Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management

The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed treatment paradigm for patients with advanced-stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR-mutant and ALK-rearranged NSCLCs have been developed, culminating in the availability of the highly effective third-generation TKIs osimertinib and lorlatinib, respectively. Despite their marked efficacy, resistance to these agents remains an unsolved fundamental challenge. Both ‘on-target’ mechanisms (largely mediated by acquired resistance mutations in the kinase domains of EGFR or ALK) and ‘off-target’ mechanisms of resistance (mediated by non-target kinase alterations such as bypass signalling activation or phenotypic transformation) have been identified in patients with disease progression on osimertinib or lorlatinib. A growing understanding of the biology and spectrum of these mechanisms of resistance has already begun to inform the development of more effective therapeutic strategies. In this Review, we discuss the development of third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth-generation TKIs to combination regimens and other investigational therapies. READ ARTICLE

Nat Rev Clin Oncol DOI:10.1038/s41571-022-00639-9

Authors: Cooper, A.J., Sequist, L.V. & Lin, J.J.

GSK3 inhibition circumvents and overcomes acquired lorlatinib resistance in ALK-rearranged non-small-cell lung cancer

Anaplastic lymphoma kinase (ALK) fusion is found in ~3%–5% of patients with non-small-cell lung cancers (NSCLCs). Although the third-generation ALK tyrosine kinase inhibitor (TKI) lorlatinib shows high clinical efficacy in ALK-positive NSCLC, most of the patients eventually relapse with acquired resistance. Recently, drug-tolerant persister (DTP) cells have been considered an important seed of acquired resistance cells. In this study, we established lorlatinib intermediate resistant cells from a patient-derived cell model. Glycogen synthase kinase 3 (GSK3) inhibitions significantly suppressed lorlatinib intermediate resistant cell growth. GSK3 inhibition also sensitized acquired resistance cells derived from alectinib-treated patients with or without secondary mutations to lorlatinib. Therefore, GSK3 plays a crucial role in developing acquired resistance against lorlatinib in ALK-positive NSCLC mediated by lorlatinib intermediate resistant cells and could be a potential molecular target to prevent acquired lorlatinib resistance and overcome ALK-TKI resistance. READ ARTICLE

Precision Oncology DOI:10.1038/s41698-022-00260-0

Authors: JYuki Shimizu, Jun Adachi, Yuichi Abe, Ryohei Narumi, Ken Uchibori, Noriko Yanagitani, Sumie Koike, Satoshi Takagi, Makoto Nishio, Naoya Fujita and Ryohei Katayama

The impact of driver mutation on the treatment outcome of early-stage lung cancer patients receiving neoadjuvant immunotherapy and chemotherapy

Neoadjuvant immunotherapy and chemotherapy have improved the major pathological response (MPR) in patients with early-stage operable non-small cell lung cancer (NSCLC). This study aimed to assess whether the presence of targetable driver mutations affects the efficacy of the combination of immunotherapy and chemotherapy. We enrolled patients with early-stage operable NSCLC who received preoperative neoadjuvant therapy between January 1, 2017, and December 30, 2020. Neoadjuvant therapy was delivered with platinum-doublet chemotherapy; moreover, pembrolizumab was added at the attending physician's discretion based on patient's request. Pathological responses were assessed; moreover, disease-free survival was estimated. Next-generation sequencing was performed in case sufficient preoperative biopsy specimens were obtained. We included 23 patients; among them, 11 received a combination of neoadjuvant immunotherapy and chemotherapy while 12 received neoadjuvant chemotherapy alone. The MPR and pathological complete response rates were 54.5% and 27.3%, respectively, in patients who received a combination of neoadjuvant immunotherapy and chemotherapy. These rates were significantly higher than those in patients who only received neoadjuvant chemotherapy. Three patients in the combination group experienced disease recurrence during the follow-up period even though two of them showed an MPR. These three patients had targetable driver mutations, including an EGFR exon 20 insertion, EGFR exon 21 L858R substitution, and MET exon 14 skipping. Only one patient who remained disease-free had a targetable driver mutation. Among patients with early-stage operable NSCLC requiring neoadjuvant therapy, comprehensive genomic profiling is crucial before the administration of the combination of neoadjuvant immunotherapy and chemotherapy. READ ARTICLE

Scientific Reports DOI:10.1038/s41598-022-07423-w

Authors: Su PL, Chen JY, Chu CY, Chen YL, Chen WL, Lin KY, Ho CL, Tsai JS, Yang SC, Chen CW, Wu YL, Tseng YL, Chang CC, Yen YT, Lin CY, Lin CC, Su WC.

Real-World OutcomesKirk SmithFebruary 28, 2022Non-small-cell lung cancer, Cancer immunotherapy

HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK-TKIs alone, cotreatment with pan-HER inhibitor afatinib and ALK-TKIs prevented tumor regrowth, leading to the eradication of tumors in ALK-rearranged tumors with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor ALK-TKI treatment outcomes. These results demonstrated that HER3 activation plays a pivotal role in the emergence of ALK-TKI-tolerant cells. Furthermore, the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer with mesenchymal features. READ ARTICLE

Precision Oncology DOI:10.1038/s41698-021-00250-8

Authors: Keiko Tanimura, Tadaaki Yamada, Koutaroh Okada, Kunihiro Nakai, Mano Horinaka, Yuki Katayama, Kenji Morimoto, Yuri Ogura, Takayuki Takeda, Shinsuke Shiotsu, Kosuke Ichikawa, Satoshi Watanabe, Yoshie Morimoto, Masahiro Iwasaku, Yoshiko Kaneko, Junji Uchino, Hirokazu Taniguchi, Kazue Yoneda, Satoaki Matoba, Toshiyuki Sakai, Hisanori Uehara, Seiji Yano, Tetsuro Kusaba, Ryohei Katayama, Koichi Takayama

Pre-ClinicalKirk SmithJanuary 18, 2022Non-small-cell lung cancer, Translational research

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

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.

YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation

Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer. READ ARTICLE

Nature Communications DOI:10.1038/s41467-019-13771-5

Authors: Takahiro Tsuji, Hiroaki Ozasa, Wataru Aoki, Shunsuke Aburaya, Tomoko Yamamoto Funazo, Koh Furugaki, Yasushi Yoshimura, Masatoshi Yamazoe, Hitomi Ajimizu, Yuto Yasuda, Takashi Nomizo, Hironori Yoshida, Yuichi Sakamori, Hiroaki Wake, Mitsuyoshi Ueda, Young Hak Kim & Toyohiro Hirai

The clinical impact of family history of cancer in female never-smoker lung adenocarcinoma

Accumulating evidence reveals the association between the risk of never-smoker lung cancer and family history of cancer. However, the clinicogenomic effect of family history of cancer in never-smoker lung cancer remains unknown.We screened 3,241 lung cancer patients who (a) underwent curative resection at National Cancer Center (Goyang, Korea) between 2001–2014, and (b) completed a pre-designed interview about family/smoking history at the time of diagnosis and identified 604 female never smoker lung adenocarcinoma. A positive family history of cancer [categorized as pulmonary cancer (FH-PC) or non-pulmonary cancer (FH-NPC)] was defined as a self-reported history of cancer in first-degree relatives. Survival data were followed up until January 2017. Multiplexed targeted next-generation sequencing was performed for genetic profiling.The study found that the type of family history of cancer was associated with distinct clinocogenomic subtypes and prognosis of never-smoker lung adenocarcinoma. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.07.031

Authors: Youngjoo Lee, Jae Hyun Jeon, Sung-Ho Goh, Hanseong Roh, Ji-Young Yun, Nak-Jung Kwon, Jin Ho Choi, Hee Chul Yang, Moon Soo Kim, Jong Mog Lee, Geon Kook Lee, Ji-Youn Han

Case StudyKirk SmithJuly 31, 2019Never smoker, Non-small-cell lung cancer, Prognosis, Family history, EGFR, ALK