Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity

Elamin, Yasir Y.; Robichaux, Jacqulyne P.; Carter, Brett W.; Altan, Mehmet; Tran, Hai T.; Gibbons, Don L.; Heeke, Simon; Fossella, Frank V.; Lam, Vincent K.; Le, Xiuning; Negrão, Marcelo V.; Nilsson, Monique B.; Patel, Anisha B.; Vijayan, Ramachandran; Cross, Jason B.; Zhang, Jianjun; Byers, Lauren A.; Lu, Charles; Cascone, Tina; Feng, Lei; Luthra, Rajyalakshmi; Lucas, F. Anthony San; Mantha, Geeta S.; Routbort, Mark; Blumenschein, George R.; Tsao, Anne S.; Heymach, John V.

doi:10.1016/j.ccell.2022.06.006

Cited by 62 publications

(65 citation statements)

References 60 publications

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“…Furthermore, the sensitivity to poziotinib was highly dependent on the insertion location. The near-loop insertions (amino acids A767-P772) were associated with a greater sensitivity compared to the far-loop insertions (H773-C775), with respective ORRs of 46% and 0% observed in near vs. farloop, respectively (Elamin et al, 2022). The blueprint of precision-targeted therapy for NSCLC patients harboring the Although we have comprehensively analyzed the clinical activity of the currently approved EGFR TKIs for the specific EGFR ex20ins variants A763_Y764insFQEA and D770delinsGY in advanced NSCLC patients and provided evidence from structural and molecular dynamics simulation, several limitations must be noted.…”

Section: Discussionmentioning

confidence: 97%

“…Mobocertinib received FDA approval for NSCLC patients harboring EGFR ex20ins who had progressed following platinum-based chemotherapy, based on an ORR of 28% and a mPFS of 7.3 months (Zhou et al, 2021). A recent study on poziotinib revealed a confirmed ORR of 32% and a mPFS of 5.5 months in NSCLC patients with EGFR ex20ins (Elamin et al, 2022). Furthermore, the sensitivity to poziotinib was highly dependent on the insertion location.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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EGFR exon 20 insertion variants A763_Y764insFQEA and D770delinsGY confer favorable sensitivity to currently approved EGFR-specific tyrosine kinase inhibitors

Gao

Yang²,

Hu³

et al. 2022

Front. Pharmacol.

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Background: The EGFR exon 20 insertions (ex20ins) D770_N771insSVD and V769_D770insASV are most frequent in non-small-cell lung cancer (NSCLC) and are associated with intrinsic resistance to currently approved EGFR tyrosine kinase inhibitors (TKIs). A763_Y764insFQEA and D770delinsGY, respectively, account for 3%–8% and 2.0%–4.8% of EGFR ex20ins in NSCLC and are associated with a more favorable response to EGFR-specific TKIs as per case reports. The aim of this study was to elucidate the molecular structures of these mutants and their binding affinities to diverse EGFR TKIs and compare the clinical outcomes in NSCLC patients harboring these mutations.Methods: A real-world cohort study was conducted to evaluate and compare the clinical outcomes of EGFR TKIs among NSCLC patients with different EGFR ex20ins mutants in response to EGFR TKIs. The structures of A763_Y764insFQEA and D770delinsGY were also analyzed and drug binding simulations were performed.Results: With a median follow-up of 24.0 months, the first-line objective response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS) were, respectively, 0 (0/16), 50.0% (8/16), and 2.07 months (95%CI, 0–6.25) in patients harboring D770_N771insSVD and V769_D770insASV variants and 33.3% (4/12), 83.3% (10/12), and 9.97 months (95%CI, 4.75–15.19) in patients with A763_Y764insFQEA and D770delinsGY variants. There was a significant difference between the PFS of these two subgroups (median, 9.97 vs.2.07 months, HR = 0.33, 95%CI, 0.13–0.85, p = 0.02). Similarly, the PFS was significantly longer after second-line treatment with EGFR TKIs in patients harboring A763_Y764insFQEA and D770delinsGY compared to those with other insertions (median, 6.77 vs.2.23 months, HR = 0.14, p < 0.001). Computational simulations indicated that A763_Y764insFQEA and D770delinsGY mutants were structurally similar to wild-type EGFR. In contrast, the C-helix and phosphate-binding loop of D770_N771insSVD and V769_D770insASV had shifted into the drug-binding pocket, resulting in significant steric hindrance and a lack of affinity for the currently approved EGFR inhibitors.Conclusion: NSCLC patients harboring A763_Y764insFQEA and D770delinsGY insertions of EGFR are responsive to the currently approved EGFR TKIs as opposed to patients with the D770_N771insSVD and V769_D770insASV variants. Therefore, A763_Y764insFQEA and D770delinsGY should be classified as active mutations among heterogeneous EGFR ex20ins subtypes and the carriers can be treated with the suitable EGFR TKIs.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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EGFR exon 20 insertion variants A763_Y764insFQEA and D770delinsGY confer favorable sensitivity to currently approved EGFR-specific tyrosine kinase inhibitors

Gao

Yang²,

Hu³

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

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“…In vitro testing has also demonstrated a positive correlation between drug sensitivity and mutation location ( R = 0.67, p = 0.0003). 69 …”

Section: Systemic Therapiesmentioning

confidence: 99%

“…Although preliminary, several pre-clinical studies have shown that on-target secondary mutations, bypass pathway activation and epithelial–mesenchymal transition ( EMT ) confer resistance to therapies targeting EGFR exon 20 insertion mutations ( Figure 4 ). 99 Identified on-target mechanisms to poziotinib 69 and tarloxotinib 100 include EGFR C797S and T790M mutations. Bypass pathway activations have been identified as acquired resistance to poziotinib, including reactivation of MAPK/phosphoinositide 3-kinase (MAPK/PI3K) pathway such as PIKCA E545K and MAP2K2 S94L, and amplifications in MET, EGFR and CDK6 .…”

Section: Mechanisms Of Acquired Resistancementioning

confidence: 99%

Advances in the management of non-small-cell lung cancer harbouring EGFR exon 20 insertion mutations

et al. 2023

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Epidermal growth factor receptor ( EGFR) mutation is one of the key oncogenic mutations in non-small-cell lung cancer with adenocarcinoma histology. Exon 19 deletions and exon 21 L858R substitutions account for 90%, while EGFR exon 20 insertions constitute 4–10% of EGFR mutations and are the third most prevalent activating EGFR mutations. EGFR exon 20 insertions are associated with decreased sensitivity to EGFR tyrosine kinase inhibitors and, until recently, effective targeted therapy against these tumours remained an unmet clinical need and chemotherapy was the only treatment of choice available. The approval of amivantamab and mobocertinib for patients who have progressed after chemotherapy represents an important step forward in the management of these patients. Here in this review, we summarize the epidemiology, structure and the tumour microenvironment of EGFR exon 20 insertion and also review the systemic treatments, including targeted therapies and ongoing clinical trials in EGFR exon 20 insertion mutations, as well as detection methods for EGFR exon 20 insertion. Lastly, resistant mechanisms and future directions are addressed.

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Mechanisms of resistance to tyrosine kinase inhibitor‐targeted therapy and overcoming strategies

Ou,

Gao,

Habaz

et al. 2024

MedComm

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Tyrosine kinase inhibitor (TKI)‐targeted therapy has revolutionized cancer treatment by selectively blocking specific signaling pathways crucial for tumor growth, offering improved outcomes with fewer side effects compared with conventional chemotherapy. However, despite their initial effectiveness, resistance to TKIs remains a significant challenge in clinical practice. Understanding the mechanisms underlying TKI resistance is paramount for improving patient outcomes and developing more effective treatment strategies. In this review, we explored various mechanisms contributing to TKI resistance, including on‐target mechanisms and off‐target mechanisms, as well as changes in the tumor histology and tumor microenvironment (intrinsic mechanisms). Additionally, we summarized current therapeutic approaches aiming at circumventing TKI resistance, including the development of next‐generation TKIs and combination therapies. We also discussed emerging strategies such as the use of dual‐targeted antibodies and PROteolysis Targeting Chimeras. Furthermore, we explored future directions in TKI‐targeted therapy, including the methods for detecting and monitoring drug resistance during treatment, identification of novel targets, exploration of dual‐acting kinase inhibitors, application of nanotechnologies in targeted therapy, and so on. Overall, this review provides a comprehensive overview of the challenges and opportunities in TKI‐targeted therapy, aiming to advance our understanding of resistance mechanisms and guide the development of more effective therapeutic approaches in cancer treatment.

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Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity

Cited by 62 publications

References 60 publications

EGFR exon 20 insertion variants A763_Y764insFQEA and D770delinsGY confer favorable sensitivity to currently approved EGFR-specific tyrosine kinase inhibitors

EGFR exon 20 insertion variants A763_Y764insFQEA and D770delinsGY confer favorable sensitivity to currently approved EGFR-specific tyrosine kinase inhibitors

Advances in the management of non-small-cell lung cancer harbouring EGFR exon 20 insertion mutations

Mechanisms of resistance to tyrosine kinase inhibitor‐targeted therapy and overcoming strategies

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