Clinical Edge

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Lorlatinib Induces Deep Responses in ROS1-Positive NSCLC

Key clinical point: Lorlatinib showed deep responses and intracranial activity in both TKI-pretreated and TKI-naive patients with advanced ROS1-positive non–small cell lung cancer (NSCLC).

Major finding: Among 40 crizotinib-pretreated patients, 14 patients (35%) had an objective response, with a median duration of response and PFS of 13.8 and 8.5 months, respectively.

Study details: A phase 1-2 study of 69 patients with advanced ROS1-positive NSCLC.

Disclosures: Pfizer funded the study. The authors reported financial affiliations with Ariad, Blueprint Medicines, Chugai Pharmaceutical, Daiichi Sankyo, EMD Serono, Pfizer, KSQ Therapeutics, Servier, TP Therapeutics, and other companies.


Shaw AT et al. Lancet Oncol. 2019 Oct 25. doi: 10.1016/S1470-2045(19)30655-2.


The tyrosine kinase inhibitor (TKI) crizotinib was recently established as an optimal first-line treatment option for patients with ROS1-positive non–small cell lung cancer (NSCLC). Despite strong efficacy seen in clinical trials, disease progression can still occur in patients on crizotinib, often through the development of resistance, which is largely the result of on-target mutations, such as Gly2032Arg.

Early results suggest the novel oral TKI candidate, lorlatinib, a potent inhibitor of the Gly2032Arg mutation, may be a treatment of choice in patients with crizotinib-resistance. Recent phase 1 data showed lorlatinib had antitumor activity in ROS1-positive patients.

Correspondingly, the deep and durable responses reported by Dr. Shaw and colleagues represents a significant milestone for lorlatinib, particularly in the setting of crizotinib resistance, where a paucity of later-line treatment options exist. In comparison to platinum-pemetrexed chemotherapy, lorlatinib is better tolerated and has demonstrated potent intracranial activity, which may prevent or delay CNS progression in the disease.

One question that remains from the current study is whether other ROS1 TKI drug candidates, such as repotrectinib and entrectinib, will show similar results to lorlatinib. Several trials are presently ongoing in an attempt to help answer this, and other remaining questions.

Michaël Duruisseaux, MD, PhD, is affiliated with the Hospices Civils de Lyon (France), Universit é Claude Bernard Lyon. Dr. Duruisseaux reported financial affiliations with Boehringer Ingelheim, Bristol-Myers Squibb, Roche, and Takeda. These comments are adapted from his editorial (Lancet Oncol. 2019 Oct 25. doi: 10.1016/S1470-2045[19]30716-8 ).