By Alice Shaw, MD, PhD
Posted: May 27, 2019
On November 2, 2018, lorlatinib, a potent and central nervous system (CNS)–penetrant next-generation ALK/ROS1 inhibitor, was granted accelerated approval by the U.S. Food and Drug Administration for the treatment of advanced ALKpositive lung cancer. The approval represents a significant advance for patients with ALK-positive lung cancer. Given lorlatinib’s dual inhibition of both ALK and ROS1, the approval also raises several important questions regarding its role in ROS1-positive lung cancer.
Clinical Activity in ROS1-Positive Lung Cancer
The phase I dose-escalation study of lorlatinib enrolled 54 patients, 12 of whom had ROS1-positive lung cancer.1 Among the 12 patients with ROS1-positive cancer, seven had received prior crizotinib. Objective responses were seen in six patients, yielding an objective response rate (ORR) of 50%; median progression-free survival (PFS) was 7 months. In the phase II study, 47 patients with ROS1-positive disease were enrolled into an expansion cohort and treated with standard-dose lorlatinib.2 Among the patients who were crizotinib naive, overall efficacy was robust with an ORR of 62% and a median PFS of 21 months. Clinical activity was also documented in the crizotinib-refractory setting for which chemotherapy is the current standard of care, with an ORR of 27% and a median PFS of 9 months, suggesting some ability to overcome resistance to crizotinib. Of particular importance, lorlatinib demonstrated marked intracranial activity regardless of prior crizotinib exposure, with more than half the patients exhibiting a significant and durable intracranial response to lorlatinib.
Off-Label Use for Patients with ROS1-Positive Disease
Since its approval 3 months ago, lorlatinib has been prescribed for many patients in the United States with ROS1-positive disease. However, the process is not straightforward, and in many cases, the initial request was denied, most often due to the apparent lack of indication. Letters of medical necessity summarizing the patient’s treatment course and citing the publicly available efficacy data (detailed previously) can often be successful in overturning a denial. In addition, referencing national guidelines such as National Comprehensive Cancer Network (NCCN) guidelines also carries significant weight, and the latest NCCN guidelines (version 3.2019) do recommend lorlatinib as a treatment option for patients with ROS1-positive disease that has progressed on crizotinib. In cases in which multiple appeals to the insurance company have failed, patients have applied successfully to the drug manufacturer (Pfizer) for free drug.
Several next-generation ROS1 inhibitors are in clinical trials for patients with ROS1-positive disease. As ROS1 rearrangement is found in only 1% of NSCLC, encouraging clinical trial participation, when appropriate, is critically important to evaluating these new therapies and advancing the field. However, if clinical trials are not available or appropriate for a given patient, then prescribing lorlatinib may be a reasonable option, especially if standard treatments (eg, crizotinib, platinum-pemetrexed chemotherapy) have failed. Lorlatinib should be considered for all patients with ROS1-positive disease that is resistant or intolerant of crizotinib. Given its potent intracranial activity, lorlatinib may be particularly helpful for patients who develop CNS metastases on crizotinib. For those patients with ROS1-positive disease who have CNS metastases at the time of diagnosis, the risk of CNS progression on crizotinib is extraordinarily high, so it may be reasonable to consider off -label lorlatinib as first-line therapy in such patients to better treat and potentially prevent CNS metastases.
Whether lorlatinib will eventually gain regulatory approval for ROS1 is unknown, but in the meantime, off-label use can be an important and in some cases life-saving option for our patients with ROS1-positive NSCLC. ✦
About the Author: Dr. Shaw is director of Thoracic Oncology, Paula O’Keeffe Endowed Chair in Thoracic Oncology, and professor of Medicine at Harvard Medical School.
1. Shaw AT, Felip E, Bauer TM, 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;18(12):1590-1599.
2. Ou SI, Shaw AT, Riely GJ, et al. Clinical Activity of Lorlatinib in Patients with ROS1+ Advanced Non-Small Cell Lung Cancer: Phase 2 Study Cohort EXP-6. Lecture presented at: IASLC 19th World Conference on Lung Cancer; September 24, 2018; Toronto, Canada.
“In The ROS1ders patient–caregiver group, we have seen many patients with ROS1-translocated NSCLC develop brain metastasis or other forms of disease progression during therapy with crizotinib. We are glad to have a second-line TKI as a treatment option, and we appreciate those providers who are willing to tackle extra paperwork to help us access it.” –Janet Freeman Daily, IASLC Lung Cancer News Associate Editor, Patient Advocacy