# Clinical Progression Modes of Crizotinib Failure and Subsequent Management of Advanced Non‐Small Cell Lung Cancer With ROS1 Rearrangement

## TL;DR

This study examines how non-small cell lung cancer patients with ROS1 rearrangements progress after crizotinib treatment and identifies patterns that influence survival and treatment options.

## Contribution

The study identifies distinct progression modes after crizotinib failure in ROS1-rearranged NSCLC and links them to survival outcomes and resistance mechanisms.

## Key findings

- Patients with gradual/local progression had significantly better survival outcomes compared to those with dramatic progression.
- Chemotherapy after crizotinib failure in dramatic progression cases provided better survival than other therapies.
- ROS1 kinase domain mutations were more common in dramatic progression, while bypass pathways were linked to gradual progression.

## Abstract

Crizotinib is the classic first‐line treatment for ROS1‐rearranged NSCLC. However, data on the clinical progression modes and recommended options for subsequent treatments after crizotinib treatment failure are limited.

Twenty‐eight patients were categorized into dramatic or gradual/local progression groups. We analyzed the clinical characteristics, survival outcomes, and potential resistance mechanisms in different progression modes.

The median progression‐free survival (mPFS) in the dramatic and gradual/local progression groups was 8.0 and 22.0 months, respectively (p < 0.001). The median overall survival (mOS) was 14.2 and 90.3 months in the dramatic progression and gradual/local progression groups, respectively (p < 0.001). Among patients with dramatic progression after crizotinib failure, significant differences were shown in median post‐progression overall survival (mpOS) (7.1 vs. 3.6 vs. 1.0 months, p = 0.037) and mOS (23.1 vs. 18.3 vs. 10.6 months, p = 0.002) across subsequent chemotherapy, targeted therapy, or best supportive care (BSC). ROS1 kinase domain point mutations were detected predominantly in the dramatic progression group, while the activation of bypass and downstream pathways occurred in the gradual/local progression group.

The progression modes of ROS1 rearrangement may predict survival benefits and provide subsequent treatment strategies in ROS1‐rearranged NSCLC.

Survival outcomes in gradual/local progression group were superior to dramatic progression group; survival period of dramatic progression group who received chemotherapy was longer than that of other therapies. ROS1 kinase domain mutations were detected predominantly in dramatic progression group, whereas activation of bypass and downstream pathways was found in gradual/local progression group.