There may be a new therapeutic option in patients with ROS1-positive non small-cell lung cancer (NSCLC), according to interim findings from an ongoing phase 1-2 study.

An international, multi-center research team concluded that lorlatinib (Lorbrena; Pfizer) demonstrated clinical activity in patients with the disease, including those with central nervous system metastases and those previously treated with crizotinib (Xalkori; Pfizer). 

Cancer cells. Source: Getty

Reporting in The Lancet Oncology, the investigators explained that lorlatinib is a third-generation tyrosine kinase inhibitor (TKI) that targets both ALK and ROS1. The agent has demonstrated preclinical activity against most known resistance mutations in ALK and ROS1. 

To further elucidate the role of the agent in the disease, the researchers -- led by Alice T. Shaw, MD, PhD, Director of Thoracic Oncology at Massachusetts General Hospital -- investigated lorlatinib’s antitumor activity and safety in a cohort of people with advanced, ROS1-positive NSCLC.

As part of the open-label, single-arm, phase 1-2 trial (NCT01970865), Dr. Shaw and her colleagues enrolled 364 adult patients from 28 hospitals in 12 countries into the international investigation between January 22, 2014 and October 2, 2016. Each participant had histologically or cytologically confirmed advanced ROS1-positive NSCLC with or without central nervous system metastases, and an Eastern Cooperative Oncology Group performance status ≤2. 

Participants each received a once-daily oral dose of 100 mg lorlatinib in a continuous 21-day cycle. Such dosing continued until patients reached one of four milestones: investigator-determined disease progression, unacceptable toxicity, withdrawal of consent, or death. In phase 1 of the trial, patients received escalating lorlatinib doses ranging from 10 mg once daily to 100 mg twice daily.

The study’s primary endpoint was overall and intracranial tumor response, which was assessed by independent central review. Patients who received at least one lorlatinib dose were also assessed for a variety of activity endpoints. 

The study found that 69 individuals had ROS1-positive NSCLC. Of these, 21 (30%) were TKI-naive, 40 (58%) had previously received crizotinib as their only TKI, and eight (12%) had previously received either one non-crizotinib ROS1 TKI or at least two ROS1 TKIs. The estimated median duration of follow-up for response was 21.1 months (interquartile range: 15.2-30.3 months). 

The study found that 13 of 21 TKI-naive patients (62%; 95% confidence interval: 38-82%) had an objective response. Similarly, 14 of the 40 patients who had been previously treated with crizotinib (35%; 95% CI: 21-52%) as their only TKI also had an objective response. 

Intracranial responses were achieved in seven of 11 TKI-naive patients (64%; 95% CI 31-89%), and 12 of 24 individuals previously treated with crizotinib only (50%; 95% CI: 29-71%). 

Hypertriglyceridemia was the most common grade 3-4 treatment-related adverse event, which affected 13 of the 69 patients (19%), followed by hypercholesterolemia (10 patients; 14%). Serious treatment-related adverse events were observed in five of the participants (7%). 

No treatment-related deaths were reported.

Although the study is ongoing and in its early stages, the researchers were nonetheless hopeful that lorlatinib may represent a therapeutic alternative in patients with ROS1-positive NSCLC, particularly among patients previously with crizotinib. 

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