Comparative efficacy and safety of first-line treatments for advanced non-small cell lung cancer with ALK-rearranged: a meta-analysis of clinical trials

Background
Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC.

Methods
We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases.

Results
A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg an..... READ ARTICLE

BMC Cancer DOI:10.1186/s12885-021-08977-0

Authors: Ma HC, Liu YH, Ding KL, Liu YF, Zhao WJ, Zhu YJ, Chang XS, Chen YD, Xiao ZZ, Yu YY, Zhou R, Zhang HB.

Review Paper, group2Kirk SmithNovember 25, 2021ALK, NSCLC, First-line treatment, clinical trial meta-analysis

The impact of the ALK fusion variant on clinical outcomes in EML4-ALK patients with NSCLC: a systematic review and meta-analysis

Background: Recent studies showed that ALK-fusion variants are associated with heterogeneous clinical outcomes. However, contradictory conclusions have been drawn in other studies showing no correlation between ALK variants and prognoses. Methods: A systematic review and meta-analysis was performed to evaluate the prognostic value of EML4-ALK fusion variants for patient outcomes. Results: 28 studies were included in the analysis. According to the pooled results, patients harboring variant 1 showed equivalent progression-free survival (PFS) and overall survival (OS) with non-v1 patients (hazard ratio [HR] for PFS: 0.91 [0.68–1.21]; p = 0.499; OS: 1.12 [0.73–1.72]; p = 0.610). Similarly, patients with v3 showed the same disease progress as non-v3 patients (pooled HR for PFS = 1.07 [0.72–1.58]; p = 0.741). However, pooled results for OS suggested that patients with v3 had worse survival than non-v3 patients (HR = 3.44 [1.42–8.35]; p = 0.006). Conclusion: Results suggest that patients with..... READ ARTICLE

Future Oncology DOI:10.2217/fon-2021-0945

Authors: Wang S, Luo R, Shi Y, Han X.

Review Paper, group2Kirk SmithNovember 16, 2021ALK fusion, ALK rearrangement, ALK variant, NSCLC, prognosis

Multiscale profiling of enzyme activity in cancer

Diverse processes in cancer are mediated by enzymes, which most proximally exert their function through their activity. Methods to quantify enzyme activity, rather than just expression, are therefore critical to our ability to understand the pathological roles of enzymes in cancer and to harness this class of biomolecules as diagnostic and therapeutic targets. Here we present an integrated set of methods for measuring specific enzyme activities across the organism, tissue, and cellular levels, which we unify into a methodological hierarchy to facilitate biological discovery. We focus on proteases for method development and validate our approach through the study of tumor progression and treatment response in an autochthonous model of Alk-mutant lung cancer. To quantitatively measure activity dynamics over time, we engineered multiplexed, peptide-based nanosensors to query protease activity in vivo. Machine learning analysis of sensor measurements revealed dramatic protease dysregulatio..... READ ARTICLE

BioRxiv DOI:10.1101/2021.11.11.468288

Authors: Ava P. Soleimany, Jesse D. Kirkpatrick, Cathy S. Wang, Alex M. Jaeger, Susan Su, Santiago Naranjo, Qian Zhong, Christina M. Cabana, Tyler Jacks, Sangeeta N. Bhatia

Review Paper, group2Kirk SmithNovember 12, 2021Multiscale profiling, enzyme activity, cancer

New Advances in Liquid Biopsy Technologies for Anaplastic Lymphoma Kinase (ALK)—Positive Cancer

A new methodology of cancer testing, called “liquid biopsy”, has been under investigation in the past few years. It is based on blood tests that can be analyzed by novel genetics and bioinformatics tools, in order to detect cancer, predict or follow the response to therapies and understand the mechanisms of relapse. This technology is still experimental, yet it has sparked much interest within the scientific community because it promises a new era of cancer management. We here review its application in a subset of tumors characterized by the presence of the ALK oncogene: patients affected by these tumors can benefit from targeted therapy, but show frequent relapses, which call for improved methods of disease detection.
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Cancers DOI:10.3390/cancers13205149

Authors: Villa, Matteo, Geeta G. Sharma, Chiara Manfroni, Diego Cortinovis, and Luca Mologni

Review Paper, group2Kirk SmithOctober 14, 2021ALK, lung cancer, liquid biopsy

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.713530

Authors: Yue Pan, Chao Deng, Zhenhua Qiu, Chenghui Cao and Fang Wu

Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update

Neuroblastoma (NBL) is an embryonic malignancy of the sympathetic nervous system and mostly affects children under the age of five. NBL is highly heterogeneous and ranges from spontaneously regressing to highly aggressive disease. One of the risk factors for poor prognosis are aberrations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), which is involved in the normal development and function of the nervous system. ALK mutations lead to constitutive activation of ALK and its downstream signalling pathways, thus driving tumorigenesis. A wide range of steric ALK inhibitors has been synthesized, and several of these inhibitors are already in clinical use. Major challenges are acquired drug resistance to steric inhibitors and pathway evasion strategies of cancer cells upon targeted therapy. This review will give a comprehensive overview on ALK inhibitors in clinical use in high-risk NBL and on the potential and limitations of novel inhibitors. Because combinatory treatment..... READ ARTICLE

Pharmaceutics DOI:10.3390/pharmaceutics13091427

Authors: Annette K. Brenner and Maria W. Gunnes

Testing for EGFR Mutations and ALK Rearrangements in Advanced Non-Small-Cell Lung Cancer: Considerations for Countries in Emerging Markets

The treatment of patients with advanced non-small-cell lung cancer (NSCLC) in recent years has been increasingly guided by biomarker testing. Testing has centered on driver genetic alterations involving the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangements. The presence of these mutations is predictive of response to targeted therapies such as EGFR tyrosine kinase inhibitors (TKIs) and ALK TKIs. However, there are substantial challenges for the implementation of biomarker testing, particularly in emerging countries. Understanding the barriers to testing in NSCLC will be key to improving molecular testing rates worldwide and patient outcomes as a result. In this article, we review EGFR mutations and ALK rearrangements as predictive biomarkers for NSCLC, discuss a selection of appropriate tests and review the literature with respect to the global uptake of EGFR and ALK testing. To help improve testing rates and unify procedures, we review our exp..... READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S313669

Authors: Mercedes L Dalurzo, Alejandro Avilés-Salas, Fernando Augusto Soares, Yingyong Hou, Yuan Li, Anna Stroganova, Büge Öz, Arif Abdillah, Hui Wan and Yoon-La Choi

Detection of Multiple Types of Cancer Driver Mutations Using Targeted RNA Sequencing in NSCLC

Currently, DNA and RNA are used separately to capture different types of gene mutations. DNA is commonly used for the detection of SNVs, indels and CNVs; RNA is used for analysis of gene fusion and gene expression. To perform both DNA sequencing (DNA-seq) and RNA-seq, material is divided into two copies, and two different procedures are required for sequencing. Due to overconsumption of samples and experimental process complexity, it is necessary to create an experimental method capable of analyzing SNVs, indels, fusions and expression.We developed an RNA-based hybridization capture panel targeting actionable driver oncogenes in solid tumors and corresponding sample preparation and bioinformatics workflows. Analytical validation with an RNA standard reference containing 16 known fusion mutations and 6 SNV mutations demonstrated a detection specificity of 100.0% [95% CI 88.7%~100.0%] for SNVs and 100.0% [95% CI 95.4%~100.0%] for fusions. The targeted RNA panel achieved a 0.73-2.63 cop..... READ ARTICLEBioRxiv DOI:10.1101/2021.08.25.457723Authors: Sheng Ju, Zihan Cui, Yuayuan Hong, Xiaoqing Wang, Weina Mu, Zhuolin Xie, Xuexia Zeng, Lin Su, Qi Zhang, Xiaofeng Song, Songxia You, Ruixin Chen, Weizhi Chen, Xuchun, Jun Zhao

Review Paper, group3Kirk SmithAugust 26, 2021Cancer Driver Mutations, Targeted RNA Sequencing, NSCLC

Guidelines for clinical practice of ALK fusion detection in non-small-cell lung cancer: a proposal from the Chinese RATICAL study group

The presence of anaplastic lymphoma kinase (ALK) rearrangement defines a molecular subtype of non-small-cell lung cancer (NSCLC). ALK inhibitors (ALKIs) confer significant clinical benefits in patients with ALK-positive advanced NSCLC; therefore, it is of great clinical significance to select accurate, rapid, and appropriate ALK testing methods to screen for patients who are suitable for anti-ALK treatment. In recent years, great progress has been made in the development and clinical application of ALKIs, as well as in our understanding of acquired drug resistance mechanisms. Meanwhile, new ALK companion diagnostic platforms have been developed and applied in clinical practice. Although many studies have shown that there is a high rate of concordance among these platforms, new problems continue to appear during testing. To maximize the benefit for patients, accurate testing results can be obtained by first selecting the appropriate testing method and then formulating, optimizing, and c..... READ ARTICLE

Journal of the National Cancer Center DOI:10.1016/j.jncc.2021.07.005

Authors: Wenbin Li, Jing Zhang, Zhijie Wang, Lin Li, Jie Ma, Xiaoyang Zhou, Jie Wang, Zhiyong Liang, Jianming Ying,

Review Paper, group3Kirk SmithJuly 30, 2021ALK, Non-small-cell lung cancer, Detection method

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

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

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.

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.

Immunotherapy and Vaccination in Surgically Resectable Non-Small Cell Lung Cancer (NSCLC)

Early-stage NSCLC (stages I and II, and some IIIA diseases) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases, with surgery being its main treatment modality. The risk of disease recurrence and cancer-related death, however, remains high among NSCLC patients after complete surgical resection. In previous studies on the long-term follow-up of post-operative NSCLC, the results showed that the five-year survival rate was about 65% for stage IB and about 35% for stage IIIA diseases. Platinum-based chemotherapy with or without radiation therapy has been used as a neoadjuvant therapy or post-operative adjuvant therapy in NSCLC, but the improvement of survival is limited. Immune checkpoint inhibitors (ICIs) have effectively improved the 5-year survival of advanced NSCLC patients. Cancer vaccination has also been explored and used in the prevention of cancer or reducing disease recurrence in resected NSCLC. Here, we review studies that have focused on the use of immunotherapies (i.e., ICIs and vaccination) in surgically resectable NSCLC. We present the results of completed clinical trials that have used ICIs as neoadjuvant therapies in pre-operative NSCLC. Ongoing clinical trials investigating ICIs as neoadjuvant and adjuvant therapies are also summarized. READ ARTICLE

Vaccines DOI: 10.3390/vaccines9070689

Authors: Chiu L.-C., Lin S.-M., Lo Y.-L., Kuo S.C.-H., Yang C.-T. and Hsu P.-C.

New Insights into the Clinical Implications of Yes-Associated Protein in Lung Cancer: Roles in Drug Resistance, Tumor Immunity, Autophagy, and Organoid Development

Innovative advancements in lung cancer treatment have developed over the past decade with the advent of targeted and immune therapies. Yes-associated protein (YAP), an effector of the Hippo pathway, promotes the resistance of these targeted drugs and modulates tumor immunity in lung cancer. YAP is involved in autophagy in lung cancer and plays a prominent role in forming the tubular structure in lung organoids and alveolar differentiation. In this review, we discuss the central roles of YAP in lung cancer and present YAP as a novel target for treating resistance to targeted therapies and immunotherapies in lung cancer. READ ARTICLE

Cancers DOI: 10.3390/cancers13123069

Authors: Yoo G, Park D, Kim Y and Chung C.

Review Paper, group5Kirk SmithJune 17, 2021YAP, TAZ, Hippo pathway, lung cancer, drug resistance, EGFR-TKI, PD-L1, autophagy, organoid

Radiotherapy for Oligometastatic Non–Small Cell Lung Cancer: Past, Present, and Future

Historically, patients with stage IV non–small cell lung cancer (NSCLC) have been treated with chemotherapy alone, reserving local therapies for symptom palliation. However, evidence has accumulated that a subset of patients with oligometastatic NSCLC (OM-NSCLC) may benefit from local ablative therapies (LATs). In this article, we review the data that have formed the rationale for LAT, specifically radiotherapy, and the prospective trials that support its use in this population. Finally, we examine the evolving role of LAT in patients with OM-NSCLC in the context of immunotherapy and targeted therapies, as well as discuss ongoing clinical trials incorporating LAT in these patients. READ ARTICLE

ONCOLOGY DOI: 10.46883/onc.2021.3506.0311

Authors: Neal S. McCall and Kristin A. Higgins

Genomic and experimental evidence that alternate transcription initiation of the Anaplastic Lymphoma Kinase (ALK) kinase domain does not predict single agent sensitivity to ALK inhibitors

Genomic data can facilitate personalized treatment decisions by enabling therapeutic hypotheses in individual patients. Conditional selection, which includes mutual exclusivity, is a signal that has been empirically useful for identifying mutations that may be sensitive to single agent targeted therapies. However, a low mutation frequency can underpower this signal for rare variants and prevent robust conclusions from genomic data. We develop a resampling based method for the direct pairwise comparison of conditional selection between sets of gene pairs. This effectively creates positive control guideposts of mutual exclusivity in known driver genes that normalizes differences in mutation abundance. We applied this method to a transcript variant of anaplastic lymphoma kinase (ALK) in melanoma, termed ALKATI, which has been the subject of a recent controversy in the literature. We reproduced some of the original cell transformation experiments, performed rescue experiments, and analyzed..... READ ARTICLE

BioRxiv DOI:10.1101/696294

Authors: Haider Inam, Ivan Sokirniy, Yiyun Rao, Anushka Shah, Farnaz Naeemikia, Edward O’Brien, Cheng Dong, David McCandlish, Justin R Pritchard

Comparison of lorlatinib, alectinib and brigatinib in ALK inhibitor–naive/untreated ALK-positive advanced non-small-cell lung cancer: a systematic review and network meta-analysis

Because of lacking of head-to-head comparison among lorlatinib, alectinib and brigatinib for patients with ALK inhibitor–naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced non-small-cell lung cancer (NSCLC), the optimal option for these patients still remains undefined. We searched published reports that described the activity and safety of those novel ALK inhibitors (lorlatinib, alectinib and brigatinib) for ALK inhibitor–naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. Five randomized controlled trials were identified, covering 1111 subjects. In the network meta-analysis, lorlatinib seemed to prolong progression free survival than brigatinib (Hazard Ratio: 0.57, P = 0.03) and alectinib (Hazard ratio: 0.65, P = 0.05) for previously untreated patients with ALK-positive advanced NSCLC as assessed by the independent review committee. Meanwhile, lorlatinib significantly improved significant progression free sur..... READ ARTICLE

Journal of Chemotherapy DOI:10.1080/1120009X.2021.1937782

Authors: Lida Wang, Zhixin Sheng, Junying Zhang, Jiwu Song, Lili Teng, Liping Liu, Qianpeng Li, Baohong Wang, Bin Li

Review Paper, group5Kirk SmithJune 17, 2021Lorlatinib, alectinib, brigatinib, crizotinib, advanced NSCLC, meta-analysis

Lung Cancer Stem Cells—Origin, Diagnostic Techniques and Perspective for Therapies

Lung cancer is still a serious oncological problem worldwide. Thus, the biology of this cancer is of interest. Cancer stem cells (CSCs) are involved in tumor initiation and progression. Spontaneously occurring mutations accumulate in stem cells or/and progenitor cells throughout a person’s lifetime resulting in the formation of CSCs. In this review, we discuss the CSC hypothesis with an emphasis on age-associated changes that govern carcinogenesis. The evidence from the scientific literature, as well as our own results and observations, has been presented. READ ARTICLE

Cancers DOI: 10.3390/cancers13122996

Authors: Agata Raniszewska, Iwona Kwiecie, Elzbieta Rutkowska, Piotr Rzepecki and Joanna Domagała-Kulawik

Review Paper, group5Kirk SmithJune 15, 2021NSCLC, cancer stem cells, liquid biopsy, immunotherapy, aging, biopsy