Lorlatinib Highly Effective for Relapsed ALK or ROS1 Rearranged NSCLC

While several targeted therapies have emerged in recent years for treatment of non-small cell lung cancer (NSCLC) carrying the anaplastic lymphoma kinase (ALK) gene fusion, development of resistance to ALK inhibitors is an increasing problem. Furthermore, only one tyrosine kinase inhibitor (TKI), crizotinib, is currently approved for patients with ROS proto-oncogene 1 (ROS1) rearrangements. Lorlatinib, a novel, highly selective ALK and ROS1 targeting third-generation TKI has shown preclinical activity against known ALK resistance mutations and can penetrate the central nervous system (CNS), a common site of metastasis in ALK-positive or ROS1-positive NSCLC.

In a multicenter, open-label, phase I dose escalation study, the safety and efficacy of lorlatinib at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily was evaluated in patients (N = 54) with advanced ALK or ROS1 rearranged NSCLC. The majority of patients had been previously treated with crizotinib, and 52% had received at least two TKIs. Central nervous system metastases were present in 72% of patients.

An objective response rate (ORR) of 46% was achieved in patients with ALK rearrangements, including 3 (7%) complete responses (CR). In patients who had received two or more distinct ALK TKIs prior to lorlatinib treatment, the ORR was 42%. Responses occurred rapidly, with a median time to response of 1.3 months, and the estimated median duration of response (DoR) in responding patients was 12.4 months. Of the 12 patients with ROS1 rearranged NSCLC, six (50%) achieved a confirmed partial response on lorlatinib treatment, and 2 (17%) had stable disease. Two responding patients had received prior treatment with crizotinib. Median DoR in ROS1 patients was 12.0 months. In the 24 patients with measurable CNS metastases at baseline, lorlatinib treatment resulted in a 46% rate of confirmed intracranial response, including a 29% CR rate. Of note, in a retrospective subset analysis of 12 patients for whom one or more second-generation TKIs had failed and who had undergone a biopsy while on the last TKI, lorlatinib demonstrated activity in 67% with known resistance mutations such as Gly1202Arg or Gly1202del, but showed no response in 4 patients without detectable ALK kinase domain mutation (other genetic alterations were identified).

Lorlatinib was generally well-tolerated. The most common treatment-related adverse events (AEs) were hypercholesterolemia (72%), hypertriglyceridemia (39%), peripheral neuropathy (39%), and peripheral edema (39%). Dose reductions due to AEs were required in 24% of patients, and 33% temporarily discontinued lorlatinib due to AEs. There was a single dose-limiting toxicity of grade 2 CNS effects at the 200-mg dose in a patient with brain metastases. A dose of 100 mg once daily was selected for future studies.

The investigators concluded that lorlatinib was well-tolerated and had both systemic and intracranial activity in patients with ALK-positive or ROS1-positive NSCLC. Lorlatinib may serve as an effective therapeutic option in patients with ALK or ROS1 rearranged NSCLC who have become resistant to currently available first-generation or second-generation TKIs.

In recently presented phase II data at 18th IASLC World Conference on Lung Cancer (abstract OA 05.06), lorlatinib 100 mg once daily confirmed clinically meaningful activity in ALK-positive and ROS1-positive treatment in both, treatment-naïve (ORR 90%) or pretreated patients, including those with brain metastases. In addition, lorlatinib improved quality of life and lung cancer symptoms such as pain, dyspnea, cough, and fatigue.


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