Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study

Girard, Nicolas; Galland-Girodet, S.; Avrillon, Virginie; Besse, Benjamin; Duruisseaux, M.; Cadranel, Jacques; Otto, Josiane; Prévost, Alain; Roch, Benoît; Bennouna, Jaafar; Bouledrak, K.; Coudurier, M.; Egenod, T.; Ricordel, Charles; Moro-Sibilot, Denis; Odier, L.; Tillon-Strozyk, J.; Zalcman, Gérard; Missy, Pascale; Westeel, Virginie; Baldacci, S.

doi:10.1016/j.esmoop.2022.100418

Cited by 7 publications

(7 citation statements)

References 25 publications

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“…The safety profile of lorlatinib in our study was consistent with previous studies. 5 , 16 Specifically, the most common treatment-related AEs were lipid abnormalities, edema, alanine aminotransferase and aspartate aminotransferase elevation, peripheral neuropathy, cognitive effects, and mood effects. Nevertheless, the overall rate of dose reduction for treatment-related AEs was higher in our study (69%) than the global phase 1/2 study (25%).…”

Section: Discussionmentioning

confidence: 99%

A Phase 2 Study of Lorlatinib in Patients With ROS1-Rearranged Lung Cancer With Brain-Only Progression on Crizotinib

Schneider

Muzikansky

Lin

et al. 2022

JTO Clinical and Research Reports

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Section: Discussionmentioning

confidence: 99%

A Phase 2 Study of Lorlatinib in Patients With ROS1-Rearranged Lung Cancer With Brain-Only Progression on Crizotinib

Schneider

Muzikansky

Lin

et al. 2022

JTO Clinical and Research Reports

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“…In particular, the study showed a median PFS of 8.5 months in crizotinib-pre-exposed patients, an ORR of 35%, and an intracranial response of 50%. This evidence allowed the authors to state that lorlatinib may be a valuable therapy in patients resistant to at least one ROS1-TKI [ 39 ].…”

Section: Place In Therapy Of Lorlatinib For Ros1 Rearranged Nsclcmentioning

confidence: 99%

“…Focusing on the toxicity profile of lorlatinib, hyperlipidemia (81% hypercholesterolemia and 60% hypertriglyceridemia), increased weight (18%), peripheral neuropathy (30%), edema (43%), and cognitive impairment were the most common side effects that emerged in the CROWN trial and were confirmed in everyday clinical practice [ 25 , 39 , 41 , 43 ]. In line with the CROWN trial and also in other studies, diarrhea (11%), nausea and emesis (5%), ALT (9%), AST (11%), and bilirubin increased, heart rate alterations (bradycardia), and anorexia, typical AEs of other ALK inhibitors like crizotinib, are less frequently referred to during lorlatinib therapy [ 25 , 41 ].…”

Section: Safety Profile and Clinical Managementmentioning

confidence: 99%

From Development to Place in Therapy of Lorlatinib for the Treatment of ALK and ROS1 Rearranged Non-Small Cell Lung Cancer (NSCLC)

Fabbri,

Di Federico,

Astore

et al. 2023

Diagnostics

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Following the results of the CROWN phase III trial, the third-generation macrocyclic ALK inhibitor lorlatinib has been introduced as a salvage option after the failure of a first-line TKI in ALK-rearranged NSCLC, while its precise role in the therapeutic algorithm of ROS1 positive disease is still to be completely defined. The ability to overcome acquired resistance to prior generation TKIs (alectinib, brigatinib, ceritinib, and crizotinib) and the high intracranial activity in brain metastatic disease thanks to increased blood–brain barrier penetration are the reasons for the growing popularity and interest in this molecule. Nevertheless, the major vulnerability of this drug resides in a peculiar profile of related collateral events, with neurological impairment being the most conflicting and debated clinical issue. The cognitive safety concern, the susceptibility to heterogeneous resistance pathways, and the absence of a valid alternative in the second line are strongly jeopardizing a potential paradigm shift in this oncogene-addicted disease. So, when prescribing lorlatinib, clinicians must face two diametrically opposed characteristics: a great therapeutic potential without the intrinsic limitations of its precursor TKIs, a cytotoxic activity threatened by suboptimal tolerability, and the unavoidable onset of resistance mechanisms we cannot properly manage yet. In this paper, we give a critical point of view on the stepwise introduction of this promising drug into clinical practice, starting from its innovative molecular and biochemical properties to intriguing future developments, without forgetting its weaknesses.

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“… 1 , 2 Lorlatinib is a brain-penetrant TKI targeting both ALK and ROS-1. It shows a response rate of 35–45% and a median PFS of 7.1–8.5 months in metastatic ROS1 -rearranged NSCLC after ROS1 TKI failure 3 , 4 and has been suggested as a subsequent treatment. 5 Therapeutic resistance in ROS1 -rearranged NSCLC has extensively been investigated in the context of crizotinib.…”

Section: Introductionmentioning

confidence: 99%

“…Limited studies described both ROS1 -dependent and independent mechanisms of resistance to lorlatinib. 4 , 6 Efficient therapeutic options remain lacking for patients upon lorlatinib failure.…”

Section: Introductionmentioning

confidence: 99%

Combined Lorlatinib, Dabrafenib, and Trametinib Treatment for ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer with a Lorlatinib-Induced BRAF V600E Mutation: A Case Report

Li¹,

Liu²,

Zhang³

et al. 2022

CMAR

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Background Lorlatinib has been suggested as the therapeutic option for patients with ROS1 -rearranged non-small-cell lung cancer (NSCLC) after ROS1 tyrosine kinase inhibitor (TKI) failure. However, the mechanism mediating lorlatinib resistance has not been well elucidated in ROS1 -rearranged NSCLC. Post- lorlatinib therapeutic options remain scarce. Case Presentation Herein, we describe a 31-year-old female patient with stage IVB ROS1 -rearranged NSCLC. She received 2nd line treatment with crizotinib after chemotherapy failure and achieved a partial response lasting for 15 months. An NF1 p.G127Ter mutation emerged as a potential crizotinib resistance mechanism. She subsequently received lorlatinib treatment and achieved a progression-free survival (PFS) of seven months. Based on the emergence of a resistant BRAF V600E, the patient was switched to a combinatorial targeted therapy with lorlatinib, dabrafenib, and trametinib and attained stable disease. She continued the treatment with a time-to-treatment failure of 5.5 months. The acquisition of NRAS p.Q61R and NTRK amplification may confer resistance to the combinatorial targeted therapy. Conclusion To the best of our knowledge, we reported the first case demonstrating that BRAF p.V600E can mediate the lorlatinib resistance in ROS1 -rearranged NSCLC and the combinational targeted therapy of ROS1 TKI with dabrafenib and trametinib may serve as an efficient therapeutic option for subsequent treatment.

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Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study

Cited by 7 publications

References 25 publications

A Phase 2 Study of Lorlatinib in Patients With ROS1-Rearranged Lung Cancer With Brain-Only Progression on Crizotinib

A Phase 2 Study of Lorlatinib in Patients With ROS1-Rearranged Lung Cancer With Brain-Only Progression on Crizotinib

From Development to Place in Therapy of Lorlatinib for the Treatment of ALK and ROS1 Rearranged Non-Small Cell Lung Cancer (NSCLC)

Combined Lorlatinib, Dabrafenib, and Trametinib Treatment for ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer with a Lorlatinib-Induced BRAF V600E Mutation: A Case Report

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