Modern Management of ROS1-Positive Non-Small Cell Lung Cancer

ROS1-rearranged non-small cell lung cancer has emerged as a rapidly evolving therapeutic landscape, driven by advances ROS1-targeted TKIs and next-generation inhibitors. In a November 2025 review published in Current Oncology, Bischoff and colleagues provide an overview of our current understanding of ROS1-rearranged disease, integrating data on efficacy, intracranial disease control, and mechanisms of resistance.

Representing approximately 2% of non-small cell lung cancer cases, ROS1+ disease is more commonly observed in women, younger patients, never-smokers, Asian populations, and patients with adenocarcinoma histology. Clinically, it is characterized by a pronounced burden of central nervous system (CNS) disease, with brain metastases present in approximately 30–40% of patients at diagnosis and developing in up to ~75% over the disease course. As a result, durable intracranial disease control has become a central therapeutic objective.

Crizotinib provided early clinical validation of ROS1 as a targetable oncogenic driver and became a standard of care following regulatory approvals in 2016. High systemic response rates and prolonged survival outcomes established proof of principle for ROS1-directed therapy. However, limited CNS penetration and predictable patterns of acquired resistance quickly highlighted the need for more potent, brain-penetrant inhibitors capable of addressing both intracranial disease and evolving tumor biology.

CNS Penetration as a Therapeutic Differentiator
Entrectinib was designed to address the CNS limitations of first-generation ROS1 inhibition and demonstrated durable systemic and intracranial activity in tyrosine kinase inhibitor (TKI)-naïve patients, including those with baseline brain metastases. These findings positioned entrectinib as a clinically meaningful option, particularly for patients with established CNS involvement. At the same time, its modest efficacy following crizotinib progression highlighted how earlier treatment choices may shape resistance patterns and influence subsequent disease control in ROS1+ non-small cell lung cancer.

Lorlatinib further advanced the field by delivering robust CNS activity and activity against select secondary ROS1 mutations, supported by both prospective studies and real-world experience. However, limited efficacy against the G2032R mutation, coupled with a distinctive neurocognitive and metabolic toxicity profile, constrains its broader positioning within the treatment landscape.

Next-Generation Inhibitors Raise the Bar
The treatment landscape has shifted with the development of next-generation ROS1 inhibitors engineered around resistance biology and CNS penetration. Repotrectinib, a compact macrocyclic TKI, has demonstrated strong systemic and intracranial efficacy in both TKI-naïve and pretreated patients, including meaningful activity against the G2032Rmutation. Its retained activity following prior ROS1 inhibition highlights a clear advance in addressing resistance compared with earlier agents.

Taletrectinib reflects a complementary design strategy. Highly selective for ROS1 and sparing of tropomyosin receptor kinase (TRK) inhibition, it delivers potent systemic and CNS activity with lower rates of neurologic adverse events consistent with its TRK-sparing profile. In integrated TRUST analyses, taletrectinib achieved a median progression-free survival of 45.6 months in TKI-naïve patients, alongside robust intracranial responses. While cross-trial comparisons warrant caution, these data suggest that early deployment of highly selective, brain-penetrant inhibition may translate into sustained disease control.

Zidesamtinib (NVL-520) is emerging as another promising addition to the ROS1 TKI armamentarium. Designed to maintain potency against G2032R while minimizing TRK-related neurologic effects, early ARROS-1 data show encouraging systemic and intracranial activity even in heavily pretreated populations, supporting its potential role across multiple lines of therapy.

Resistance Remains Inevitable, but Increasingly Actionable
Despite these therapeutic advances, disease progression remains common. Approximately 40% of resistance events are driven by on-target ROS1 kinase mutations, with the remainder arising from off-target mechanisms such as MET amplification or activation of the KRAS signaling pathway. This heterogeneity highlights the importance of molecular reassessment at progression. Both tissue re-biopsy and liquid biopsy play a critical role in guiding rational treatment sequencing rather than empiric therapy changes.

From a clinical standpoint, management is increasingly pattern-based. Isolated CNS progression may be managed with local therapy while maintaining the current TKI, whereas systemic progression should prompt mutation-directed switching to a next-generation inhibitor or consideration of clinical trial enrollment. Pemetrexed-based chemotherapy continues to have a role when no actionable resistance mutation is identified or targeted options are exhausted. Immune checkpoint inhibitor monotherapy demonstrates limited activity and is not recommended in current guidance for ROS1-rearranged non-small cell lung cancer, while any benefit from chemo-immunotherapy appears largely attributable to the chemotherapy component.

Looking Ahead
While prospective head-to-head trials are needed to refine optimal sequencing in ROS1+ non-small cell lung cancer, existing evidence highlights the limitations of crizotinib and the emerging role of next-generation ROS1 inhibitors in the first-line setting. For clinicians, these advances frame comprehensive molecular testing, early CNS-active therapy selection, and adaptive treatment strategies as increasingly important considerations.

Reference:
Bischoff H, Gendarme S, Somme L, Chouaid C, Schott R. Evolving therapeutic landscape of ROS1-positive non-small cell lung cancer: An updated review. Curr Oncol. 2025;32:626. doi:10.3390/curroncol32110626