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Lorlatinib induces deep responses in ROS1-positive NSCLC

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Early results promising

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 ).



The tyrosine kinase inhibitor (TKI) 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), according to results from a phase 1-2 trial.

“We investigated the antitumour activity and safety of lorlatinib in advanced, ROS1-positive NSCLC,” wrote Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center, Boston, and colleagues. Their report is in The Lancet Oncology.

The single-arm, open-label study included 69 patients with advanced ROS1-positive disease with or without CNS involvement. The effects of lorlatinib were evaluated across 28 institutions in 12 different countries around the globe.

At baseline, the median age of study participants was 54 years (range, 44-61 years), and 57% were positive for brain metastases.

Study participants received 100 mg of oral lorlatinib once daily in repeated 21-day cycles. Drug therapy was continued until death, disease progression, unacceptable toxicity, or withdrawal of consent.

The primary outcome measured was intracranial and overall response. Activity outcomes were evaluated in subjects given a minimum of one dose of lorlatinib.

A total of 58% of patients were previously treated with crizotinib, while 30% of patients were TKI-naive. 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.

Among 21 TKI-naive patients, 13 patients (62%) had an objective response, with a median duration of response and PFS of 25.3 and 21 months, respectively.

“Intracranial responses were achieved in seven (64%) of 11 TKI-naive patients and 12 (50%) of 24 previous crizotinib-only patients,” they reported.

With respect to safety, serious lorlatinib-related adverse events were observed in 7% of patients, with no therapy-related deaths reported. The most frequently seen grade 3-4 TEAEs were hypertriglyceridemia (19%) and hypercholesterolemia (14%).

The researchers noted a key limitation of the study was the small sample size; however, due to the rare nature of ROS1 rearrangements in patients with NSCLC, increasing enrollment for future studies could be challenging.

“Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent,” they concluded.

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.

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

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