive lung cancer. READ ARTICLE

Scientific Reports DOI: 10.1038/s41598-021-93484-2

Authors: Xiaolin Ji, Yan Liu, Fang Mei, Xinyang Li, Mengxue Zhang, Buwen Yao, Rui Wu, Jiangfeng You and Fei Pei

Pre-Clinical, group4Kirk SmithJuly 7, 2021SSP1, outcome, PI3K/AKT

Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma

This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies. READ ARTICLE

ESMO Open DOI: 10.1016/j.esmoop.2021.100172

Authors: V. Subbiah, S. Kuravi, S. Ganguly, D.R. Welch, C.J. Vivian, M.U. Mushtaq, A. Hegde, S. Iyer, A. Behrang, S.M. Ali, R.W. Madison, J.M. Venstrom, R.A. Jensen, J.P. McGuirk, H.M. Amin and R. Balusu

SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy

The screening of non-small cell lung cancer (NSCLC) tumors for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is important because of the dramatically favorable therapy response to ALK inhibitor. However, the exact mechanism of poor survival in ALK fusion lung cancer patients without receiving targeted therapy is unclear. In this study, total of 521 tumor specimens from Chinese patients with lung cancer were screened for ALK fusion by immunohistochemistry (IHC) and confirmed by fluorescence in situ hybridization (FISH). As results, there were no cases of coexisting EGFR and ALK mutations identified. Fourteen cases (2.7%) harbored ALK fusion, including eight solid adenocarcinomas with signet ring cell features, four acinar adenocarcinomas with cribriform pattern containing mucin, one adenosquamous carcinoma and one micropapillary adenocarcinoma with mucin. Six (42.9%) of fourteen patients with ALK-positive lung cancer had stage IV disease, and five ALK-positive p..... READ ARTICLE

Scientific Reports DOI:10.1038/s41598-021-93484-2

Authors: Xiaolin Ji, Yan Liu, Fang Mei, Xinyang Li, Mengxue Zhang, Buwen Yao, Rui Wu, Jiangfeng You & Fei Pei

Pre-Clinical, group4Kirk SmithJuly 7, 2021SPP1, ALK, lung cancer, TKI, chemotherapy

An overview of alectinib hydrochloride as a treatment option for ALK positive non-small cell lung cancer

Introduction: Alectinib is a second-generation inhibitor of anaplastic lymphoma kinase (ALK) and RET. Phase III clinical trials have established its superiority to crizotinib in the first-line ALK inhibitor-naïve setting. Studies also support its use over chemotherapy in the post-crizotinib setting. It is currently one of several FDA- and EMA-approved ALK inhibitors, and it is listed as a preferred initial therapy for treatment-naïve ALK-positive non-small cell lung cancer (NSCLC).Areas covered: Herein, the authors provide the reader with details of the chemical structure, pharmacologic properties, resistance mutations, phase I, II, and III clinical trials, and safety profile of alectinib. Furthermore, the authors provide the reader with the expert opinion and future perspectives on the drug.Expert opinion: Alectinib compares favorably to other second-generation ALK inhibitors with regards to safety, tolerability, and efficacy. Based on currently available data, it is an appropriate first-line option. Ongoing studies will better resolve the ideal sequencing of ALK inhibitors in the treatment of ALK-positive NSCLC. READ ARTICLE

Expert Opinion on Pharmacotherapy DOI: 10.1080/14656566.2021.1948014

Authors: Schokrpur S, Hilburn V, Giustini N and Bazhenova L.

Detection of acquired resistance mutation ALK G1202R after treatment with alectinib and response of lorlatinib

In the era of personalized medicine, the identification of driver mutations has paved the way towards targeted therapy. With the identification of anaplastic lymphoma kinase (ALK) as an oncogenic driver mutation, ALK rearrangements became druggable by tyrosine kinase inhibitors and, thus, have improved the prognosis for patients. Nevertheless, these approaches are limited by resistances occurring within the first or second year of administering ALK inhibitors. Among the different ALK resistant mutations, G1202R is the most common mutation, located in the kinase domain of the ALK protein resulting in resistance to treatment with the first- and second-generation kinase inhibitors (e.g., crizotinib, ceritinib, brigatenib and alectinib). Conflicting reports exist regarding the efficacy of lorlatinib, a next generation ALK inhibitor. The aim of this study is to access the potential impact of lorlatinib as a second-line treatment for a metastatic progressive NSCLC disease harboring genomic a..... READ ARTICLE

Magazine of European Medical Oncology (memo) DOI:

Authors: Louisa Hempel, Jakob Molnar, Andreas Gaumann, Sebastian Robert, Josef Scheiber, Axel Kleespies, Kristina Riedmann, Susanne Schreiber, Beate Gandorfer, Armin Piehler & Dirk Hempel

Case Study, group4Kirk SmithJuly 6, 2021alectinib, ALK rearrangement, lorlatinib

Tumor shrinkage with Combination of Alectinib and Trastuzumab in a Patient with ALK-Rearranged NSCLC Harboring HER2-amplification as an Acquired Resistance Mechanism to ALK Inhibitor Therapy

HER2 amplification is an acquired resistance mechanism in ALK-rearranged non-small cell lung cancer. READ ARTICLE

Clinical Lung Cancer DOI: 10.1016/j.cllc.2021.06.012

Authors: David Chun Cheong Tsui, Dara Aisner, Hala Nijmeh, Liming Bao, Alexander Menter and Ross Camidge

Case Study, group4Kirk SmithJuly 3, 2021ALK, HER2, lung cancer, acquired resistance, trastuzumab

$Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)$

Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)

Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The ..... READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-20-4224

Authors: Jennifer H. Foster, Stephan D. Voss, David C. Hall, Charles G. Minard, Frank M. Balis, Keith Wilner, Stacey L. Berg, Elizabeth Fox, Peter C. Adamson, Susan M. Blaney, Brenda J. Weigel and Yael P. Mossé

Case Study, group4Kirk SmithJuly 1, 2021ALK, neuroblastoma, pediatric, crizotinib

Bonnie Addario shares with the ALK Positive community why we are better together and stronger together; a patient advocate point of view

Bonnie Addario shares with the ALK Positive community why we are better together and stronger together. SEE VIDEO

ALK Positive Inc.

Author: Bonnie Addario

Video, group4Kirk SmithJuly 1, 2021ALKtALK

Actionability of on-target ALK resistance mutations in patients with non-small cell lung cancer: local experience and review of the literature

ALK-fusion-positive NSCLC patients treated with ALK inhibitors frequently develop on-target resistance mutations. We provide clinical evidence for targeting these mutations with currently available inhibitors using a pooled population of 387 patients. The majority achieved clinical benefit, but the likelihood of clinical benefit differed for each mutation-inhibitor combination. Our comprehensive overview can facilitate guidance for treating similar patients in clinical practice. READ ARTICLE

Clinical Lung Cancer DOI: 10.1016/j.cllc.2021.06.011

Authors: Bart Koopman, Harry J.M. Groen, Ed Schuuring, T. Jeroen N. Hiltermann, Wim Timens, Wilfred F.A. den Dunnen, Anke van den Berg, Arja ter Elst, Michel van Kruchten, Joost L. Kluiver, Birgitta I. Hiddinga, Lucie B.M. Hijmering-Kappelle, Matthew R. Groves, Juliana F. Vilacha, Léon C. van Kempen and Anthonie J. van der Wekken

Review Paper, group4Kirk SmithJuly 1, 2021ALK, NSCLC, mutation, resistance, sensitivity

Local ablative therapies in oligometastatic NSCLC-upfront or outback?—a narrative review

Patients with oligometastatic (OM) non-small cell lung cancer (NSCLC) have favorable outcomes compared to patients presenting with diffuse metastatic disease. Recent randomized trials have demonstrated safety and efficacy signals for local ablative therapies with radiotherapy, surgery, or radiofrequency ablation for OM-NSCLC patients alongside systemic therapies. However, it remains unclear whether local ablative therapy (LAT) should be offered either upfront preceding systemic therapies or following initial systemic therapies as local consolidative therapy (LCT). Establishing optimal timing of RT and systemic therapy combinations is essential to maximize efficacy while maintaining safety. Most published randomized trial evidence surrounding the benefits of LAT and systemic therapies were generated from OM-NSCLC patients receiving cytotoxic chemotherapy agents. With increasing use of novel agents such as targeted therapies (i.e., tyrosine kinase inhibitors) and immune checkpoint inhibitors in management of metastatic NSCLC patients, LAT timing may need to be modulated based on the use of specific agents. This narrative review will discuss the current evidence on either upfront LAT or LCT for OM-NSCLC based on published trials and cohort studies. We briefly explored the possible biological mechanisms of the potential clinical advantages of either approach. This review also summarized the ongoing trials incorporating both upfront LAT and LCT, and considerations for future LAT strategies. READ ARTICLE

Translational Lung Cancer Research DOI:10.21037/tlcr-20-994

Authors: Tjong MC, Louie AV, Iyengar P, Solomon BJ, Palma DA, Siva S.

Successful rechallenge of alectinib after remission of severe alectinib-induced interstitial lung disease

Discussion: Given that the ALK inhibitors are the treatment of choice for advanced lung cancer patients with ALK rearrangement. Our report demonstrated the potential feasibility of alectinib re-use in cases of severe druginduced ILD. READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220961557

Authors: Huang JR, Chou CW, Chao HS.

group4Kirk SmithJuly 1, 2021

Abstract LB043: Efficacy of Lorlatinib in Treatment-Naïve Patients (pts) With ALK-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) in Relation to EML4-ALK Variant Type and ALK Mutations

Conference PaperKirk SmithJuly 1, 2021Lorlatinib, Treatment-Naïve Patients, ALK +, Non-Small Cell Lung Cancer (NSCLC), EML4-ALK Variants, https://cancerres.aacrjournals.org/content/81/13_Supplement/LB043.short

Abstract 1468: NUV-655 (NVL-655) is a selective, brain-penetrant ALK inhibitor with antitumor activity against the lorlatinib-resistant G1202R/L1196M compound mutation

ALK is a proto-oncogene that encodes the receptor tyrosine kinase ALK, which can be aberrantly activated by gene rearrangement or point mutation to drive tumor cell proliferation, survival, and metastasis. In advanced non-small cell lung cancer (NSCLC), ALK rearrangements are detected in about 4% of patients; at the time of diagnosis, 30% to 40% of these patients present with accompanying central nervous system (CNS) metastases. Brain-penetrant tyrosine kinase inhibitors (TKIs) alectinib, brigatinib, ceritinib, and lorlatinib are FDA-approved treatments for ALK-positive NSCLC; however, durability of response to these treatments has been limited in many cases by the emergence of mutations in ALK that confer resistance. A major resistance mutation to alectinib, brigatinib, and ceritinib is the ALK G1202R solvent front mutation. Although patients with tumors harboring the ALK G1202R mutation have responded to lorlatinib, many have subsequently relapsed by emergence of ALK compound mutatio..... READ ARTICLE

Cancer Research DOI:10.1158/1538-7445.AM2021-1468

Authors: Henry E. Pelish, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair and Joshua C. Horan

Clinical features and intervention timing in patients with pregnancy-associated non-small-cell lung cancer

Seventy-seven cases were collected including 11 patients from our center. The anaplastic lymphoma kinase (ALK) gene rearrangement and epidermal growth factor receptor (EGFR) mutation rates were 47% and 32%, respectively. The OS of patients treated during pregnancy, after delivery, and those not treated differed significantly [12 months vs. not reached (NR) vs. 1 month; P<0.001]. However, the OS between patients treated during pregnancy and after delivery was similar (P=0.173). Patients with ALK or EGFR exhibited a significantly better OS than those with wild-type [NR vs. 22 months vs. 8 months; P<0.001; hazard ratio (HR) =0.02, 95% confidence interval (CI): 0.00–0.22; HR =0.08, 95% CI: 0.01–0.76]. Fetal complications were observed in babies whose mothers were treated during pregnancy. The pregnancy-associated NSCLC population exhibited a high prevalence of driver genes and a promising effect of targeted therapy. No significant difference in the OS was observed between patients treated..... READ ARTICLE

Journal of Thoracic Disease DOI:10.21037/jtd-21-234

Authors: Lei Yang, Yun-Ting He, Jin Kang, Ming-Ying Zheng, Zhi-Hong Chen, Hong-Hong Yan, Xu-Chao Zhang, Jin-Ji Yang, Yi-Long Wu and Qing Zhou

Exceptional response to the ALK and ROS1 inhibitor lorlatinib and subsequent mechanism of resistance in relapsed ALK F1174L-mutated neuroblastoma

In summary, we describe a patient with relapsed, refractory neuroblastoma harboring the ALK F1174L mutation resistant to the first-generation ALK inhibitor crizotinib combined with chemotherapy in whom lorlatinib induced a durable complete remission of 13 mo. However, as is often the case with targeted therapeutic approaches, resistance, potentially mediated by new genomic alterations including CDK4 and FGFR1 amplification and NRAS mutation, led to disease recurrence. Our case provides an example of clinical benefit made possible by the development of next-generation ALK inhibitors but also highlights the need for increased understanding of mechanisms of acquired resistance. We propose that molecular monitoring during therapy may guide rational combination multidrug approaches to overcome and prevent resistance. READ ARTICLE

Cold Spring Harbor: Molecular Case Studies DOI:10.1101/mcs.a006064

Authors: Tingting Liu, Matthew D., Merguerian, Steven P. Rowe, Christine A. Pratilas, Allen R. Chen and Brian H. Ladle

Case Study, group4Kirk SmithJuly 1, 2021neuroblastoma, pediatric, ALK, lorlatinib, crizotinib combination

E273 Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration Screen reader support enabled.

Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in ~10%
of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor, which is aberrantly expressed in most
non-mutated cases, is unclear. Both WT and mutant proteins undergo extracellular domain (ECD) cleavage.
Here, we map the cleavage site to Asn654-Leu655 and demonstrate that cleavage inhibition of WT ALK significantly impedes NB cell migration with subsequent prolongation of survival in mouse models. Cleavage inhibition results in the downregulation of an epithelial-to-mesenchymal transition (EMT) gene signature, with decreased nuclear localization and occupancy of b-catenin at EMT gene promoters. We further show that
cleavage is mediated by matrix metalloproteinase 9, whose genetic and pharmacologic inactivation inhibits
cleavage and decreases NB cell migration. Together, our results indicate a pivotal role for WT ALK ECD cleavage in NB pathogenesis, which may be harnessed for therapeutic benefit. READ ARTICLE

Cell Reports DOI:10.1016/J.CELREP.2021.109363

Authors: Hao Huang, Alexander Gont, Lynn Kee, Ruben Dries, Kathrin Pfeifer, Bandana Sharma, David N. Debruyne, Matthew Harlow, Satyaki Sengupta, Jikui Guan, Caleb M. Yeung, Wenchao Wang, Bengt Hallberg, Ruth H. Palmer, Meredith S. Irwin, Rani E. George

$Case Report: Treatment of Alectinib in NSCLC With Brain Metastasis Patient Refractory to Radiotherapy After Resistance to Crizotinib$

Case Report: Treatment of Alectinib in NSCLC With Brain Metastasis Patient Refractory to Radiotherapy After Resistance to Crizotinib

This case revealed some new insights. First, liquid biopsy is complementary to tissue biopsy in patients with NSCLC, mainly in those with EGFR mutation. However, ALK rearrangement should be assessed using tissue biopsy as much as possible. Second, brain metastasis of NSCLC might respond to second-generation tyrosine kinase inhibitors (TKIs), such as alectinib and ceritinib, after resistance to crizotinib regardless of the presence or absence of ALK rearrangement in liquid biopsy. Finally, combined radiotherapy and TKI therapy appears optimal in patients with brain metastasis of NSCLC after resistance to crizotinib in the absence of a definitive driver gene. READ ARTICLE

Frontiers in Oncology DOI: 10.3389/fonc.2021.709188

Authors: Zhang Chunzhi

Case Study, group4Kirk SmithJune 28, 2021NSCLC, ALK+, radiotherapy