Will the clinical development of 4th-generation “double mutant active” ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?

Ou, Sai‐Hong Ignatius; Nagasaka, Misako; Brazel, Danielle; Hou, Yujie; Zhu, Viola W.

doi:10.1016/j.tranon.2021.101191

Cited by 28 publications

(19 citation statements)

References 52 publications

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“…While second- and third-generation ALK inhibitors helped to overcome single mutation ALK resistance, double mutant ALK resistance seems inevitable [ 194 ]. Fourth-generation ALK TKIs are being developed that target double ALK-resistant mutations to help overcome drug resistance.…”

Section: Targeted Therapy Resistance In Lung Cancer and Overcoming St...mentioning

confidence: 99%

“…Fourth-generation ALK TKIs are being developed that target double ALK-resistant mutations to help overcome drug resistance. Even so, double and triple mutation may develop against 4G ALK TKIs, but would still likely achieve a minimum of 35–40 months of PFS [ 194 ]. Off-target resistance mechanisms such as EGFR TKIs, including parallel bypass mechanisms such as MET amplification or RET rearrangement, or downstream signaling pathways such as BRAF fusions and MAP2K1 mutations, among several others, may occur [ 195 ].…”

Section: Targeted Therapy Resistance In Lung Cancer and Overcoming St...mentioning

confidence: 99%

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Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

Ashrafi

Akter

Modareszadeh

et al. 2022

Cancers

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Lung cancer is one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 18%. Current treatment modalities include surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Despite advances in therapeutic options, resistance to therapy remains a major obstacle to the effectiveness of long-term treatment, eventually leading to therapeutic insensitivity, poor progression-free survival, and disease relapse. Resistance mechanisms stem from genetic mutations and/or epigenetic changes, unregulated drug efflux, tumor hypoxia, alterations in the tumor microenvironment, and several other cellular and molecular alterations. A better understanding of these mechanisms is crucial for targeting factors involved in therapeutic resistance, establishing novel antitumor targets, and developing therapeutic strategies to resensitize cancer cells towards treatment. In this review, we summarize diverse mechanisms driving resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy, and promising strategies to help overcome this therapeutic resistance.

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Section: Targeted Therapy Resistance In Lung Cancer and Overcoming St...mentioning

confidence: 99%

Section: Targeted Therapy Resistance In Lung Cancer and Overcoming St...mentioning

confidence: 99%

Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

Ashrafi

Akter

Modareszadeh

et al. 2022

Cancers

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“…The fourth-generation ALK-TKIs are currently considered the most promising treatment for compound ALK mutation. Two fourth-generation ALK TKIs (TPX-0131 and NVL-655) are under development [ 88 , 89 , 90 , 91 ]. Both TPX-0131 and NVL-655 can inhibit acquired compound ALK mutations in addition to a wide spectrum of single ALK mutations.…”

Section: Mechanism Of Resistance Against Alk-tkimentioning

confidence: 99%

Review of Therapeutic Strategies for Anaplastic Lymphoma Kinase-Rearranged Non-Small Cell Lung Cancer

Fukui

Tachihara

Nagano

et al. 2022

Cancers

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Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase rearrangement (ALK) was first reported in 2007. ALK-rearranged NSCLC accounts for about 3–8% of NSCLC. The first-line therapy for ALK-rearranged advanced NSCLC is tyrosine kinase inhibitors (TKI) targeting ALK. Following the development of crizotinib, the first ALK-TKI, patient prognosis has been greatly improved. Currently, five TKIs are approved by the FDA. In addition, clinical trials of the novel TKI, ensartinib, and fourth-generation ALK-TKI for compound ALK mutation are ongoing. Treatment with angiogenesis inhibitors and immune checkpoint inhibitors is also being studied. However, as the disease progresses, cancers tend to develop resistance mechanisms. In addition to ALK mutations, other mechanisms, including the activation of bypass signaling pathways and histological transformation, cause resistance, and the identification of these mechanisms is important in selecting subsequent therapy. Studies on tissue and liquid biopsy have been reported and are expected to be useful tools for identifying resistance mechanisms. The purpose of this manuscript is to provide information on the recent clinical trials of ALK-TKIs, angiogenesis inhibitors, immune checkpoint inhibitors, and chemotherapy to describe tissue and liquid biopsy as a method to investigate the mechanisms of resistance against ALK-TKIs and suggest a proposed treatment algorithm.

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“… 51 Fourth-generation ALK inhibitors are being developed to retain activity against compound ALK -resistance mutations. 52 Different fusion variants may also shape sensitivity to ALK TKIs and the emergence of ALK -resistance mutations. 53 – 56 …”

Section: Alk -Rearranged Nsclcmentioning

confidence: 99%

Non-small-cell lung cancer: how to manage ALK-, ROS1- and NTRK-rearranged disease

Marinelli¹,

Siringo²,

Metro³

et al. 2022

DIC

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Oncogene addiction in non-small-cell lung cancer (NSCLC) has profound diagnostic and therapeutic implications. ALK , ROS1 and NTRK rearrangements are found in about 2–7%, 1–2% and 0.2% of unselected NSCLC samples, respectively; however, their frequency is markedly higher in younger and never-smoker patients with adenocarcinoma histology. Moreover, ALK , ROS1 and NTRK rearrangements are often mutually exclusive with other known driver alterations in NSCLC. Due to such a low frequency, diagnostic screening with accurate and inexpensive techniques such as immunohistochemistry is useful to identify positive cases; however, confirmation with fluorescent in situ hybridization or next-generation sequencing is often required due to higher specificity. In ALK -rearranged NSCLC, sequential treatment with second-generation and third-generation tyrosine kinase inhibitors leads to long-lasting disease control with most patients surviving beyond 5 years with metastatic disease. In ROS1 -rearranged NSCLC, first-line treatment with crizotinib or entrectinib and subsequent treatment with lorlatinib at disease progression leads to similar results in patients with metastatic disease. NTRK1–3 fusions are extremely rare in unselected NSCLC. However, treatment with TRK inhibitors yields high response rates and durable disease control in most patients; diagnostic screening through multigene DNA/RNA-based next-generation sequencing testing is therefore crucial to identify positive cases. This article is part of the Treatment of advanced non-small-cell lung cancer: one size does not fit all Special Issue: https://www.drugsincontext.com/special_issues/treatment-of-advanced-non-small-cell-lung-cancer-one-size-does-not-fit-all/

show abstract

Will the clinical development of 4th-generation “double mutant active” ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?

Cited by 28 publications

References 52 publications

Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

Review of Therapeutic Strategies for Anaplastic Lymphoma Kinase-Rearranged Non-Small Cell Lung Cancer

Non-small-cell lung cancer: how to manage ALK-, ROS1- and NTRK-rearranged disease

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