Lorlatinib Versus Pemetrexed-Based Chemotherapy in Patients With ALK-rearranged NSCLC Previously Treated With Alectinib

Among 90 patients who experienced disease progression during alectinib treatment, 38 of them received either PEM (n = 22) or LOR (n = 16) as subsequent treatment. The objective response rate and the median progression-free survival were similar in the PEM and LOR groups (objective response rate: 45% versus 44%, p = 0.92; median progression-free survival: 6.9 mo versus 6.2 mo, p = 0.83, respectively). Disease progression during treatment occurred in 22 patients with PEM and 14 patients with LOR. The central nervous system (CNS) was the most common site of progression in both groups. In patients without CNS metastasis at baseline, the cumulative incidence rate of CNS progression was lower over time in the LOR group compared with the PEM group (p = 0.045), whereas in patients with CNS metastasis at baseline, there were no significant differences in cumulative incidence rate of CNS progression between both groups (p = 0.43). READ ARTICLE

Journal of Thoracic Oncology DOI:https://doi.org/10.1016/j.jtocrr.2022.100311

Authors: Yuki Takeyasu, MD, Tatsuya Yoshida, MD, Ken Masuda, MD, Yuji Matsumoto, MD, Yuki Shinno, MD, Yusuke Okuma, MD, Yasushi Goto, MD, Hidehito Horinouchi, MD, Noboru Yamamoto, MD, Yuichiro Ohe, MD

Molecular Targetable Pathways—ALK

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase which becomes oncogenic and drives tumor growth in multiple tumor types, including non-small cell lung cancer (NSCLC). We discuss the pathophysiology of ALK in NSCLC, which is driven predominantly by ALK gene rearrangements. We review the various methods of molecular testing for ALK gene rearrangements in NSCLC, and their limitations.
Oral Tyrosine Kinase Inhibitors (TKIs) targeting the ALK pathway have been rapidly developed in the past 10 years. These drugs are well tolerated and offer prolonged disease control. We highlight the most up-to-date clinical data for each of the agents currently available which target the ALK pathway, and discuss adverse events associated with each agent. We discuss mechanisms of resistance to the ALK-targeted TKIs, and options for treatment at disease progression. READ ARTICLE

Encyclopedia of Respiratory Medicine (Second Edition) DOI:10.1016/B978-0-12-801238-3.11701-5

Authors: Maria Coakley, Sanjay Popat

Genetic landscape of patients with ALK-rearranged non–small-cell lung cancer (NSCLC) and response to ceritinib in ASCEND-1 study

NGS data were generated for 85 pts (ALKi-pretreated [n = 54]; ALKi-naïve [n = 31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients; several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib; with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment.
Of the 14 ALKi-naïve patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF amplificatio..... READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.11.007

Authors: D.S-W.Tana, M.Thomas, DW.Kim, S. Szpakowski, P. Urban, R. Mehra, L.Q.M. Chow, S. Sharma, B.J. Solomon, E.Felip, D.R. Camidge, J. Vansteenkiste, L. Petruzzelli, S. Pantano and A.T. Shaw

Coexistence of a novel NBEA-ALK, EML4-ALK double-fusion in a lung adenocarcinoma patient and response to alectinib: A case report

This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. Alectinib may be a viable therapeutic option for NSCLC patients with double-ALK fusion, and liquid biopsy could dynamically monitor clinical curative effect. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.10.015

Authors: Qi Liang, Huanhuan Xu, Yiqian Liu, Weiming Zhang, Chongqi Sun, Meng Hu, Yizhi Zhu, Shanyue Tan, Xian Xu, Sumeng Wang and Lingxiang Liu

Brigatinib Versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial

Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superi..... READ ARTICLE

Journal of Thoracic Oncology
DOI:10.1016/j.jtho.2021.07.035

Authors: D. Ross Camidge, Hye Ryun Kim, Myung-Ju Ahn, James C.H. Yang, Ji-Youn Han, Maximilian J. Hochmair, Ki Hyeong Lee, Angelo Delmonte, Maria Rosario, Garcia Campelo, Dong-Wan Kim, Frank Griesinger, Enriqueta Felip, Raffaele Califano, Alexander I. Spira, Scott N. Gettinger, Marcello Tiseo, Huamao M. Lin, Yuyin Liu, Florin Vranceanu, Huifeng Niu, Pingkuan Zhang and Sanjay Popat

Genetic landscape of patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and response to ceritinib in ASCEND-1 study

Objectives: To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥ 300 mg in the ASCEND-1 study. Conclusions: This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.11.007

Authors: D S-W Tan, M Thomas, D-W Kim, S Szpakowski, P Urban, R Mehra, L Q M Chow, S Sharma, B J Solomon, E Felip, D R Camidge, J Vansteenkiste, L Petruzzelli, S Pantano, A T Shaw

Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib

Fusion proteins of the anaplastic lymphoma kinase (ALK) are promising therapeutic targets for cancer and other human diseases, especially for non-small cell lung cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). We described herein a structure-based design, synthesis, and evaluation of ALK PROTACs (proteolysis-targeting chimeras) based on Alectinib as the warhead. We firstly screened CRBN ligands as the E3 ligase moiety, then obtained a series of potent ALK degraders based on different CRBN ligands, exemplified by SIAIS091 and SIAIS001 with lenalidomide/thalidomide-based linkers. Both of them induced effective ALK degradation at low nanomolar concentrations in cells, and showed much better growth inhibition effects than Alectinib. SIAIS091 or SIAIS001 also promoted cell cycle arrest in G1/S phase. Finally, SIAIS001 exhibited good oral bioavailability in Pharmacokinetics study. READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2021.113335

Authors: Chaowei Ren, Ning Sun, Ying Kong, Xiaojuan Qu, Haixia Liu, Hui Zhong, Xiaoling Song, Xiaobao Yang, Biao Jiang

Lorlatinib-induced visual and auditory hallucinations: A case report

Lorlatinib can cause visual and auditory hallucinations. And, it is necessary to keep in mind that hallucinations can persist even after discontinuation in patients who develop hallucinations while receiving lorlatinib. READ ARTICLE

Clinical Case Reports

Authors: Jun Hakamata, Hideo Nakada, Hiroshi Muramatsu, Keita Masuzawa, Hideki Terai, Shinnosuke Ikemura, Koichi Fukunaga, Tohru Aomori

306P Detection of anaplastic lymphoma kinase (ALK) mutations using circulating tumour DNA (ctDNA) in advanced non-squamous non-small cell lung cancer (non-Sq-NSCLC) in Asia

Background: ... We assessed clinical utility of ctDNA NGS for ALK testing for non-Sq-NSCLC in Asia... Conclusions: NGS testing for ALK fusions and genomic alterations in plasma ctDNA has clinical utility in non-Sq-NSCLC patients in guiding ALK targeted treatment at initial diagnosis and upon cancer progression. Detection rate and distribution of ALK fusion partners are comparable to existing data of tumor ALK testing. Further data on ALK treatment outcomes of patients with detectable ALK fusion on plasma ctDNA is warranted. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2020.10.300

Authors: K. W. C. Lee, S. T. Wu, P. Y. Lo, C. T. Choy, T. C. Kwong, Y. T. N. Lau, L. Lin, S. W. Lau

Real-World Treatment Patterns and Progression-Free Survival Associated with Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Inhibitor Therapies for ALK+ Non-Small Cell Lung Cancer

Median rwPFS in patients with advanced ALK+ NSCLC was < 8 months for first‐ and second‐line ALK TKI therapy and was even shorter in patients with brain metastasis, highlighting the need for more effective treatments in this patient population. Results presented herein describe real‐world treatment of advanced ALK+ NSCLC with ALK TKI therapies from January 2011 through June 2018. Crizotinib was the most commonly prescribed first‐line ALK TKI therapy in this patient population, but the majority of data analyzed were obtained prior to Food and Drug Administration approval of alectinib and ceritinib in the first‐line ALK TKI setting. Physicians should monitor patients closely to help identify when a change in treatment should occur. READ ARTICLE

The Oncologist DOI:10.1634/theoncologist.2020-0011

Authors: Mohammad Jahanzeb, Huamao M. Lin, Xiaoyun Pan, Yu Yin, Yanyu Wu, Beth Nordstrom, and Mark A. Socinski

Treatment Optimization for Brain Metastasis from Anaplastic Lymphoma Kinase Rearrangement Non-Small-Cell Lung Cancer

Background: Brain metastasis is common in non-small-cell lung cancer (NSCLC) with driver gene mutations. Anaplastic lymphoma kinase (ALK) gene rearrangement is one of the common driver mutations in NSCLC. Tyrosine kinase inhibitor (TKI) has been the research hotspot at present. However, there are relatively few studies specified on the treatment of brain metastasis from ALK gene rearrangement NSCLC. The prognosis of these patients, the role of ALK-TKI, and the proper combination model of ALK-TKI with radiotherapy are worth further exploring. This review focuses on new data on the prognosis of ALK-TKI and the proper combination model of ALK-TKI with radiotherapy. Key Messages: Next-generation ALK-TKIs are now replacing crizotinib as first-line treatment in ALKi-naïve ALK rearrangement NSCLC patients with brain metastasis, and they alone might have a strong efficacy against intracranial tumors in crizotinib-refractory situations in which occasion radiotherapy might be omitted. SRS and W..... READ ARTICLE

Oncology Research and Treatment DOI:10.1159/000502755

Authors: Wang W., Sun X., Hui Z.

Association of Programmed Death-Ligand 1 Expression with Fusion Variants and Clinical Outcomes in Patients with Anaplastic Lymphoma Kinase-Positive Lung Adenocarcinoma Receiving Crizotinib

Background: Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib. Conclusion: Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib. READ ARTICLE

The Oncologist DOI:10.1634/theoncologist.2020-0088

Authors: Yang CY, Liao WY, Ho CC, Chen KY, Tsai TH, Hsu CL, Liu YN, Su KY, Chang YL, Wu CT, Liao BC, Hsu CC, Hsu WH, Lee JH, Lin CC, Shih JY, Yang JC, Yu CJ.

Anaplastic lymphoma kinase (ALK) partners identified by next-generation sequencing in Chinese patients with solid tumors

Background: Anaplastic lymphoma kinase (ALK) rearrangement is a validated therapeutic driver gene in non-small cell lung cancer (NSCLC). More than 30 different fusion partner genes of ALK in NSCLC have been reportedand most of these ALK fusions respond well to ALK inhibitors crizotinib. With the development of next-generation sequencing (NGS), more novel partners for ALK rearrangement have been identified. Here, we aimed to report the landscape of ALK rearrangement in Chinese patients with solid tumors... Conclusions: Novel ALK fusions are detected in patients with not only NSCLC but also other solid tumors. NGS fusion assay is an optional method for screening novel fusions. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.3555

Authors: Sheng Yang, Fuyu Gong, Guoqiang Wang, Xiaohui He

3rd-line anaplastic lymphoma kinase (ALK) inhibitors (ALKi) in advanced non-small cell lung cancer (aNSCLC): Real-world comparison to non-ALKi therapy

Background: ALKi represent the standard 1st- and 2nd -line treatment (Tx) for ALK+ aNSCLC patients (pts). The value of ALKi in the 3rd-line setting is unclear. We retrospectively assessed the real-world impact of a 3rd -line ALKi vs. non-ALKi Tx in ALK+ aNSCLC pts... Conclusions: Following progression on a 2ndALKi, OS and TNT were numerically higher for pts receiving a 3rd ALKi, but statistically NS. Extensive exposure of pts in the non-ALKi Tx Gr to an ALKi at a later stage might have impacted these results. Further studies are required to identify patients likely to benefit from ALKi after progressing on 2 or more ALKi Tx lines. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.e21685

Authors: Natalie Maimon, Elizabeth Dudnik, Yakir Rottenberg, Noa Popovits-Hadari, Noam Asna, Mira Wollner, Alona Zer, Maya Gottfried, Moshe Mishaeli, Yulia Rovitsky-Gelis, Anastasiya Lobachov, Amir Onn, Damien Urban, Mor Tal Moskovitz, Jair Bar, Israel Lung Cancer Group

Association of Programmed Death‐Ligand 1 Expression with Fusion Variants and Clinical Outcomes in Patients with Anaplastic Lymphoma Kinase‐Positive Lung Adenocarcinoma Receiving Crizotinib

Background. Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)- positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiv- ing crizotinib.
Materials and Methods. PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments.
Results. A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants
were identified in 32 patients, and those with ..... READ ARTICLE

The Oncologist DOI:10.1634/theoncologist.2020-0088

Authors: CHING-YAO YANG, WEI-YU LIAO, CHAO-CHI HO, KUAN-YU CHEN, TZU-HSIU TSAI, CHIA-LIN HSU, YI-NAN LIU, KANG-YI SU, YIH-LEONG CHANG, CHEN-TU WU, BIN-CHI LIAO, CHIA-CHI HSU, WEI-HSUN HSU, JIH-HSIANG LEE, CHIA-CHI LIN, JIN-YUAN SHIH, JAMES CHIH-HSIN YANG, CHONG-JEN YU

Anaplastic Lymphoma Kinase Mutation–Positive Non–Small Cell Lung Cancer

KEY POINTS:
Non–small cell lung cancer with anaplastic lymphoma kinase (ALK) chromosomal rearrangement is
sensitive to treatment with tyrosine kinase inhibitors (TKIs).
Numerous TKIs have been developed in recent years, including alectinib, which is the current
preferred first-line agent for treatment-naı¨ve patients.
The development of resistance has led to next-generation ALK inhibitors that better penetrate the
central nervous system, which has improved the treatment of brain metastasis. READ ARTICLE

Thoracic Surgery Clinics DOI:10.1016/j.thorsurg.2019.12.001

Authors: Anthony V. Serritella, Christine M. Bestvina

Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced nonsmall cell lung cancer: a meta-analysis

The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non–small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments. Conclusions This meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced NSCLC. READ ARTICLE
BMC Cancer DOI:10.1186/s12885-020-06805-5

Authors: Kang Qin, Helei Hou, Yu Liang and Xiaochun Zhang

"Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non- small cell lung cancer: a meta-analysis "

Background: The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non–small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments.
Methods: Eligible studies were identified by searching the online databases PubMed, Embase, Medline, The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Results: In total, 15 studies wit..... READ ARTICLE

BMC Cancer DOI:10.1186/s12885-020-06805-5

Authors: Kang Qin, Helei Hou, Yu Liang and Xiaochun Zhang*

Next-generation sequencing to dynamically detect mechanisms of resistance to ALK inhibitors in ALK-positive NSCLC patients: a case report

Tyrosine kinase inhibitors (TKIs) of the anaplastic lymphoma kinase gene (ALK) have significantly improved the quality of life and survival of non-small cell lung cancer (NSCLC) patients whose tumors harbor an ALK translocation. However, most of these patients relapse within 2 to 3 years as the tumor acquires resistance mutations. Unlike beaming and digital PCR (dPCR), which only allow a few mutations to be analyzed, next-generation sequencing (NGS) approaches enable the simultaneous screening of multiple genetic alterations even when the frequencies of the variants are very low. We present the case of a 52-year-old man who was diagnosed with an ALK-positive NSCLC and was treated with crizotinib and, subsequently, ceritinib. The analysis of serial liquid biopsies by NGS detected two asynchronous mutations arising in the ALK locus during disease progression, namely p.Gly1269Ala (c.3806G>C) and p.Gly1202Arg (c.3604G>A), that conferred resistance to crizotinib and ceritinib, respectively...... READ ARTICLE

Translational Lung Cancer Research DOI:10.21037/tlcr.2020.02.07

Authors: Sánchez-Herrero E, Blanco Clemente M, Calvo V, Provencio M, Romero A.

Association of ALK rearrangement and risk of venous thromboembolism in patients with non-small cell lung cancer: A prospective cohort study

Background: Isolated reports are inconsistent regarding the risk of venous thromboembolism (VTE) in patients with anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC). This study examined whether ALK rearrangement could have an influence on VTE in a prospective cohort. Conclusions: The presence of ALK rearrangement is associated with increased risk of VTE in patients with NSCLC. READ ARTICLE

Thrombosis Research DOI:10.1016/j.thromres.2019.12.009

Authors: Feifei Dou, Yuan Zhang, Jiawen Yi, Min Zhu, Shu Zhang, Di Zhang, Yuhui Zhang