Recent advancements in the treatment of ROS1-positive non-small cell lung cancer (NSCLC) have significantly improved patient outcomes, offering a wider array of therapeutic options. Dr. Jorge J. Nieva, an associate professor of clinical medicine at the University of Southern California, highlighted these developments during his presentation at the 26th Annual International Lung Cancer Congress held in March 2024.
Dr. Nieva emphasized that following the introduction of crizotinib (Xalkori), subsequent generations of drugs have demonstrated enhanced efficacy and reduced toxicity, facilitating personalized treatment strategies. “The great news is that we have a world of choices,” he stated. “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 noted that each new generation of treatments appears to outperform its predecessor.
In total, there are five additional targeted agents available for ROS1-positive NSCLC beyond crizotinib: entrectinib (Rozlytrek), repotrectinib (Augtyro), taletrectinib (Ibtrozi), lorlatinib (Lorbrena), and zidesamtinib, the latter of which is not yet approved by the FDA. While lorlatinib lacks specific approval for ROS1-positive disease, it exhibits significant ROS1 activity.
Comparative Efficacy of New Treatments
Dr. Nieva referenced a series of matching-adjusted indirect comparisons (MAICs) that evaluated the effectiveness of these agents. In one MAIC published in the Journal of Comparative Effectiveness Research, entrectinib was compared to crizotinib. The data indicated that entrectinib achieved significantly better response rates, with odds ratios ranging from 2.43 to 2.74, though progression-free survival (PFS) rates were similar for both treatments.
Another MAIC compared repotrectinib to crizotinib, revealing a notable PFS advantage for patients treated with repotrectinib, with a hazard ratio (HR) of 0.44 (95% confidence interval [CI], 0.29-0.67). Dr. Nieva remarked, “The PFS data are similar between entrectinib and crizotinib. However, looking at repotrectinib vs crizotinib, the HR for PFS is much better in favor of repotrectinib.”
Further comparisons involving taletrectinib showed that it provided significant overall survival (OS) and PFS benefits relative to crizotinib. After population adjustment, taletrectinib users experienced a 52% reduction in the risk of disease progression or death (HR, 0.48; 95% CI, 0.27-0.88) and a 66% decrease in mortality risk (HR, 0.34; 95% CI, 0.15-0.77).
Additionally, taletrectinib was shown to be superior to entrectinib in patients who had not previously received a tyrosine kinase inhibitor (TKI). The adjusted HR for OS was 0.48 (95% CI, 0.27-0.88), and it also outperformed entrectinib regarding PFS and duration of response (DOR).
In comparisons of taletrectinib and repotrectinib, taletrectinib demonstrated an overall response rate (ORR) of 88.8% in TKI-naive patients, while repotrectinib had an ORR of 78.9%. In patients previously treated with a TKI, the ORR for taletrectinib was 55.8%, compared to 37.5% for repotrectinib.
Focus on Treatment Tolerability
Dr. Nieva concluded his presentation by addressing the importance of considering toxicity profiles when choosing among these agents for patients with ROS1-positive NSCLC. He noted that crizotinib is associated with central nervous system (CNS) toxicities alongside common side effects like nausea, vomiting, diarrhea, and fatigue, which are typically manageable.
Both entrectinib and repotrectinib may lead to side effects such as weight gain, constipation, and diarrhea. In contrast, taletrectinib presents a different toxicity profile, with fewer instances of CNS-related side effects but an increased occurrence of gastrointestinal issues, including liver function test abnormalities and nausea.
“I’d like to see more trials that are similar to the phase 3 FLAURA2 trial (NCT04035486) that look at these agents in combination with chemotherapy,” Dr. Nieva stated, advocating for further research to enhance treatment intensification and achieve longer-term disease control for patients with ROS1-positive NSCLC.
The evolving landscape of targeted therapies for ROS1-positive NSCLC highlights the potential for improved outcomes through individualized treatment approaches, offering hope to patients facing this challenging diagnosis.