Advancing Care and Future Impact of NCCN Updates in ROS1+ NSCLC

A key barrier in advancing care for ROS1-positive non-small cell lung cancer (NSCLC) is the rarity of the condition, affecting only about 1.5% to 2% of patients. While this still represents a notable population given the prevalence of lung cancer overall, the low incidence makes clinical trial enrollment difficult. Recruiting enough patients to detect meaningful treatment signals is challenging, especially for studying resistance mechanisms or evaluating next-generation therapies. Additionally, it's harder to develop combination strategies to address acquired resistance because the specific mutations involved are even rarer subsets within an already small group.

Access to clinical trials remains another significant issue. Many patients may not live near centers running ROS1-specific studies, or may not be aware of these opportunities. This limits the ability to move beyond standard-of-care options, particularly when newer agents are being tested or when combination treatments are being explored for post-resistance scenarios. Despite these challenges, continued efforts in trial design, patient referral networks, and industry engagement are essential to push the field forward.

The 2025 NCCN guideline updates are expected to positively impact clinical workflows and patient outcomes. The inclusion of talotrectinib—due to its high response rate and extended progression-free survival—marks a significant advance. These updates reinforce the importance of initiating treatment with targeted ROS1 therapies rather than immunotherapy, which lacks efficacy in this setting and may increase toxicity if used prior to TKIs. Ensuring comprehensive molecular testing is completed before initiating therapy is critical. These changes will help streamline sequencing decisions, encourage appropriate drug selection from the outset, and ultimately improve the prognosis for ROS1-positive patients. Avoiding immune checkpoint inhibitors in this population and acting swiftly once molecular results are available are emphasized as practical changes in clinical strategy moving forward.