Phase 1 Trial of Lorlatinib for Non-Small Cell Lung Cancer
Introduction to Non-Small Cell Lung Cancer
A phase 1, first-in-man trial has been initiated to evaluate lorlatinib as a treatment option for non-small cell lung cancer (NSCLC), which is the most prevalent type of lung cancer. Treatments for cancer are often tailored to specific patient subgroups, including those with mutations in the ALK and ROS1 genes. These mutations result in genetic rearrangements that lead to the persistent activation of ALK and ROS1 proteins, causing uncontrolled tumor cell growth.
Understanding ALK and ROS1 Mutations
ALK and ROS1 are part of the tyrosine kinase enzyme family, targeted by drugs known as tyrosine kinase inhibitors (TKIs). While TKIs are effective in slowing cancer progression, they are not curative, and resistance to these drugs can develop over time. The first-line treatment for NSCLC typically involves the first-generation TKI crizotinib, followed by second-generation TKIs when resistance occurs.
Overview of Lorlatinib
Lorlatinib is a third-generation, selective TKI that targets both ALK and ROS1. It is specifically designed to penetrate the blood-brain barrier and overcome ALK resistance mechanisms. Promising outcomes have been observed in preclinical studies, prompting a dose-finding study funded by Pfizer to assess lorlatinib’s safety and efficacy in NSCLC patients.
Study Design and Methodology
The study included 54 patients with advanced NSCLC caused by ALK/ROS1 mutations. Participants received escalating doses of lorlatinib, ranging from 10 to 200 mg daily, administered in 21-day cycles until toxicity was noted. Blood samples were collected on the first and fifteenth days of each cycle, while urinalysis was conducted once per cycle. Safety assessments occurred weekly during the first cycle and once per cycle thereafter. Tumor measurements were taken via CT scans at baseline and every six weeks.
Results of the Study
The findings indicated that lorlatinib was generally well tolerated and demonstrated clinical activity in patients with ALK and ROS1 mutations. Among patients who had previously developed resistance to other TKIs, 42% showed a confirmed tumor response to lorlatinib. The most frequently reported adverse event was hypercholesterolemia, affecting 72% of participants. One patient experienced significant side effects at the 200 mg dose, including slowed speech and cognitive impairment, which resolved after discontinuing treatment. Additional side effects included peripheral edema, weight gain, and constipation, suggesting that lorlatinib may disrupt lipid metabolism.
Conclusion and Future Directions
The researchers concluded that lorlatinib holds promise as an effective treatment for NSCLC patients resistant to first and second-generation TKIs. It is currently undergoing evaluation in a phase 3 randomized controlled trial, comparing its efficacy to that of crizotinib.
Reference
Shaw et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017 Dec;18(12):1590-1599. doi: 10.1016/S1470-2045(17)30680-0. Epub 2017 Oct 23.