Mutational Complexity in ROS1-Positive mNSCLC: Insights from Real-World Practice

In the diverse landscape of metastatic non-small cell lung cancers (mNSCLC), ROS1 rearrangements occupy a rare but clinically significant niche, emerging in just under 2 percent of cases. While targeted therapies have reshaped the trajectory for these patients, the presence of additional mutations and the nuances of real-world treatment delivery can alter outcomes in important ways. A recent retrospective review of community oncology practice data sheds fresh light on the molecular heterogeneity, treatment choices, and survival patterns in this small patient population.

This analysis drew from a sizable base of 2,281 mNSCLC cases diagnosed between March 2018 and September 2024, identifying 43 patients (1.88 percent) with ROS1-positive disease. Data from electronic medical records were mined to capture clinical and molecular details.

Molecular Portrait and Testing Patterns

The median patient age was 60 years, but notably, four individuals were diagnosed before age 40, underscoring that ROS1 rearrangements can strike much earlier than typical lung cancer demographics suggest. Men slightly outnumbered women (M:F ratio 1.15:1).

Testing methods were varied:

• FISH identified rearrangements in 3 out of 43 cases
• IHC in 10 out of 33 cases
• NGS in 14 out of 43 cases
• 16 cases had undocumented methods

NGS data revealed a spectrum of fusion partners, with SDC4, CD74, SLC34A2, and EZR appearing most frequently. The analysis also uncovered co-mutations in 15 out of 43, most often involving EGFR and TP53. A single patient harbored both EGFR and ALK alterations alongside ROS1.

Brain metastases were present at diagnosis in 10 out of 43 patients, with some undergoing immediate local interventions—four received upfront radiation, and two underwent surgical resection.

Most patients in the study were treated with tyrosine kinase inhibitors (TKIs), with 28 individuals (65.1 percent) receiving them as monotherapy and two patients (4.6 percent) receiving them in combination with chemotherapy.

Median overall survival (mOS) across the cohort reached 42.3 months, with a median follow-up of 32.8 months. Outcomes did not significantly differ between men and women.

When parsing the impact of molecular complexity:

• ROS1-positive patients without additional mutations had an mOS of 39.1 months.
• Those with co-mutations lived a median of 42.3 months (p = 0.33).
• However, the type of co-mutation mattered: EGFR co-mutations still saw mOS of 42.3 months, while TP53 co-mutations dropped sharply to 21.9 months.

Key Takeaways and Clinical Reflections

Several considerations emerge from this real-world dataset:

1. Fusion partners and co-mutations may hold prognostic and therapeutic implications.
2. TKIs remain central, even as newer agents with better intracranial penetration become available for those with brain metastases.
3. Not all co-mutations are equal; TP53 alterations in particular may herald poorer outcomes and could warrant more aggressive or experimental approaches.

While targeted therapy has markedly improved survival for ROS1-driven disease, this analysis reinforces the need for comprehensive molecular profiling—not just to confirm ROS1 status, but to uncover additional drivers that may shape prognosis and treatment.

Reference:
Joshi K, Maheshwari U, Jobanputra K, et al. Real-world data of ROS-1 positive nsclcs- Mutational heterogeneity, clinical characteristics and its outcomes [abstract]. 2025 World Conference on Lung Cancer; September 9, 2025; Barcelona, Spain. Session EP.12.01. https://cattendee.abstractsonline.com/meeting/21151/Session/169