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.