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

Schneider, Jaime L.; Muzikansky, Alona; Lin, Jessica J.; Krueger, Elizabeth; Lennes, Inga T.; Jacobson, Joseph O.; Cheng, Michael L.; Heist, Rebecca S.; Piotrowska, Zofia; Gainor, Justin F.; Shaw, Alice T.; Dagogo-Jack, Ibiay

doi:10.1016/j.jtocrr.2022.100347

Cited by 4 publications

(5 citation statements)

References 16 publications

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“…Interestingly, the present report suggests that the CSF penetration of repotrectinib is intermediate between crizotinib (median = 0.2%) and lorlatinib (median for unbound drug = 67.9%) (Table 2 ) [ 13 – 16 ]. In line with this, lorlatinib has demonstrated an exceptional antitumor activity in ROS1 -positive NSCLCs with CNS-only disease progression who were refractory to the ROS1-TKI crizotinib [ 4 ]. Consistently, a recently published case report has described a “Lazarus” response to lorlatinib in a patient with meningeal carcinomatosis without additional mutation(s) potentially implicated in resistance across the ROS1 kinase domain (e.g., G2032R) [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the management of central nervous system (CNS) metastases from ROS1 -positive disease remains a relevant issue, since 25–35% of ROS1 -rearranged advanced NSCLCs present with brain metastases at first diagnosis, while more than 40% of patients will develop CNS metastases after treatment with ≥ 1 ROS1-TKI(s) [ 3 ]. The highly CNS-penetrant ROS1/ALK-TKI lorlatinib could be a valid option in ROS1-TKI(s)-pretreated patients with CNS-only progression [ 4 ]. However, lorlatinib lacks efficacy against the ROS1 solvent front mutation (SFM) G2032R, which occurs in approximately one third of ROS1-TKI(s)-pretreated patients, thus potentially limiting its use in the refractory setting [ 5 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…The study showed notable efficacy of lorlatinib in controlling brain disease, with an intracranial ORR of 87% and a complete intracranial response in 60% of patients. The median intracranial PFS was 38.8 months, and the extracranial PFS was 41.1 months [ 40 ].…”

Section: Place In Therapy Of Lorlatinib For Ros1 Rearranged Nsclcmentioning

confidence: 99%

“… LOR = Lorlatinib; CRI = Crizotinib; ORR = Overall Response Rate; DoR = Duration of Response; IC-ORR = IntraCranial Overall Response Rate; IC-DoR = IntraCranial Duration of Response; PFS = Progression Free Survival; NR = Not Reached; BM = Brain Metastases; 2G = Second Generation; TKI = Tyrosine Kinase Inhibitor; ALK = Anaplastic Lymphoma Kinase; CHT = Chemotherapy; NSCLC = Non Small Cell Lung Cancer; PEM = Pemetrexed; ALE = Alectinib; 1–2–3L = First–Second–Third Line; R = Retrospective [ 18 , 25 , 26 , 27 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. …”

Section: Figurementioning

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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“…In the crown phase 3 study, the 3-year PFS was 64% and 19%, respectively ( 39 ). Lorlatinib also showed good intracranial activity in patients with ros1 rearranged NSCLC who developed CNS progression after Crizotinib treatment ( 40 ). At present, the efficacy of ALK/ROS1-TKI combined with radiotherapy is not clear, and most of them are for NSCLC patients with brain metastasis.…”

Section: Alk/ros1-tki Combined With Radiotherapymentioning

confidence: 99%

Recent advances progress of targeted drugs combined with radiotherapy for advanced non-small cell lung cancer: a review

Xu,

Wang

2023

Front. Oncol.

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Targeted drug therapy plays an important role in the clinical application of non-small cell lung cancer, especially adenocarcinoma. However, for patients with advanced disease, drug resistance after targeted therapy, unclear target, and other reasons that cannot or do not want surgery, the combination of chemotherapy, radiotherapy, immunity, etc. is often used. The synergistic effect of targeted drugs and radiotherapy in non-small cell lung cancer has shown good clinical efficacy. This article reviews the clinical progress of targeted drug therapy combined with radiotherapy in advanced non-small cell lung cancer in recent years, in order to provide new ideas for further clinical research of this treatment mode.

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

Cited by 4 publications

References 16 publications

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

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

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

Recent advances progress of targeted drugs combined with radiotherapy for advanced non-small cell lung cancer: a review

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