Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer

Recondo, Gonzálo; Mezquita, Laura; Facchinetti, Francesco; Planchard, David; Gazzah, Anas; Bigot, Ludovic; Rizvi, Ahsan Z.; Frias, Rosa L.; Thiery, Jean Paul; Scoazec, Jean‐Yves; Sourisseau, Tony; Howarth, Karen; Déas, Olivier; Samofalova, Dariia; Galissant, Justine; Tesson, Pauline; Brayé, Floriane; Naltet, Charles; Lavaud, Pernelle; Mahjoubi, Linda; Lovergne, Aurélie Abou; Vassal, Gilles; Bahleda, Rastilav; Hollebecque, Antoine; Nicotra, Claudio; Ngo-Camus, Maud; Michiels, Stefan; Lacroix, Ludovic; Richon, Catherine; Auger, Nathalie; Baère, Thierry De; Tsélikas, Lambros; Solary, Éric; Angevin, Eric; Eggermont, Alexander M.M.; Varga, Andrea; Massard, Christophe; Olaussen, Ken A.; Soria, Jean‐Charles; Besse, Benjamin; Friboulet, Luc

doi:10.1158/1078-0432.ccr-19-1104

Cited by 132 publications

(128 citation statements)

References 30 publications

(50 reference statements)

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“…Acquired resistance during long-term treatment with targeted therapies is a major concern, as experienced with EGFR, ALK, and ROS1 inhibitors [149][150][151][152][153][154]. NTRK inhibitors make no exception to this statement, and disease progression has been now observed within the ongoing clinical trials.…”

Section: Resistance Mechanisms To First-generation Ntrk Inhibitorsmentioning

confidence: 99%

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

Gambella

Senetta

Collemi

et al. 2020

IJMS

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The neurotrophic tropomyosin receptor kinase (NTRK) genes (NTRK1, NTRK2, and NTRK3) code for three transmembrane high-affinity tyrosine-kinase receptors for nerve growth factors (TRK-A, TRK-B, and TRK-C) which are mainly involved in nervous system development. Loss of function alterations in these genes can lead to nervous system development problems; conversely, activating alterations harbor oncogenic potential, promoting cell proliferation/survival and tumorigenesis. Chromosomal rearrangements are the most clinically relevant alterations of pathological NTRK activation, leading to constitutionally active chimeric receptors. NTRK fusions have been detected with extremely variable frequencies in many pediatric and adult cancer types, including central nervous system (CNS) tumors. These alterations can be detected by different laboratory assays (e.g., immunohistochemistry, FISH, sequencing), but each of these approaches has specific advantages and limitations which must be taken into account for an appropriate use in diagnostics or research. Moreover, therapeutic targeting of this molecular marker recently showed extreme efficacy. Considering the overall lack of effective treatments for brain neoplasms, it is expected that detection of NTRK fusions will soon become a mainstay in the diagnostic assessment of CNS tumors, and thus in-depth knowledge regarding this topic is warranted.

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Section: Resistance Mechanisms To First-generation Ntrk Inhibitorsmentioning

confidence: 99%

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

Gambella

Senetta

Collemi

et al. 2020

IJMS

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“…7,9 Recent studies of lorlatinib resistance suggest an even more complicated array of resistance mechanisms, including diverse compound ALK mutations in one-third of patients and ALK-independent resistance mechanisms in the remaining two-thirds of patients. 9,10 To date, ALK-independent resistance mechanisms remain poorly characterized. In preclinical studies, multiple bypass mechanisms have been described, including activation of MET, EGFR, SRC, and IGF-1R.…”

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

144

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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“…For instance, we characterized diverse resistance mechanisms occurring in patients with ALK-rearranged NSCLC progressing on the third-generation ALK inhibitor lorlatinib such as additional ALK secondary compound mutations, and NF2 loss of function mutations 25 . In addition, we described the ROS1 S1986Y/F kinase domain resistance mutations in a patient with ROS1-rearranged lung cancer progressing on crizotinib 26 . Similarly, multiple oncogenic fusions involving FGFR3, RET or ALK were identified as common resistance mechanisms to the third-generation EGFR TKI osimertinib in EGFR-mutant NSCLC patients 27 .…”

Section: Resultsmentioning

confidence: 99%

Feasibility and first reports of the MATCH-R repeated biopsy trial at Gustave Roussy

et al. 2020

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Unravelling the biological processes driving tumour resistance is necessary to support the development of innovative treatment strategies. We report the design and feasibility of the MATCH-R prospective trial led by Gustave Roussy with the primary objective of characterizing the molecular mechanisms of resistance to cancer treatments. The primary clinical endpoints consist of analyzing the type and frequency of molecular alterations in resistant tumours and compare these to samples prior to treatment. Patients experiencing disease progression after an initial partial response or stable disease for at least 24 weeks underwent a tumour biopsy guided by CT or ultrasound. Molecular profiling of tumours was performed using whole exome sequencing, RNA sequencing and panel sequencing. At data cut-off for feasibility analysis, out of 333 inclusions, tumour biopsies were obtained in 303 cases (91%). From these biopsies, 278 (83%) had sufficient quality for analysis by high-throughput next generation sequencing (NGS). All 278 samples underwent targeted NGS, 215 (70.9%) RNA sequencing and 222 (73.2%) whole exome sequencing. In total, 163 tumours were implanted in NOD scid gamma (NSG) or nude mice and 54 patient-derived xenograft (PDX) models were established, with a success rate of 33%. Adverse events secondary to invasive tumour sampling occurred in 24 patients (7.6%). Study recruitment is still ongoing. Systematic molecular profiling of tumours and the development of patient-derived models of acquired resistance to targeted agents and immunotherapy is feasible and can drive the selection of the next therapeutic strategy.

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Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer

Cited by 132 publications

References 30 publications

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

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

Feasibility and first reports of the MATCH-R repeated biopsy trial at Gustave Roussy

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