Lorlatinib Promising For Advanced ALK-, ROS1-Rearranged NSCLC

Preliminary findings indicate a role for the tyrosine kinase inhibitor lorlatinib in the treatment of ALK- or ROS1-rearranged locally advanced or metastatic non-small-cell lung cancer

medwireNews: Results of a first-in-man trial suggest that the third-generation ALK and ROS1 tyrosine kinase inhibitor (TKI) lorlatinib is well tolerated and has systemic and intracranial antitumour activity in patients with advanced non-small-cell lung cancer (NSCLC) harbouring ALK or ROS1 rearrangements.

The investigators explain that although ALK- or ROS1-positive NSCLC is responsive to TKI therapy, resistance invariably develops and relapses in the central nervous system (CNS) are common. Lorlatinib, a highly selective TKI that targets ALK and ROS1, “was designed to penetrate the blood–brain barrier and to overcome known ALK resistance mutations”, they add.

The phase I trial, reported in The Lancet Oncology, included 54 patients with locally advanced or metastatic NSCLC, of whom 41 were ALK-positive and 12 were ROS1-positive, while one patient had an unconfirmed status and was not included in the efficacy analyses. Participants received oral lorlatinib at doses ranging from 10 to 200 mg once a day or 35 to 100 mg twice a day until disease progression, unacceptable toxicity or death.

Hypercholesterolaemia was the most frequent treatment-related side effect of any grade, occurring in 72% of patients, followed by hypertriglyceridaemia, peripheral neuropathy and peripheral oedema, which were each observed in 39% of patients.

One patient in the 200 mg/day group experienced a dose-limiting toxicity, specifically grade 2 CNS effects including slowed speech and mentation and word-finding difficulty, which led to the patient not receiving 16 of the planned 21 doses. The neurological symptoms resolved 48 hours after the drug was discontinued.

Alice Shaw, from Massachusetts General Hospital in Boston, USA, and co-researchers say that a maximum tolerated dose was not established and they recommend the 100 mg/day dose for phase II trials on the basis of the safety profile, pharmacokinetic analysis and ease of administration.

Over a median follow-up of 17.4 months, 46% of 41 ALK-positive patients and 50% of 12 ROS1-positive patients had an objective response to lorlatinib treatment. The researchers report that the responses were “often rapid”, with median times to first response of 1.3 and 1.4 months, respectively.

Of note, lorlatinib elicited an intracranial response in 46% of the 24 patients (19 ALK-positive, five ROS1-positive) who had measurable CNS lesions at intake, and among 42% of 26 ALK-positive participants who had received two or more TKIs previously.

Interestingly, among ALK-positive patients, tumour regression was observed in all patients harbouring ALK resistance mutations – such as Gly1202Arg or Gly1202del – in pretreatment tumour samples, but not in those lacking such alterations. This suggests that the tumours remain ALK dependent, say Alice Shaw et al, adding that “[l]arger studies are needed to establish whether ALK resistance mutations detected at the time of relapse on a second-generation inhibitor can serve as a molecular predictor of response to lorlatinib.”

Writing in an accompanying commentary, Christine Bestvina and Everett Vokes, both from the University of Chicago in Illinois, USA, say that the trial “provides evidence of the systemic and CNS activity of lorlatinib for ALK-positive and ROS1-positive patients.”

And they conclude: “Lorlatinib could be an excellent therapeutic option for patients with CNS metastases, but additional trials are needed to establish the optimal sequencing of TKIs for patients who have NSCLC with ALK or ROS1 rearrangement.”


Shaw AT, Felip E, Bauer TM, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol; Advance online publication 23 October 2017. doi: http://dx.doi.org/10.1016/S1470-2045(17)30680-0

Bestvina CM, Vokes EE. ALK and ROS1 rearrangement in NSCLC: rapidly evolving standards. Lancet Oncol; Advance online publication 23 October 2017. doi: http://dx.doi.org/10.1016/S1470-2045(17)30708-8

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