Pemetrexed is currently mainly considered for the treatment of advanced nonsquamous non-small-cell lung cancer (NSCLC) negative for gene mutations/rearrangements (wild-type disease (WTD)). This narrative review aimed to highlight the role of pemetrexed in the treatment of onco-driven nonsquamous advanced NSCLC by reviewing published clinical studies. For epidermal growth factor receptor (EGFR) mutations, patient survival following first-line pemetrexed–platinum was longer than for WTD. Later-line pemetrexed-based treatment after tyrosine kinase inhibitor (TKI) failure provided greater benefits than non-pemetrexed regimens. First- and later-line pemetrexed-based therapy also provided survival benefits in patients with anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearrangements. In patients with rearranged during transfection (RET) proto-oncogene rearrangements, survival with pemetrexed was similar to that in ALK- and ROS1-positive patients and longer than that in pati..... READ ARTICLE
Cancers DOI:10.3390/cancers12092658
Authors: Jin-Yuan Shih, Akira Inoue, Rebecca Cheng, Rocio Varea, Sang-We Kim
To our knowledge, this is the first description of an STRN-ALK fusion(+) MPM sequentially treated with two different ALK inhibitors. This case underlines the benefit of molecular testing in MPM. Furthermore, it suggests the generalizability of the lessons learned from lung cancer to another entity, which can offer some guidance in the treatment of this rare disease. READ ARTICLE
Journal of Clinical Oncology: Precision Oncology DOI:10.1200/PO.21.00184
Authors: Valeria Gerthofer, Alexander Scheiter, Florian Lüke, Felix Keil, Kirsten Utpatel, Laura-Maria-Giovanna
Pöhmerer, Johannes Seitz, Christoph Niessen, Atanas Ignatov, Wolfgang Dietmaier, Diego F. Calvisi, Matthias Evert, Olaf Ortmann, and Stephan Seitz
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
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
Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a cur..... READ ARTICLE
Pharmaceuticals DOI: 10.3390/ph14020080
Authors: Elsayed M., Christopoulos P.
Read MoreTherapeutic Strategies to Overcome ALK Resistance in Cancer, Volume 13, presents current strategies to improve and prolong clinical benefit in ALK driven cancers. Most patients with ALK-driven cancer are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops. This book discusses topics such as structure and function of ALK, ALK rearranged lung cancer, resistance mechanisms to ALK TKI tumors, and novel therapeutic strategies to enhance crizotinib anti-tumor efficacy in ALCL. Additionally, it encompasses information on drug combinations to enhance ALK TKI anti-tumor efficacy in neuroblastoma and future perspectives in the field. This book is a valuable resource for cancer researchers, clinicians and several members of biomedical field who need to understand more about how to fight ALK resistance in cancer treatment. READ ARTICLE
Academic Press DOI: 10.1016/C2019-0-03295-5
Edited by: Luc Friboulet
Read MoreInitially discovered in anaplastic large cell lymphoma (ALCL), the ALK anaplastic lymphoma kinase is a tyrosine kinase which is affected in lymphomas by oncogenic translocations, mainly NPM-ALK. To date, chemotherapy remains a viable option in ALCL patients with ALK translocations as it leads to remission rates of approximately 80%. However, the remaining patients do not respond to chemotherapy and some patients have drug-resistant relapses. It is therefore crucial to identify new and better treatment options. Nowadays, different classes of ALK tyrosine kinase inhibitors (TKI) are available and used exclusively for EML4-ALK (+) lung cancers. In fact, the significant toxicities of most ALK inhibitors explain the delay in their use in ALCL patients, who are predominantly children. Moreover, some ALCL patients do not respond to Crizotinib, the first generation TKI, or develop an acquired resistance months following an initial response. Combination therapy with ALK inhibitors in ALCL is th..... READ ARTICLE
Cancers (Basel) DOI:10.3390/cancers13010144
Authors: Elissa Andraos, Joséphine Dignac, Fabienne Meggetto
In both cases, conventional chemotherapy was proven lifesaving for the patients, which enabled them to receive subsequent-line targeted therapy and led to meaningful prolonged survival and an excellent quality of life that they continue to enjoy. The option of chemotherapy, even in this revolutionized era of precision medicine, should not be undermined. Chemotherapy continues to play a vital role in decreasing cancer burden and making this cancer salvageable in appropriately selected patients. READ ARTICLE
JCO Precision Oncology DOI: http://doi.org/10.1200/JCO.20.00505
Authors: Kunal Gawri, Richa Dawar, Kayla Haines, Mohammad Jahanzeb
Read MoreAnaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer most commonly arises through EML4-ALK chromosomal fusion. We have previously demonstrated that combination of the ALK inhibitor crizotinib with the MEK inhibitor selumetinib was highly effective at reducing cell viability of ALK-positive NSCLC (H3122) cells. In this study, we further investigated the efficacy of crizotinib and selumetinib combination therapy in an in vivo xenograft model of ALK-positive lung cancer. Crizotinib decreased tumor volume by 52% compared to control, and the drug combination reduced tumor growth compared to crizotinib. In addition, MEK inhibition alone reduced tumor growth by 59% compared to control. Crizotinib, selumetinib, alone and in combination were non-toxic at the dose of 25 mg/kg with values for ALT (< 80 U/L) and creatinine (<2 mg/dL) within the normal range. Our results support the combined use of crizotinib with selumetinib in ALK-positive lung cancer but raise the possibility tha..... READ ARTICLE
Journal of Pharmacology and Experimental Therapeutics DOI:10.1124/jpet.120.266049
Authors: Nensi Shrestha, Abigail R Bland, Rebecca L Bower, Rhonda Rosengren, John Ashton
Lung cancer is a common cancer associated with high mortality rates worldwide. Unfortunately, it usually presents at a late stage, precluding the chance of curative therapy. The discovery of oncogenic driver mutations in patients with non-small cell lung cancer over the past 20 years has led to new molecular targeted therapies that have dramatically improved treatment efficacy and quality of life. New generations of therapy that target the drug-resistant mutations have also quickly evolved, benefiting patients who are refractory or intolerant to first-line targeted therapy. Eastern patients, from Southeast Asia, Japan and China, are known to have a higher incidence of epidermal growth factor receptor mutation. Therefore, compared with the West, more patients would benefit from these recent advances. In contrast, survival of patients without driver mutations has benefited from advances in novel therapeutics, including the immune checkpoint inhibitors. The current review aims to highligh..... READ ARTICLE
Clinical Oncology DOI:10.1016/j.clon.2019.07.014
Authors: V. H. F. Lee, T. S. K. Mok, Y. Goto, V. C. C. Hsue, L. Yang, Y. Jiang, D. K. C. Leung, K. S. Lau, P. Y. Tse
Primary signet ring cell carcinoma of the lung is a rare non-small cell carcinoma of the lung with extremely aggressive features and poor prognosis. The diagnosis mainly required tissue biopsy with immunohistochemical analysis and gene mutation studies. We describe a unique case of primary signet ring cell carcinoma of the lung presenting with life threatening haemoptysis along with literature review of prognosis and management of this rare clinical entity. READ ARTICLE
Respiratory Medicine Case Reports DOI:10.1016/j.rmcr.2020.101195
Authors: Shamsuddin Anwar, Sudeep Acharya, Dany Elsayegh, Alisa Sokoloff, Maryam Rehan
The ALUR (NCT02604342) primary analysis (cut-off January 2017) demonstrated improved efficacy and safety with alectinib versus chemotherapy in patients with ALK+ NSCLC previously treated with chemotherapy and crizotinib. These patients can develop crizotinib resistance through ALK secondary mutations, but limited data exist regarding alectinib’s efficacy in patients with different post-crizotinib genetic profiles. We report final data from ALUR including treatment outcomes according to genetic profile. Overall, 119 patients with locally determined ALK+ NSCLC were randomised 2:1 to receive alectinib 600mg bid or chemotherapy (pemetrexed 500mg/m2 or docetaxel 75mg/m2 q3w). The primary endpoint was PFS by investigator. Targeted genomic sequencing (FoundationONE® [tissue; 315 genes] and FoundationACT® [plasma; 62 genes]) was performed retrospectively using tumour tissue (n=33) and baseline plasma (n=59). Final data from ALUR confirm the primary analysis, demonstrating improved efficacy and..... READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.416
Authors: J. Wolf, Å. Helland, I. Oh, M.R. Migliorino, R. Dziadziuszko, J. De Castro Carpeno, J. Mazieres, F. Griesinger, M. Chlistalla, A. Cardona, T. Ruf, K. Trunzer, V. Smoljanovic, S. Novello
Aim: Using the available literature, this meta-analysis aimed to compare reports of the incidence of grade 3–4 neutropenia with ALK inhibitors and chemotherapy in patients with ALK-positive NSCLC. Conclusion: This meta-analysis of Phase III randomized clinical trials found no significant difference in the incidence of grade 3–4 neutropenia among patients with ALK-positive NSCLC treated with either an ALK inhibitor or chemotherapy, and this was not affected by adjusting for baseline tumor stage. READ ARTICLE
FUTURE ONCOLOGY
DOI:10.2217/fon-2018-0863
Authors: Bernardo Rapoport, Ramin B Arani, Nicola Mathieson, Andriy Krendyukov