Secondary ROS1 mutations and lorlatinib sensitivity in crizotinib-refractory ROS1 positive NSCLC: Results of the prospective PFROST trial

Landi, Lorenza; Tiseo, Marcello; Heukamp, Lukas C.; Menon, Roopika; Spitaleri, Giosafat; Cortinovis, Diego; Delmonte, Angelo; Galetta, Domenico; D’Arcangelo, M.; D’Incà, Federica; Bertrand, Miriam; Jóri, Balázs; Zacher, Angela; Gridelli, Cesare; Novello, Silvia; Chiari, Rita; Verusio, Claudio; Crinò, Lucio; Cappuzzo, F.

doi:10.1093/annonc/mdz260.011

Cited by 9 publications

(17 citation statements)

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“…Another mutation, analogous to the ALK D1203N, located in the solvent front is the D2033N which affects the ATP-binding pocket (35). Additional mutations reported in clinical samples are the S1986Y/F, the gatekeeper L2026M, the L1951R, with other recently described (25,26).…”

Section: Basics Of Acquired Resistance To Crizotinibmentioning

confidence: 99%

“…Interestingly, the same mutation was detected in all disease sites, supporting the hypothesis of an early clonal event. Subsequent studies demonstrated that acquired mutations are responsible for more than 50% of crizotinib failure, with the G2032R being the most frequent (6,22,25,26). Another mutation, analogous to the ALK D1203N, located in the solvent front is the D2033N which affects the ATP-binding pocket (35).…”

Section: Basics Of Acquired Resistance To Crizotinibmentioning

confidence: 99%

“…In preclinical models, lorlatinib potently inhibits ROS1 and retains activity against different ROS1 resistance mutations (41)(42)(43). So far, two prospective studies have evaluated the drug in patients with ROS1positive NSCLC (25,26). In the global phase I/II, daily lorlatinib 100 mg was given to ROS1 positive patients who were ROS1-TKIs naïve or who failed one or more ROS1 targeted agents.…”

Section: Lorlatinibmentioning

confidence: 99%

“…Of them, 21 were TKI-naïve and 48 were pretreated, with crizotinib being the most frequent ROS1 TKI previously taken. In TKI-naïve group, systemic and intracranial RR were similar (62% and 64%), extracranial DoR exceeded 25 months, while in the brain The second trial, the Italian PFROST, aimed to investigate the activity of lorlatinib in the crizotinibrefractory setting only (26). Twenty-two patients received lorlatinib 100 mg daily until progression.…”

Section: Lorlatinibmentioning

confidence: 99%

“…Unfortunately, no patient obtained a definitive cure and the majority of patients become refractory to crizotinib due to the emergence of acquired resistance, mainly sustained by the occurrence of acquired mutations or intracranial progression, highlighting once again the inadequate CNS drug penetration (6,22,23). In order to overcome these limitations, novel and more potent ROS1 inhibitors have been designed and recent available data are showing encouraging results in crizotinib pretreated as well as in naïve patients (24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

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How selecting best upfront therapy for metastatic disease?—Focus on ROS1-rearranged disease

Landi¹,

Cappuzzo²

2020

Transl Lung Cancer Res

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ROS proto-oncogene 1 (ROS1) rearrangements defines a distinct group of non-small cell lung cancer (NSCLC), mainly represented by younger subjects, never smokers and with adenocarcinoma histology. Fusions involving ROS1 gene are present in 1-2% of lung adenocarcinomas and other solid tumors. Identification of patients harboring ROS1 rearrangements is a critical issue and current guidelines recommend screening of all advanced non-squamous NSCLC and certain squamous lung cancer patients. A number of trials have supported crizotinib as the best option for NSCLC patients with ROS1 translocations, irrespective of line of therapy. Unfortunately, the majority of patients become insensitive to crizotinib, due to the occurrence of secondary ROS1 mutations or failure within the central nervous system (CNS). Several highly potent and CNS penetrant ROS1 inhibitors have been developed and recent data highlight their potential role in the front-line treatment of this disease. Among them entrectinib, also known as RXDX-101, is a potent second-generation, multitarget oral inhibitor against the neurotrophin receptors TRKA, TRKB, TRKC ALK, and ROS1 with the ability to cross the blood-brain barrier. In the next few years, results of ongoing trials with novel ROS1 inhibitors and dedicated translational research studies might help to define the optimal sequence of treatment for ROS1-positive NSCLC patients.

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Section: Basics Of Acquired Resistance To Crizotinibmentioning

confidence: 99%

Section: Basics Of Acquired Resistance To Crizotinibmentioning

confidence: 99%

Section: Lorlatinibmentioning

confidence: 99%

Section: Lorlatinibmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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How selecting best upfront therapy for metastatic disease?—Focus on ROS1-rearranged disease

Landi¹,

Cappuzzo²

2020

Transl Lung Cancer Res

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Repotrectinib’s Clinical Benefit and Its Brain Penetration in a Patient with Meningeal Carcinomatosis from G2032R-Mutated ROS-1 Positive Non-Small Cell Lung Cancer

Metro,

Gariazzo,

Costabile

et al. 2023

Oncol Ther

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In this work, we report on a clinically significant response of meningeal carcinomatosis to repotrectinib in a woman with a heavily pretreated ROS1-rearranged non-small cell lung cancer (NSCLC) that harbored the concomitant solvent front G2032R mutation. Meningeal carcinomatosis has a higher incidence in oncogene addicted NSCLC due to increased life expectancy, yet no report has ever documented the activity of repotrectinib in this context. In line with its activity, we documented the presence of the drug at potentially active concentrations in the cerebrospinal fluid. Nevertheless, the short-lived response reported by our patient highlights the importance for novel ROS1-tyrosine kinase inhibitors (TKIs) to be specifically developed to be able to penetrate the blood–brain barrier.

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Current treatment and future challenges in ROS1- and ALK-rearranged advanced non-small cell lung cancer

Remón

Pignataro

Novello

et al. 2021

Cancer Treatment Reviews

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Secondary ROS1 mutations and lorlatinib sensitivity in crizotinib-refractory ROS1 positive NSCLC: Results of the prospective PFROST trial

Cited by 9 publications

References 0 publications

How selecting best upfront therapy for metastatic disease?—Focus on ROS1-rearranged disease

How selecting best upfront therapy for metastatic disease?—Focus on ROS1-rearranged disease

Repotrectinib’s Clinical Benefit and Its Brain Penetration in a Patient with Meningeal Carcinomatosis from G2032R-Mutated ROS-1 Positive Non-Small Cell Lung Cancer

Current treatment and future challenges in ROS1- and ALK-rearranged advanced non-small cell lung cancer

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