Suitability of endobronchial ultrasound-guided transbronchial needle aspiration samples for programmed death ligand-1 testing in non-small cell lung cancer, the Bristol experience

To assess EBUS-TBNA biopsy adequacy for ALK, EGFR and PD-L1 testing, we conducted a prospective study of 279 consecutive NSCLC patients referred to a tertiary EBUS-TBNA centre in South West England. One hundred eight-four (62.6%) patients were found to have adenocarcinoma, 83 (28.2%) had squamous cell carcinoma, and 27 (9.2%) were identified as NSCLC-not otherwise specified. EGFR testing was successful in 166 of 168 patients (98.8%), ALK testing in all 115 and PD-L1 testing in 43 of 49 patients (88.2%). Previous EGFR and ALK testing did not affect biopsy PD-L1 testing success. PD-L1 testing failures occurred in three of five (60.0%) of 22G needle biopsies, one of five (20.0%) of 21G needle biopsies and two of 39 (5.1%) of 19G needle biopsies, P = .016. EBUS-TBNA biopsies are mostly suitable for PD-L1 testing. Larger needle size may improve PD-L1 (but not EGFR and ALK) testing success but requires further study in a controlled trial...... READ ARTICLE

Asia-Pacific Journal of Clinical Oncology DOI:10.1111/ajco.13549

Authors: Joanna Hardy, Nidhi Bhatt, Andrew R L Medford

Real-World OutcomesKirk SmithApril 18, 2021ALK p, ceritinib, resistance, lorlatinib, ALK, NSCLC, next generation sequencing, NGS

Adherence to National Comprehensive Cancer Network ALK Testing Guidelines for Patients with Advanced Non-Small Cell Lung Cancer in U.S. Community Medical Centers

Background: National Comprehensive Cancer Network (NCCN) guidelines recommend biomarker testing as the first step in the management of patients with advanced non-small cell lung cancer (aNSCLC). We assessed anaplastic lymphoma kinase (ALK) testing rates and factors related to underuse in community medical systems between 2012 and 2019 to understand guideline adoption. Conclusion: This analysis of real-world data shows increasing test use by year; however, one fifth of patients eligible for ALK testing still remain untested and potentially missing therapeutic options. READ ARTICLE

The Oncologist DOI:doi.org/10.1002/onco.13779

Authors: Eric H. Bernicker,Yan Xiao,Anup Abraham,Baiyu Yang,Denise A. Croix,Stella Redpath,Julia Engstrom-Melnyk,Roma Shah,Jaya Madala,Timothy C. Allen

Clinical Relevance of an Amplicon-Based Liquid Biopsy for Detecting ALK and ROS1 Fusion and Resistance Mutations in Patients With Non–Small-Cell Lung Cancer

PURPOSE Liquid biopsy specimen genomic profiling is integrated in non–small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for ALK/ROS1 alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with ALK/ROS1-positive NSCLC and its impact on outcomes. CONCLUSION Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of ALK/ROS1 fusions in TKI-naïve patients and allows for the identification of resistance mutations in patients treated with TKIs. Liquid biopsy specimens from patients treated with TKIs may affect clinical outcomes and capture heterogeneity of TKI resistance, supporting their role in selecting sequential therapy. READ ARTICLE

JCO Precision Oncology DOI:10.1200/PO.19.00281

Authors: Laura Mezquita, Aurélie Swalduz, Cécile Jovelet, Sandra Ortiz-Cuaran, Karen Howarth, David Planchard, Virginie Avrillon, Gonzalo Recondo, Solène Marteau, Jose Carlos Benitez, Frank De Kievit, Vincent Plagnol, Ludovic Lacroix, Luc Odier, Etienne Rouleau, Pierre Fournel, Caroline Caramella, Claire Tissot, Julien Adam, Samuel Woodhouse, Claudio Nicotra, Edouard Auclin, Jordi Remon, Clive Morris, Emma Green, Christophe Massard, Maurice Pérol, Luc Friboulet, Benjamin Besse, and Pierre Saintigny

Real-World OutcomesKirk SmithApril 2, 2021Next-generation sequencing, liquid biopsy, ALK, ROS1, resistance

Retrospective Real-World Outcomes for Patients With ALK-Rearranged Lung Cancer Receiving ALK Receptor Tyrosine Kinase Inhibitors

Clinical trials have firmly established that ALK TKIs are safe, well tolerated, and effective; these findings reveal that their impact in a real-world setting is just as profound. The availability and use of ALK TKI therapies contribute to the impressive gains in survival experienced by contemporary patients with ALK-rearranged disease, rendering patients with this oncodriven form of NSCLC among the longest surviving patients with lung cancer. READ ARTICLE

Journal of Thoracic Oncology, Clinical and Research Reports DOI:10.1016/j.jtocrr.2021.100157

Authors: Amanda J. W. Gibson, Adrian Box, Michelle L. Dean, Anifat A. Elegbede, Desiree Hao, Randeep Sangha, D. Gwyn Bebb

Real-World OutcomesKirk SmithApril 1, 2021ALK, NSCLC, Targeted therapy, adverse events

The landscape of ALK alterations in non-small cell lung cancer

Most ALK variants are described as VUS, limiting the
impact of precision oncology. ALK fusions occur in 2.6%% of the lung adenocarcinomas, with EML4 being the most common upstream partner.
Meanwhile, G1202R mutations occur only among 0.07% of the ALK alterations. Heat shock protein and Neuregulin-1 pathway may present additional opportunities for combination targeted therapies in the future for ALK-positive NSCLC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/S1556-0864(21)01863-3

Authors: A. Desai, T. Mohammed, S. Rakshit, J. Krull

Real-World OutcomesKirk SmithApril 1, 2021ALK variants

High discrepancy in thrombotic events in non-small cell lung cancer patients with different genomic alterations

NSCLC patients with ALK/ROS1 rearrangements are more likely to develop thrombosis than patients with other oncogenic alterations. Thrombosis may also be associated with an inferior response and PFS after TKI therapy. READ ARTICLE.

Translational Lung Cancer Research DOI: 10.21037/tlcr-20-1290

Authors: Yiwei Liu, Wanying Wang, Fengying Wu, Guanghui Gao, Jian Xu, Xuefei Li, Chao Zhao, Shuo Yang, Shiqi Mao, Yingying Pan, Keyi Jia, Chuchu Shao, Bin Chen, Shengxiang Ren, Caicun Zhou

Real-World OutcomesKirk SmithMarch 23, 2021

Feasibility and challenges for sequential treatment in ALK-rearranged non-small-cell lung cancer

Despite absence of regulatory obstacles and no requirement for specific acquired mutations, 25-30% of ALK+ NSCLC patients forego subsequent systemic therapy due to rapid clinical deterioration, in several cases (approximately 1/3) associated with an ineffective first next-line choice. These results underline the need for closer patient monitoring and broader profiling in order to support earlier and better directed use of available therapies. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.670483

Authors: Mei Elsayed, Farastuk Bozorgmehr, Daniel Kazdal, Anna-Lena Volckmar, Holger Sültmann, Jürgen Fischer, Mark Kriegsmann, Albrecht Stenzinger, Michael Thomas, Petros Christopoulos

Concomitant mutation status of ALK-rearranged non-small cell lung cancers and its prognostic impact on patients treated with crizotinib

The spectrum of ALK-fusion variants and the landscape of concomitant genomic alterations were delineated in 96 NSCLC patients. Our study also demonstrated the prognostic value of concomitant alterations in crizotinib-treated patients, which could facilitate improved stratification of ALK-rearranged NSCLC patients in the selection of candidates who could optimally benefit from therapy. READ ARTICLE

Translational Lung Cancer Research DOI:10.21037/tlcr-21-160

Authors: Jingjing Li, Bin Zhang, Yu Zhang, Feng Xu, Zhenfa Zhang, Lin Shao, Chunhe Yan, Paola Ulivi, Marc G Denis, Petros Christopoulos, Vincent Thomas de Montpréville, Eric H Bernicker, Anthonie J van der Wekken, Changli Wang, Dongsheng Yue

Phase II, Open-label, Single-arm, Multicenter Study to Assess the Activity and Safety of Alectinib as Neoadjuvant Treatment in Surgically Resectable Stage III ALK-positive NSCLC: ALNEO Trial

Patients with potentially resectable stage III ALK+ NSCLC (any T with N2, T4N0-1) will be registered to receive oral alectinib 600 mg twice daily for 2 cycles of 4 weeks each (8 weeks totally) during the neoadjuvant phase. After definitive surgery, patients will enter in the adjuvant setting, during which they will receive alectinib 600 mg twice daily for 24 cycles (96 weeks). The primary endpoint is MPR, defined as ≤10% residual viable tumor cells histologically detected in the resected primary tumor and all resected lymph nodes after surgery. Secondary endpoints include pathological complete response, objective response, event-free survival, disease-free survival, overall survival, adverse events. Our case report supports the feasibility of alectinib as neoadjuvant treatment. ALNEO study will further explore the activity and safety of this novel treatment strategy. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2021.02.014

Authors: Alessandro Leonetti, Roberta Minari, Luca Boni, Letizia Gnetti, Michela Verzè, LuigiVentura LucaMusini, Michele Tognetto and Marcello Tiseo

Rare coexistence of three novel CDCA7-ALK, FSIP2-ALK, ALK-ERLEC1 fusions in a lung adenocarcinoma patient who responded to Crizotinib

In some occasions, intergenic ALK fusions were identified, whereas one or both breakpoints localized in intergenic regions. However, whether intergenic fusions could retain full coding transcripts and generate chimeric proteins was not clear, causing difficulties in target therapy selection. READ ARTICLE

Lung Cancer DOI: 10.1016/j.lungcan.2020.12.013

Authors: Zhao G, Chen L, Xiao M, Yang S.

Real-World OutcomesKirk SmithFebruary 15, 2021coexistence of three ALK fusions, Crizotinib

Feasibility of next-generation sequencing test for patients with advanced NSCLC in clinical practice

he usefulness of the Oncomine Dx Target test (Oncomine Dx), a next‐generation sequencing (NGS) test, has already been proven in clinical trials. However, NGS requires high‐quality tumor samples and takes a long time to generate results. The usefulness of a next‐generation sequencing (NGS) test has been proven in clinical trials. The feasibility of NGS is lower than other diagnostics in clinical practice especially with regard to nonsurgical biopsy. It is necessary to improve the feasibility of NGS in clinical practice. To improve NGS feasibility, turnaround time must be shortened, and larger samples must be obtained during surgical procedures. READ ARTICLE

Thoracic Cancer DOI: 10.1111/1759-7714.13786

Authors: Ariyasu R, Uchibori K, Ninomiya H, Ogusu S, Tsugitomi R, Manabe R, Sakamaoto H, Tozuka T, Yoshida H, Amino Y, Kitazono S, Yanagitani N, Takeuchi K, Nishio M.

Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program

Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis. READ ARTICLE

Therapeutic advances in Medical Oncology DOI: 10.1177/1758835920980558

Authors: Nikolaj Frost, Petros Christopoulos, Diego Kauffmann-Guerrero, Jan Stratmann, Richard Riedel, Monica Schaefer, Jürgen Alt, Sylvia Gütz, Daniel C Christoph, Eckart Laack, Martin Faehling, Richard Fischer, Klaus Fenchel, Sebastian Haen, Lukas Heukamp, Christian Schulz and Frank Griesinger

Alectinib induces marked red cell spheroacanthocytosis in a near-ubiquitous fashion and is associated with reduced eosin-5-maleimide binding

We reviewed haematological investigations for 43 patients treated at a single centre with alectinib, an inhibitor of anaplastic lymphoma kinase (ALK) which is considered standard first-line treatment for patients with ALK-rearranged advanced non-small cell lung cancer. Ninety-five percent of patients developed marked acanthocytosis, echinocytosis and/or spheroacanthocytosis, not observable with prior treatment with other ALK-inhibitors. Anaemia developed in 73% of patients (38% <100 g/L, 8% <80 g/L), though definite new haemolysis was present in only 11%. Eosin-5-maleimide binding was reduced in all assessed patients, and increased membrane cholesterol was identified in one patient assessed with lattice light sheet microscopy. We have identified a previously undescribed phenomenon whereby alectinib induces red cell membrane abnormalities in nearly all patients through an unclear, but likely ALK-independent, mechanism, resulting in mild anaemia without universal haemolysis. READ ARTICLE

Pathology DOI: 10.1016/j.pathol.2020.10.023

Authors: James A. Kuzich, Sarah Heynemann, Niall Geoghegan, Cindy Evelyn, Susan O'Mahoney, Susan Wilson, Janine Campbell, Kelly Rogers, Benjamin Solomon, David Westerman, Sant-Rayn Pasricha

Real-World OutcomesKirk SmithFebruary 1, 2021alectinib, spherocytosis, acanthocytosis, eosin-5-maleimide

SPACEWALK: A Remote Participation Study of ALK Resistance Leveraging Plasma Cell-Free DNA Genotyping

Through the leveraging of remote participation, plasma NGS offers an optimal mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations, though sensitivity depends on adequate tumor DNA samples. Repeat cfDNA analysis on therapy may offer an objective monitoring approach to remotely study treatment response. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtocrr.2021.100151

Authors: Marissa N. Lawrence, Rubii M. Tamen, Pablo Martinez, Alicia Sable-Hunt, Tony Addario, Pete Barbour, Tristan Shaffer, Seyed Ali Hosseini, Caterina Bertucci, Lee P. Lim, Fangxin Hong, Kesi Michael, George R. Simon, Jonathan W. Riess, Mark M. Awad, Geoffrey R. Oxnard

Real-World OutcomesKirk SmithFebruary 1, 2021ALK, Drug resistance, Plasma NGS, Remote participation

Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program

We report on the results of the German early access program (EAP) with the
third-generation ALK- and ROS1-inhibitor lorlatinib. Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis. READ ARTICLE

Therapeutic advances in Medical Oncology DOI: 10.1177/1758835920980558

Authors: Nikolaj Frost, Petros Christopoulos, Diego Kauffmann-Guerrero, Jan Stratmann, Richard Riedel, Monica Schaefer, Jürgen Alt, Sylvia Gütz, Daniel C. Christoph, Eckart Laack, Martin Faehling, Richard Fischer, Klaus Fenchel, Sebastian Haen, Lukas Heukamp, Christian Schulz, Frank Griesinger

Real-World OutcomesKirk SmithFebruary 1, 2021ALK, brain metastases, early access program, NSCLC, ROS1, TP53, lorlatinib

Out-of-Pocket Costs for Tyrosine Kinase Inhibitors and Patient Outcomes in EGFR- and ALK-Positive Advanced Non–Small-Cell Lung Cancer

Among patients with advanced EGFR- and ALK-positive NSCLC, higher TKI Out-Of-Pocket costs are associated with decreased TKI adherence, a higher likelihood of TKI discontinuation, and inferior survival. READ ARTICLE

Journal of Clinical Oncology: Oncology Practice DOI: 10.1200/OP.20.00692 JCO

Authors: Bernardo H.L. Goulart, Joseph M. Unger, Shasank Chennupati, Catherine R. Fedorenko, Scott D. Ramsey

Real-World OutcomesKirk SmithFebruary 1, 2021Cost, TKI, Patient Outcomes, EGFR, ALK, Advanced NSCLC

Real-world adherence and persistence with anaplastic lymphoma kinase inhibitors in nonsmall cell lung cancer

Several anaplastic lymphoma kinase (ALK) inhibitors have been approved for the treatment of metastatic ALK-positive nonsmall cell lung cancer (NSCLC), including alectinib, crizotinib, brigatinib, ceritinib, and lorlatinib. While efficacy and safety are well documented, real-world data on the use of ALK inhibitors are currently limited. In this pooled analysis of 3 US insurance claims databases, alectinib was associated with longer real-world persistence than other ALK inhibitors, despite similar adherence. This is the first study to assess adherence and persistence with ALK inhibitors for the treatment of patients with ALK-positive NSCLC in real-world clinical practice. READ ARTICLE

Journal of Managed Care and Specialty Pharmacy DOI:10.18553/jmcp.2021.21310

Authors: Apar Kishor Ganti, Chia-Wei Lin, Erru Yang, William B Wong, and Sarika Ogale

Real-World OutcomesKirk SmithJanuary 12, 2021ALK inhibitors, adherence, persistence

Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients

Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms. READ ARTICLE

Journal of Cancer Research and Clinical Oncology DOI:10.1007/s00432-020-03476-4

Authors: Xin, S., Fang, W., Li, J. et al.

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

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

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

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

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

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

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

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

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