ALKtALK: Dr. Justin Gainor and Dr. Aaron Hata

Dr. Justin Gainor and Dr. Aaron Hata talk about their ALK Funded research and the ALCMI funded ENIGMA study. Followed by a question answer session. WATCH VIDEO

ALK Positive Inc.

Authors: Justin Gainor, Aaron Hata

VideoKirk SmithMarch 1, 2021ALKtALK

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

Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression.

These clinical and preclinical results indicate concomitant TP53 mutations reduce the efficacy of alectinib for ALK-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for ALK-rearranged/TP53-mutated NSCLC. READ ARTICLE

Clinical Cancer Research DOI: 10.1158/1078-0432.ccr-20-2853

Authors: Azusa Tanimoto, Shingo Matsumoto, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Akihiro Nishiyama, Kiyotaka Yoh, Takaya Ikeda, Naoki Furuya, Kazumi Nishino, Yuichiro Ohe, Koichi Goto and Seiji Yano

Review PaperKirk SmithMarch 1, 2021Review Papers

Efficacy of combination treatment using YHO-1701, an orally active STAT3 inhibitor, with molecular-targeted agents on cancer cell line

Investigation into efficacy of combination treatment using YHO-1701, an orally active STAT3 inhibitor, with molecular-targeted agents on cancer cell lines. Studied the contribution of YHO-1701 to enhance the antitumor properties of alectinib, YHO-1701 was combined with different doses of alectinib. The combination therapy of YHO-1701 with alectinib was found to be significantly effective against H2228 xenografts under both conditions, where the tumors remained larger and almost stable throughout the experimental period with alectinib monotherapy. This indicates that YHO-1701 offers an ideal and practical combination efficacy when used in combination with alectinib. Remarkably, in contrast with monotherapies, YHO-1701 plus alectinib diminished survivin levels in tumor tissues, suggesting that the superior antitumor activity of this combination is, at least partially, attributable to this downregulation. Regarding survivin, some studies have shown its potential characteristics as a usefu..... READ ARTICLE

Scientific reports DOI: 10.1038/s41598-021-86021-8

Authors: Keisuke Taniguchi, Hiroaki Konishi, Akiko Yoshinaga, Momomi Tsugane, Hiroyuki Takahashi, Fukiko Nishisaka, Yoshiyuki Shishido, Akira Asai

Pre-ClinicalKirk SmithMarch 1, 2021STAT3 inhibitor, combination treatment

Immunotherapy for ALK-Rearranged Non-Small Cell Lung Cancer: Challenges Inform Promising Approaches

Review Paper describing the mechanisms of ALK aberrations in non-small cell lung cancer by which an immunosuppressed tumor microenvironment is created, leading to host immune evasion. Reports pre-clinical and clinical studies evaluating novel immunotherapeutic approaches and describes the promises and challenges of incorporating immune-based treatments for ALK-rearranged non-small cell lung cancer. READ ARTICLE

Cancers DOI: 10.3390/cancers13061476

Authors: Kamya Sankar, Sunitha Nagrath, Nithya Ramnath

Review PaperKirk SmithMarch 1, 2021ALK, ALK-rearrangements, NSCLC, TKI, immune evasion, immunotherapy, cancer vaccine

Brigatinib After Progression From Alectinib or Crizotinib: Paving the Way for Treatment Sequencing of ALK Inhibitors in ALK-Positive NSCLC

Among the 47 Japanese patients who received brigatinib at the standard dose after progression from alectinib with or without history of crizotinib use, objective response rate (ORR) and disease control rate (DCR) were 34% (16 of 47) and 79% (37 of 47), respectively, with a median progression-free survival (PFS) of 7.3 months. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/J.JTHO.2020.11.023

Authors: Lianxi Song, Qinqin Xu, Analyn Lizaso, Yongchang Zhang,

EditorialKirk SmithMarch 1, 2021Alectinib progression, Crizotinib progression, Brigatinib

ALKtALK: Dr. Mark Awad and Dr. Roberto Chiarle at ALKtALK

Dr. Awad and Dr. Chiarle talk to the ALK Positive patient group about their research on the first in-human ALK positive Vaccine trial- funded in part by the ALK Positive patient group. SEE VIDEO

ALK Positive Inc.

Authors: Awad M., Chiarle R.

VideoKirk SmithMarch 1, 2021ALKtALK

Targeting a neoantigen derived from a common TP53 mutation

Like our ALK vaccine, this group had worked on a TP53 vaccine, using a similar technique Dr. Chairle described for ALK. TP53 (tumor protein p53) is the most commonly mutated cancer driver gene, but drugs that target mutant tumor suppressor genes, such as TP53, are not yet available. Here, we describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen–A (HLA-A) allele on the cell surface. We describe the structural basis of this specificity and its conversion into an immunotherapeutic agent: a bispecific single-chain diabody. Despite the extremely low p53 peptide-HLA complex density on the cancer cell surface, the bispecific antibody effectively activated T cells to lyse cancer cells that presented the neoantigen in vitro and in mice. This approach could in theory be used to target cancers containing mutations that are difficult to target..... READ ARTICLE

Science DOI: 10.1126/science.abc8697

Authors: Emily Han-Chung Hsiue, Katharine M. Wright, Jacqueline Douglass, Michael S. Hwang, Brian J. Mog, Alexander H. Pearlman, Suman Paul, Sarah R. DiNapoli, Maximilian F. Konig, Qing Wang, Annika Schaefer, Michelle S. Miller, D. Skora, P. Aitana Azurmend, Michael B. Murphy, Liu, Evangeline Watson, Yana Li, M. Pardoll, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein,Sandra B. Gabelli, Shibin Zhou

Pre-ClinicalKirk SmithMarch 1, 2021TP53, T cells

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

ALKtALK: Dr Upal Basu Roy at ALKtALK

ALKtALK 2/21/2021 with Dr. Upal Basu Roy. LUNGevity's Senior Director of Research speaks with ALK Positive patients and caregivers in an informal chat to help educate and empower patients living with ALK Positive Cancer. WATCH VIDEO

ALK Positive Inc

Authors: Upal Basu Roy

VideoKirk SmithFebruary 21, 2021

Discovery of a PROTAC targeting ALK with in vivo activity

Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. To overcome the drug resistance, proteolysis targeting chimeras (PROTACs) could be an alternative strategy. In this study, a series of ALK degraders were designed and synthesized. The degraders were developed through the conjugation of LDK378 and CRBN E3 ubiquitin ligase ligands. Among all the molecules, compound B3 showed potent selective inhibitory activity to ALK and can decrease the cellular levels of ALK fusion proteins in a concentration- and time-dependent manner in H3122 cell line. Meanwhile, B3 showed improved anticancer activity in vitro comparing with LDK378 and the antiproliferative activity to xenograft tumor model was acceptable. All the results demonstrated that ALK degrader B3 with in vitro and in vivo anti-cancer activities was valua..... READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2020.113150

Authors: Guoyi Yan, Xinxin Zhong, Lin Yue, Chunlan Pu, Huifang Shan, Suke Lan, Meng Zhou, Xueyan Hou, Jie Yang and Rui Li

Pre-ClinicalKirk SmithFebruary 15, 2021ALK, Degrader, Oral anticancer bioactivities, PROTAC

Strong ALK and PD-L1 positive IHC expression related ALK amplification in an advanced lung sarcomatoid carcinoma: A therapeutic trap?

We demonstrated that IHC positive test, in these cases, must be interpreted with caution. FISH analysis has to be recommended to confirm IHC results in case of unusual phenotype, such as smoker or lung cancer other than adenocarcinoma. Although lung carcinoma with ALK rearrangement seems to be not sensitive to ICI, further investigations should be conducted on other types of ALK molecular alterations. ALK amplifications, as observed in the present case, should not be an impediment to taking into account the PD-L1 marking for the initiation of treatment by immunotherapy. READ ARTICLE

Lung Cancer DOI: 10.1016/j.lungcan.2020.12.022.

Authors: Gendarme S, Matton L, Antoine M, Kerrou K, Ruppert AM, Epaud C, Cadranel J, Fallet V.

Case StudyKirk SmithFebruary 15, 2021ALK, Amplification, Immunotherapy, Lung cancer, Sarcomatoid

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.

Concurrent EGFR mutation and ALK rearrangement in stage IV lung adenocarcinoma-a case report and a literature review

EGFR mutation and ALK rearrangement were considered mutually exclusive mutations in non-small cell lung cancer. Upfront comprehensive mutation screening, like next-generation sequencing, enabled the discovery of simultaneous mutations. We describe a case of a woman with stage IV lung adenocarcinoma with 2 synchronous mutations at diagnosis, the EGFR p.(Leu858Arg) mutation, and an ALK rearrangement. The patient is on gefitinib for 16 months, maintaining this strategy currently. Co-occurrence of 2 targetable mutations is a particular challenge when choosing first-line treatment. We discuss the treatment options and results in patients with both mutations, which were generally associated with a poor prognosis in multiple studies comparing with one single mutation. READ ARTICLE

Porto Biomedecial Journal DOI: 10.1097/j.pbj.0000000000000124

Authors: Élia Cipriano, Helena Magalhães, Catarina Tavares, João Pinto, Luís Cirnes, Fernanda Estevinho

Case StudyKirk SmithFebruary 11, 2021ALK rearrangement, EGFR mutation, concurrent EGFR and ALK mutations, NSCLC

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

Outcomes According to ALK Status Determined by Central Immunohistochemistry or Fluorescence In Situ Hybridization in Patients With ALK-Positive NSCLC Enrolled in the Phase 3 ALEX Study

Introduction: We retrospectively examined progression-free survival (PFS) and response by ALK fluorescence in situ hybridization (FISH) status in patients with advanced ALK immunohistochemistry (IHC)-positive NSCLC in the ALEX study. Conclusions: Outcomes of patients with ALK IHC-positive and FISH-positive and ALK IHC-positive and FISH-uninformative NSCLC were similar to those of the overall ALEX population. These results suggest that Ventana ALK IHC is a standard testing method for selecting patients for treatment with alectinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.10.007

Authors: Tony Mok, Solange Peters, Ross Camidge, Johannes Noé, Shirish Gadgeel, Sai-Hong Ignatius Ou, Dong-Wan Kim, Krzysztof Konopa, Emanuela Pozzi, Ting Liu, Isabell R. Loftin, Crystal Williams, Alice T. Shaw

Clinical TrialsKirk SmithFebruary 1, 2021Alectinib, ALK-positive, IHC, FISH, NSCLC

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

Current Knowledge about Mechanisms of Drug Resistance against ALK Inhibitors in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer subtypes. Two to seven percent of NSCLC patients harbor gene rearrangements of the anaplastic lymphoma kinase (ALK) gene or, alternatively, harbor chromosomal fusions of ALK with echinoderm microtubule-associated protein-like 4 (EML4). The availability of tyrosine kinase inhibitors targeting ALK (ALK-TKIs) has significantly improved the progression-free and overall survival of NSCLC patients carrying the respective genetic aberrations. Yet, increasing evidence shows that primary or secondary resistance to ALK-inhibitors during the course of treatment represents a relevant clinical problem. This necessitates a switch to second- or third-generation ALK-TKIs and a close observation of NSCLC patients on ALK-TKIs during the course of treatment by repetitive molecular testing. With this review of the literature, we aim at providing an overview of current knowledge about resistance mechanisms to ALK-TKIs in NSCLC. READ ARTICLE

Cancers DOI: 10.3390/cancers13040699

Authors: Elisabeth Smolle, Valentin Taucher, Joerg Lindenmann, Philipp J. Jost, Martin Pichler

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