Intracranial Response of ALK+ Non-Small-cell Lung Cancer to Second-line Dose-escalated Brigatinib After Alectinib Discontinuation Due to Drug-induced Hepatitis and Relapse After Whole Brain Radiotherapy Followed by Stereotactic Radiosurgery

Urbanska, Edyta Maria; Santoni-Rugiu, Eric; Melchior, Linea Cecilie; Carlsen, Jonathan Frederik; Sørensen, Jens Benn

doi:10.1016/j.cllc.2020.04.012

Cited by 9 publications

(6 citation statements)

References 16 publications

(19 reference statements)

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“…As 87% of patients in our study had received alectinib or brigatinib before initiating lorlatinib, this raises the possibility that ALK-dependent mechanisms might have accounted for some CNS relapses. As escalating the dose of alectinib or brigatinib can overcome CNS progression, 18,19 it is also conceivable that ALK is incompletely inhibited in the CNS at standard dosing of both drugs. Considering the challenges of distinguishing between resistance and pharmacokinetic failure, our study supports empiric use of lorlatinib for patients with CNS-confined progression on second-generation ALK TKIs.…”

Section: Discussionmentioning

confidence: 99%

Phase II Study of Lorlatinib in Patients With Anaplastic Lymphoma Kinase–Positive Lung Cancer and CNS-Specific Relapse

Dagogo‐Jack

Oxnard

Evangelist

et al. 2022

JCO Precision Oncology

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PURPOSE The CNS is a recurrent site of progression in anaplastic lymphoma kinase (ALK)–rearranged (ALK+) lung cancer. Lorlatinib is a third-generation ALK inhibitor developed to penetrate the CNS and overcome ALK resistance mutations. We conducted a phase II study to evaluate the intracranial activity of lorlatinib in patients with CNS-only progression on second-generation ALK inhibitors. METHODS Patients with ALK+ lung cancer who had intracranial progression on ≥ 1 ALK inhibitor without measurable extracranial disease received lorlatinib 100 mg once daily. The primary end point was intracranial disease control rate at 12 weeks per modified RECIST v1.1. Secondary end points included intracranial progression-free survival, intracranial objective response rate, and safety/tolerability. RESULTS Twenty-three patients were enrolled between November 2016 and January 2019. Fifteen (65%) patients had irradiated CNS metastases, with a median of 20.2 months between radiation and lorlatinib. Control of intracranial disease was observed in 21 (95%) evaluable patients at 12 weeks. The intracranial objective response rate was 59% with six complete and seven partial responses. The median intracranial progression-free survival was 24.6 months (95% CI, 20.2 to not reached). With a median follow-up of 16.8 months, nine patients developed disease progression, including four patients with CNS progression. The most common treatment-related adverse events were hypercholesterolemia (96%), hypertriglyceridemia (87%), edema (65%), cognitive effects (52%), and mood effects (43%). Three patients discontinued treatment because of toxicity, including two patients with fatal respiratory events. CONCLUSION Lorlatinib induced durable intracranial disease control in patients with CNS-only relapse on second-generation ALK inhibitors, suggesting that tumors with CNS-limited progression on brain-penetrant ALK tyrosine kinase inhibitors remain ALK-dependent.

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Section: Discussionmentioning

confidence: 99%

Phase II Study of Lorlatinib in Patients With Anaplastic Lymphoma Kinase–Positive Lung Cancer and CNS-Specific Relapse

Dagogo‐Jack

Oxnard

Evangelist

et al. 2022

JCO Precision Oncology

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“…Moreover, the risk of brain dissemination is higher in those tumors driven by oncogenes, including EGFR , ALK , ROS1 , and KRAS [ 109 , 110 ]. When it is possible to target these mutations, patients demonstrate good responses to targeted therapy with tyrosine kinase inhibitors (TKIs) [ 111 , 112 , 113 , 114 , 115 , 116 , 117 ]. However, a significant fraction of NSCLC is not driven by a specific oncogene [ 84 ] and therefore cannot benefit from targeted therapy.…”

Section: Ici For Brain Metastasesmentioning

confidence: 99%

The Current Landscape of Immune Checkpoint Inhibitor Immunotherapy for Primary and Metastatic Brain Tumors

Alimonti

Castro

2023

Antibodies

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Antibodies against immune checkpoint inhibitors (ICIs) have revolutionized the treatment of multiple aggressive malignancies, including melanoma and non-small cell lung cancer. ICIs for the treatment of primary and metastatic brain tumors have been used with varying degrees of success. Here, we discuss the available evidence for the use of ICIs in the treatment of primary and metastatic brain tumors, highlighting challenges and opportunities for furthering this type of cancer immunotherapy in neuro-oncology.

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“…109 Series and case reports suggest that dose escalation of TKIs could be beneficial. However, plasma and cerebrospinal fluid levels are not routinely tested or reported in these series, 137,[175][176][177][178] so it is possible that dose escalation is beneficial, specifically if patients do not achieve adequate plasma and cerebrospinal fluid levels. Of note, for osimertinib at 80-mg doses, the plasma concentrations of the drug (high 568 nM versus low < 568 nM) were not correlated with intracranial activity in terms of RR and PFS, which does not support the idea that higher upfront doses (such as 160 mg) achieve better intracranial outcomes.…”

Section: Systemic Treatment Of Nsclc Brain Metastasesmentioning

confidence: 99%

“…Currently robust trial data for patients with symptomatic brain metastases do not exist, although small retrospective series with CNS-penetrating TKIs have reported favorable outcomes, and further studies are warranted. [178][179][180][181][182] Despite the utility of TKIs among patients with NSCLC, a large subset of patients do not have an oncogenic driver event. Among these patients, ICIs as monotherapy or as combination with chemotherapy have become the standard first-line therapy.…”

Section: Systemic Treatment Of Nsclc Brain Metastasesmentioning

confidence: 99%

Emerging Systemic Treatment Perspectives on Brain Metastases: Moving Toward a Better Outlook for Patients

Alvarez‐Breckenridge

Remón

Piña

et al. 2022

American Society of Clinical Oncology Educational Book

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The diagnosis of brain metastases has historically been a dreaded, end-stage complication of systemic disease. Additionally, with the increasing effectiveness of systemic therapies that prolong life expectancy and improved imaging tools, the incidence of intracranial progression is becoming more common. Within this context, there has been increasing attention directed at understanding the molecular underpinnings of intracranial progression. Exploring the unique features of brain metastases compared with their extracranial counterparts to identify aberrant signaling pathways, which can be targeted pharmacologically, may help lead to new treatments for this patient population. Additionally, critical discoveries outside the sphere of the central nervous system are increasingly being applied to brain metastases with the emergence of immune checkpoint inhibition, becoming a prevalent treatment option for patients with brain metastases across multiple histologies. As novel treatment strategies are considered, they require thoughtful incorporation of agents that can cross the blood-brain barrier and can synergize with pre-existing agents through rational combinations. Lastly, as clinicians and scientists continue to understand key molecular features of these tumors, they will continue to influence the treatment algorithms that are developing for the management of these patients. Due to the complexity of treatment decisions for patients with brain metastases, an emerging tool is the utilization of multidisciplinary brain metastasis tumor boards to ensure optimal treatment decisions are made and that patients are provided access to applicable clinical trials. Looking to the future, the collective effort to understand the various tumor-intrinsic and tumor-extrinsic factors that promote central nervous system seeding and propagation will have the potential to change the clinical trajectory for these patients.

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Intracranial Response of ALK+ Non-Small-cell Lung Cancer to Second-line Dose-escalated Brigatinib After Alectinib Discontinuation Due to Drug-induced Hepatitis and Relapse After Whole Brain Radiotherapy Followed by Stereotactic Radiosurgery

Cited by 9 publications

References 16 publications

Phase II Study of Lorlatinib in Patients With Anaplastic Lymphoma Kinase–Positive Lung Cancer and CNS-Specific Relapse

Phase II Study of Lorlatinib in Patients With Anaplastic Lymphoma Kinase–Positive Lung Cancer and CNS-Specific Relapse

The Current Landscape of Immune Checkpoint Inhibitor Immunotherapy for Primary and Metastatic Brain Tumors

Emerging Systemic Treatment Perspectives on Brain Metastases: Moving Toward a Better Outlook for Patients

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