Recent advancements in the treatment of ROS1-positive non-small cell lung cancer (NSCLC) have opened new avenues for personalized therapy. Jorge J. Nieva, MD, an associate professor of clinical medicine at the University of Southern California Keck School of Medicine, highlighted these innovations during a presentation at the 26th Annual International Lung Cancer Congress. He noted that the evolution of targeted therapies, starting with crizotinib (Xalkori), has led to improved efficacy and reduced toxicity.
Nieva emphasized the increasing variety of treatment options, stating, “The great news is that we have a world of choices. For the vast majority of us in the US, we’re going to have more drugs than we have patients with ROS1-positive disease.” He indicated that as new generations of drugs are developed, each shows enhanced effectiveness compared to its predecessor.
Emerging Therapies and Comparative Data
Beyond crizotinib, there are five additional targeted agents available for ROS1-positive NSCLC: entrectinib (Rozlytrek), repotrectinib (Augtyro), taletrectinib (Ibtrozi), lorlatinib (Lorbrena), and zidesamtinib. While zidesamtinib is not yet approved by the FDA, and lorlatinib has not gained approval specifically for ROS1-positive patients, it exhibits significant ROS1 activity.
Nieva presented findings from a series of matching-adjusted indirect comparisons (MAICs) that examined the efficacy of these drugs. Results from a study published in the Journal of Comparative Effectiveness Research demonstrated that entrectinib achieved significantly better response rates compared to crizotinib, although progression-free survival (PFS) data were comparable between the two agents.
In a separate analysis comparing repotrectinib with crizotinib, patients receiving repotrectinib showed a substantial PFS benefit, with a hazard ratio (HR) of 0.44 (95% CI, 0.29-0.67). Nieva commented on these findings, noting, “While the PFS data are similar between entrectinib and crizotinib, the HR for PFS is much better in favor of repotrectinib.”
A third MAIC indicated that taletrectinib provided significant overall survival (OS) and PFS benefits compared to crizotinib. Specifically, patients treated with taletrectinib experienced a 52% reduction in the risk of disease progression or death (HR, 0.48; 95% CI, 0.27-0.88) and a 66% lower risk of death (HR, 0.34; 95% CI, 0.15-0.77).
Key Findings and Treatment Considerations
Further data revealed that taletrectinib demonstrated distinct benefits over entrectinib for patients with ROS1-positive disease who had not previously received a tyrosine kinase inhibitor (TKI), with an adjusted HR of 0.48 for OS (95% CI, 0.27-0.88). Taletrectinib also showed superior PFS and duration of response (DOR) when compared to entrectinib.
When evaluating taletrectinib against repotrectinib, results showed an overall response rate (ORR) of 88.8% for taletrectinib compared to 78.9% for repotrectinib in TKI-naive patients. In those who had previously received a TKI, the ORR for taletrectinib was 55.8% while repotrectinib’s rate was 37.5%.
Nieva concluded his presentation by highlighting that the choice of agents often revolves around the toxicity profiles of the drugs. While crizotinib is associated with central nervous system (CNS) toxicities and gastrointestinal issues such as nausea and fatigue, both entrectinib and repotrectinib can lead to weight gain and constipation. Taletrectinib, in contrast, has a different toxicity profile, resulting in fewer CNS-related side effects but more gastrointestinal complications, including liver function abnormalities.
Nieva expressed the need for more clinical trials, particularly those similar to the phase 3 FLAURA2 trial (NCT04035486), to explore the effectiveness of these agents in combination with chemotherapy. He stated that such studies could lead to enhanced treatment intensification and improved long-term disease control for patients with ROS1-positive NSCLC.
