Repotrectinib or entrectinib as first-line?

Repotrectinib (TRIDENT-1) showed an objective response rate of 79% in TKI-naive patients with sustained CNS efficacy. Entrectinib remains a strong option with good CNS data. Repotrectinib also covers G2032R, which entrectinib does not — relevant if early resistance signal emerges.

Is crizotinib still appropriate?

Crizotinib has FDA approval for ROS1+ NSCLC and remains effective, but its CNS efficacy is limited. For patients with brain metastases or younger patients where CNS protection matters, entrectinib or repotrectinib is preferred.

Does ROS1 fusion-positive NSCLC respond to checkpoint inhibitors?

Generally no. ROS1 fusion-positive NSCLC mirrors ALK fusion-positive NSCLC in poor response to single-agent PD-1/PD-L1 inhibitors. Targeted TKI therapy is the standard.

Variant cheat sheet · NSCLC

ROS1 fusions in non-small cell lung cancer

Free clinical reference. Educational use only — not a substitute for professional medical advice.

TL;DR

ROS1 fusion-positive NSCLC is AMP/ASCO/CAP Tier I-A. First-line standard is entrectinib or repotrectinib (TRIDENT-1), both with FDA approval and good CNS penetration. Crizotinib remains an option but has weaker CNS efficacy. ROS1 G2032R is the dominant solvent-front resistance allele; repotrectinib retains activity.

Biology

ROS1 is a receptor tyrosine kinase with ~77% kinase-domain homology to ALK. Fusions arise from rearrangements on chromosome 6q22 involving partners like CD74, SDC4, SLC34A2, EZR. The fusion protein constitutively activates MAPK and PI3K/AKT signaling. Fusions are mutually exclusive with EGFR, KRAS, ALK, and other oncogenic drivers.

Epidemiology

ROS1 fusions occur in roughly 1-2% of NSCLC, enriched in adenocarcinoma, never-smokers, and younger patients. CD74-ROS1 is the most common partner.

Detection

FISH (Vysis ROS1 Break Apart): companion diagnostic.
IHC screening: less standardized than ALK.
RNA NGS: optimal for fusion detection with partner identification.
Comprehensive vendor panels (FoundationOne CDx, Tempus xT, Caris) include ROS1 fusion calling.

FDA-approved targeted therapies

Drug	Indication	Line	Tier
Repotrectinib	ROS1+ metastatic NSCLC, TKI-naive and TKI-pretreated	1L / 2L+	I-A
Entrectinib	ROS1+ metastatic NSCLC; also tumor-agnostic NTRK fusions	1L	I-A
Crizotinib	ROS1+ NSCLC, historical first-line	Historical 1L	I-A
Lorlatinib	Off-label / post-crizotinib ROS1 in some contexts	Later-line	II-C

Tier = AMP/ASCO/CAP 2017 (Li MM et al., J Mol Diagn 2017). Drug names link to openFDA labels where available. Synthetic data; consult primary sources before treatment.

Resistance pathways

ROS1 G2032R — solvent-front mutation, dominant resistance allele on crizotinib and entrectinib. Repotrectinib retains activity.
ROS1 D2033N, L2026M, S1986F/Y — secondary kinase-domain alterations.
Bypass-track activation (KRAS, BRAF, MET) — less common; biopsy-driven therapy switch.

Frequently asked questions

Repotrectinib or entrectinib as first-line?: Repotrectinib (TRIDENT-1) showed an objective response rate of 79% in TKI-naive patients with sustained CNS efficacy. Entrectinib remains a strong option with good CNS data. Repotrectinib also covers G2032R, which entrectinib does not — relevant if early resistance signal emerges.
Is crizotinib still appropriate?: Crizotinib has FDA approval for ROS1+ NSCLC and remains effective, but its CNS efficacy is limited. For patients with brain metastases or younger patients where CNS protection matters, entrectinib or repotrectinib is preferred.
Does ROS1 fusion-positive NSCLC respond to checkpoint inhibitors?: Generally no. ROS1 fusion-positive NSCLC mirrors ALK fusion-positive NSCLC in poor response to single-agent PD-1/PD-L1 inhibitors. Targeted TKI therapy is the standard.