lorlatinib
Sources réglementaires consultées
Indications approuvées
- Adultes atteints de CBNPC métastatique ALK positif confirmé par test. L’étiquette FDA sélectionnée n’inclut pas ROS1.
Contre-indications
Absolues
- Utilisation concomitante d’inducteurs puissants du CYP3A.
- CIMA : hypersensibilité à la substance active ou aux excipients ; l’étiquette FDA n’établit aucune contre-indication formelle.
Mises en garde cliniques
- Peut provoquer des effets graves du SNC : troubles cognitifs, de l’humeur ou du langage, psychose, idées suicidaires ou convulsions. Évaluer et suspendre, réduire ou arrêter selon gravité. — OpenFDA, set_id 004f93d7-a1cd-4b67-9207-31cdcb5c5976
- Contrôler les lipides au départ, à 1 et 2 mois puis périodiquement ; ECG pour bloc AV, symptômes pulmonaires, pression artérielle au départ/2 semaines/mensuelle et glycémie. Toute PID confirmée impose l’arrêt. — OpenFDA, set_id 004f93d7-a1cd-4b67-9207-31cdcb5c5976
Interactions médicamenteuses
- ModéréeInducteurs puissants du CYP3A
Mécanisme: Ils peuvent provoquer une hépatotoxicité sévère et réduire l’exposition au lorlatinib.
Recommandation: Contre-indiqués ; arrêter l’inducteur pendant au moins 3 demi-vies avant de commencer.
OpenFDA, set_id 004f93d7-a1cd-4b67-9207-31cdcb5c5976
- SévèreAutres modulateurs CYP3A et substrats critiques CYP3A/P-gp
Mécanisme: Ils modifient l’exposition au lorlatinib ou au substrat.
Recommandation: Avec un inducteur modéré inévitable, augmenter à 125 mg ; avec un inhibiteur puissant, réduire à 75 mg ou 50 mg. Éviter les substrats critiques.
OpenFDA, set_id 004f93d7-a1cd-4b67-9207-31cdcb5c5976
Effets indésirables
Communs (≥1%)
œdème · neuropathie périphérique · prise de poids · effets cognitifs · fatigue · dyspnée · arthralgie
Grossesse et allaitement
Vérifier la grossesse. Les femmes doivent utiliser une contraception non hormonale pendant et 6 mois après ; les hommes pendant et 3 mois après. Ne pas allaiter pendant ni 7 jours après. Peut altérer la fertilité masculine.
Bibliographie récente (PubMed)
Lorlatinib improved progression-free survival (PFS) and intracranial activity versus crizotinib in patients with previously untreated, advanced, ALK-positive non-small cell lung cancer (NSCLC) in the phase III CROWN study. Here, we report long-term outcomes from CROWN after 5 years of follow-up. Two hundred ninety-six patients with ALK-positive NSCLC were randomly assigned 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses. With a median follow-up for PFS of 60.2 and 55.1 months, respectively, median PFS was not reached (NR [95% CI, 64.3 to NR]) with lorlatinib and 9.1 months (95% CI, 7.4 to 10.9) with crizotinib (hazard ratio [HR], 0.19 [95% CI, 0.13 to 0.27]); 5-year PFS was 60% (95% CI, 51 to 68) and 8% (95% CI, 3 to 14), respectively. Median time to intracranial progression was NR (95% CI, NR to NR) with lorlatinib and 16.4 months (95% CI, 12.7 to 21.9) with crizotinib (HR, 0.06 [95% CI, 0.03 to 0.12]). Safety profile was consistent with that in prior analyses. Emerging new ALK resistance mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment. After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK-positive NSCLC and set a new benchmark for targeted therapies in cancer.
The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed treatment paradigm for patients with advanced-stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR-mutant and ALK-rearranged NSCLCs have been developed, culminating in the availability of the highly effective third-generation TKIs osimertinib and lorlatinib, respectively. Despite their marked efficacy, resistance to these agents remains an unsolved fundamental challenge. Both 'on-target' mechanisms (largely mediated by acquired resistance mutations in the kinase domains of EGFR or ALK) and 'off-target' mechanisms of resistance (mediated by non-target kinase alterations such as bypass signalling activation or phenotypic transformation) have been identified in patients with disease progression on osimertinib or lorlatinib. A growing understanding of the biology and spectrum of these mechanisms of resistance has already begun to inform the development of more effective therapeutic strategies. In this Review, we discuss the development of third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth-generation TKIs to combination regimens and other investigational therapies. No information is available on the clinical use of lorlatinib during breastfeeding. The manufacturer recommends that breastfeeding be discontinued during lorlatinib therapy and for 7 days after the last dose.
Lung cancer in nonsmoking individuals (defined as people who have smoked fewer than 100 cigarettes in their lifetime) accounts for 15% to 20% of all lung cancer cases worldwide. In the US, the annual incidence of lung cancer in nonsmoking individuals is 14.4 to 20.8 per 100 000 person-years in females and 4.8 to 12.7 per 100 000 person-years in males. Most lung cancers in nonsmoking individuals are histologically adenocarcinomas (60%-80%) with the remainder being squamous or adenosquamous (10%-20%) and rarely small cell lung cancer (<10%). Risk factors include exposure to passive smoking, radon exposure, air pollution, asbestos, and history of lung cancer in a first-degree family member. Therapeutically targetable genomic variants, such as EGFR mutations or ALK gene rearrangements, are more common in tumors from nonsmoking individuals compared with those with a smoking history (defined as people who currently or formerly smoked) (43% vs 11% for EGFR and 12% vs 2% for ALK). In contrast, tumor mutation burden, the number of somatic mutations in a tumor cell, is lower in lung cancer among nonsmoking individuals (0-3 mutations/megabase [Mb] vs 0-30 mutations/Mb). Similar to individuals with a history of smoking, nonsmoking individuals with lung cancer may present with wheeze, chest pain, dyspnea, hemoptysis, or symptoms attributable to metastatic disease (eg, bone pain and headache) or be diagnosed with incidentally detected disease. The US Preventive Services Task Force does not currently recommend lung cancer screening with low-dose computed tomographic scans for nonsmoking individuals, although screening guidelines vary globally. Treatment typically involves a combination of surgery, radiotherapy, and systemic therapies depending on stage, performance status, and molecular features of the tumor. Comprehensive next-generation sequencing should be performed on stage Ib to IIIa lung cancer tumor tissue from nonsmoking individuals because actionable genomic alterations,
Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.