Response to Crizotinib Re-administration After Progression on Lorlatinib in a Patient With ALK-rearranged Non–small-cell Lung Cancer

Sakakibara‐Konishi, Jun; Kitai, Hidenori; Ikezawa, Yasuyuki; Hatanaka, Yutaka; Sasaki, Takaaki; Yoshida, Ryohei; Chiba, Shinichi; Matsumoto, Shingo; Goto, Kōichi; Mizugaki, Hidenori; Shinagawa, Naofumi

doi:10.1016/j.cllc.2019.06.021

Cited by 22 publications

(15 citation statements)

References 22 publications

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“…To evaluate the role of MET as a resistance mechanism, we first assessed MET copy number in 86 tumor biopsies using FISH or the FoundationOne assay ( Figure 1A, Supplementary Table 1). Eleven (13%) biopsies harbored MET amplification ( Figure 1B), including four with low-level MET amplification (MET/CEP7 2.4-3.9) and six with high-level MET amplification based on FISH (MET/CEP7 5.2 to >25) or NGS (16)(17)(18)(19) Research. To determine whether the development of MET amplification may be impacted by prior crizotinib exposure, we evaluated the frequency of MET amplification according to prior TKI therapy.…”

Section: Met Amplification In Tissue Biopsiesmentioning

confidence: 99%

See 1 more Smart Citation

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer

Dagogo‐Jack

Yoda

Lennerz

et al. 2020

Clinical Cancer Research

148

101

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Background: Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed. Methods: We performed fluorescence in-situ hybridization and/or next-generation sequencing on 207 post-treatment tissue (n=101) or plasma (n=106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and two patients with MET-driven resistance. Results: MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (p=0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition re-sensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy. Conclusions: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may select for MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.

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Section: Met Amplification In Tissue Biopsiesmentioning

confidence: 99%

“…Several case reports suggest that MET amplification can mediate resistance to ALK TKIs and that the ALK/ROS1/MET TKI crizotinib may be able to overcome MET-driven resistance. 17,18 However, larger studies are needed to validate MET as a clinically relevant driver of resistance in ALK-positive NSCLC.…”

Section: Introductionmentioning

confidence: 99%

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer

Dagogo‐Jack

Yoda

Lennerz

et al. 2020

Clinical Cancer Research

148

101

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“…case reports have also confirmed this, and suggest that the ALK/ROS1/MET TKI crizotinib may be able to overcome MET-dependent resistance. 78,79 In a comprehensive analysis of MET alterations in ALKfusion-positive NSCLC, 77 FISH and/or NGS were performed on 207 post-treatment tissue (n ¼ 101) or plasma (n ¼ 106) specimens from patients with ALK-fusion-positive lung cancer to detect MET genetic alterations. The analysis also evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of the ALK/MET dual blockade in ALK-fusion cell lines and two subsequent patients with MET-dependent resistance.…”

Section: Esmo Openmentioning

confidence: 99%

“… 77 Several case reports have also confirmed this, and suggest that the ALK/ROS1/MET TKI crizotinib may be able to overcome MET -dependent resistance. 78 , 79 …”

Section: Introductionmentioning

confidence: 99%

Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer

et al. 2021

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The rapidly changing treatment paradigm for patients with metastatic oncogene-driven lung cancer continues to evolve, and consequently our understanding of the landscape of resistance must also advance. MET amplification is an established and frequent driver of resistance in EGFR-mutant non-small-cell lung cancer (NSCLC). Recently, the combination of MET proto-oncogene (MET) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has shown promise in overcoming this molecularly defined resistance in clinical trials, and this combination strategy is being pursued in ongoing trials. Emerging data also demonstrate MET amplification as a resistance driver to TKI-treated ALK-, RET-, and ROS-1-fusion NSCLC, consistently at the range of 15%, while the resistance profiling data are maturing for other molecular targets. In this review, we discuss MET amplification as a driver of acquired resistance in well-defined molecular subsets of NSCLC, explore the biology behind this mechanism of resistance, and summarize the recently published clinical data, including the proposed combination strategies in the clinic achieving success in overcoming acquired MET amplification-dependent resistance.

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“…MET gene amplification has previously been described as a bypass resistance mechanism to TKIs, first discovered in EGFR mutant NSCLC resistant to gefitinib 47 and subsequently observed in ALK rearranged and RET rearranged NSCLC. 26 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 More recently, MET gene amplification has been observed in ROS1+ lung cancers that progressed on lorlatinib, a next‐generation ROS1 TKI utilized to target some ROS1 mutations driven by first‐generation ROS1 TKIs. 22 To our knowledge, this represents the first case of MET‐mediated resistance to entrectinib in ROS1+ NSCLC, and importantly shows a novel mechanism involving ecDNA MET gene amplification.…”

Section: Discussionmentioning

confidence: 99%

MET gene amplification is a mechanism of resistance to entrectinib in ROS1+ NSCLC

Tyler

Chen

et al. 2022

Thoracic Cancer

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Background: ROS1 tyrosine kinase inhibitors (TKIs) have demonstrated significant clinical benefit for ROS1+ NSCLC patients. However, TKI resistance inevitably develops through ROS1 kinase domain (KD) modification or another kinase driving bypass signaling. While multiple TKIs have been designed to target ROS1 KD mutations, less is known about bypass signaling in TKI-resistant ROS1+ lung cancers. Methods: Utilizing a primary, patient-derived TPM3-ROS1 cell line (CUTO28), we derived an entrectinib-resistant line (CUTO28-ER). We evaluated proliferation and signaling responses to TKIs, and utilized RNA sequencing, whole exome sequencing, and fluorescence in situ hybridization to detect transcriptional, mutational, and copy number alterations, respectively. We substantiated in vitro findings using a CD74-ROS1 NSCLC patient's tumor samples. Last, we analyzed circulating tumor DNA (ctDNA) from ROS1+ NSCLC patients in the STARTRK-2 entrectinib trial to determine the prevalence of MET amplification. Results: CUTO28-ER cells did not exhibit ROS1 KD mutations. MET TKIs inhibited proliferation and downstream signaling and MET transcription was elevated in CUTO28-ER cells. CUTO28-ER cells displayed extrachromosomal (ecDNA) MET amplification without MET activating mutations, exon 14 skipping, or fusions. The CD74-ROS1 patient samples illustrated MET amplification while receiving ROS1 TKI. Finally, two of 105 (1.9%) entrectinib-resistant ROS1+ NSCLC STARTRK-2 patients with ctDNA analysis at enrollment and disease progression displayed MET amplification. Conclusions: Treatment with ROS1-selective inhibitors may lead to MET-mediated resistance. The discovery of ecDNA MET amplification is noteworthy, as ecDNA is associated with more aggressive cancers. Following progression on ROS1-selective inhibitors, MET gene testing and treatments targeting MET should be explored to overcome MET-driven resistance.

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Response to Crizotinib Re-administration After Progression on Lorlatinib in a Patient With ALK-rearranged Non–small-cell Lung Cancer

Cited by 22 publications

References 22 publications

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer

Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer

MET gene amplification is a mechanism of resistance to entrectinib in ROS1+ NSCLC

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