First‑Line Targeted Therapy for ROS1‑Positive Metastatic NSCLC

Preferred First‑Line Agents

The NCCN guideline designates crizotinib as the gold‑standard first‑line oral TKI for treatment‑naïve ROS1‑rearranged NSCLC, based on FDA approval and the most robust clinical data (Phase I PROFILE 1001, Phase II EUCROSS, Asian Phase II). Objective response rates (ORR) are 70‑80% with median progression‑free survival (PFS) of 19‑20 months and median overall survival of ~51 months. Evidence level: Phase I/II trials. 1
Crizotinib inhibits ROS1, ALK, and MET kinases. Evidence level: Pharmacologic data from NCCN‑reviewed studies. 1, 2

FDA‑approved for first‑line ROS1‑positive disease; NCCN highlights its superior central nervous system (CNS) penetration, making it the preferred option when brain metastases are present. Intracranial response rate is 55% (including complete responses) among patients with baseline CNS disease. Evidence level: Pooled analysis of three trials (STARTRK‑1, STARTRK‑2, ALKA‑372‑001). 1
Overall ORR across 53 treatment‑naïve ROS1‑positive patients in the pooled analysis is 77%. Evidence level: Combined Phase I/II data. 1
Grade 3‑4 adverse events occur in ~34% of patients, with notable neurologic and cardiac toxicities, indicating a higher toxicity profile than crizotinib. Evidence level: Safety data from NCCN‑cited trials. 1

FDA‑approved as a preferred first‑line ROS1 inhibitor, especially for patients with CNS involvement; NCCN cites the TRIDENT‑1 trial showing a confirmed ORR of 79% in 71 treatment‑naïve patients. Evidence level: Phase II trial. 1
Repotrectinib is a next‑generation oral TKI targeting ROS1, TRK, and ALK. Evidence level: Pharmacologic profile from NCCN‑reviewed literature. 1

Considered only when crizotinib is unsuitable; NCCN does not list it as a preferred agent. A Phase II study in crizotinib‑naïve patients reported an ORR of 62% and median PFS of 19.3 months. Evidence level: Phase II trial. 3, 4

ROS1 rearrangement testing must be performed on tumor tissue using fluorescence in‑situ hybridization (FISH) or an FDA‑approved assay before initiating any ROS1‑directed therapy. NCCN notes that ROS1 fusions occur in ~1‑2 % of NSCLC, more frequently in younger, female, never‑smoker patients with adenocarcinoma histology. Evidence level: NCCN guideline epidemiology. 1, 2
Validated next‑generation sequencing (NGS) platforms may also detect ROS1 fusions when appropriately calibrated. Evidence level: NCCN technical recommendation. 2

ALK‑specific inhibitors (e.g., alectinib) are ineffective for ROS1‑positive disease; NCCN explicitly advises against their use. Evidence level: Expert consensus and trial data. 3, 2
Platinum‑based chemotherapy should not be used as first‑line when a ROS1 rearrangement is identified, as targeted TKIs provide markedly superior outcomes. Evidence level: NCCN guideline recommendation supported by outcome data. 1, 4

After progression on crizotinib or ceritinib, NCCN recommends next‑line ROS1 TKIs such as repotrectinib or lorlatinib. Evidence level: Guideline‑based sequencing. 1
For CNS progression, entrectinib, repotrectinib, or lorlatinib are preferred, with consideration of stereotactic radiosurgery when appropriate. Evidence level: NCCN algorithm for CNS disease. 1
Platinum‑based chemotherapy (carboplatin + pemetrexed for non‑squamous histology) remains an option after failure of all ROS1‑directed agents. Evidence level: NCCN guideline recommendation. 3, 4

The National Comprehensive Cancer Network recommends crizotinib or entrectinib as preferred first-line options for treatment-naïve patients with ROS1-positive metastatic NSCLC, with repotrectinib also being a preferred choice if available 5, 6
Crizotinib remains a strongly recommended first-line option, demonstrating objective response rates of 70-80% with median progression-free survival (PFS) of 19.2 months in ROS1-positive NSCLC 7, 8, 9
Entrectinib is FDA-approved for first-line treatment and offers superior CNS penetration compared to crizotinib, making it particularly valuable for patients with brain metastases 5
Repotrectinib is recommended as a preferred option, especially for patients with CNS involvement 6

For patients progressing on first-line crizotinib or ceritinib, repotrectinib or lorlatinib are recommended targeted therapy options 6
Entrectinib can be considered if previously treated with crizotinib or ceritinib 6
Definitive local therapy (SABR or surgery) should be considered for oligoprogression 6
For CNS progression, entrectinib, repotrectinib, or lorlatinib are recommended 6
Stereotactic radiosurgery (SRS) with or without surgical resection should be considered for symptomatic lesions 6
For symptomatic systemic progression, repotrectinib or lorlatinib are recommended targeted therapy options 6
Platinum-based chemotherapy may be considered following non-driver mutation guidelines 7, 8, 10, 9
Clinical trial enrollment should be strongly considered 7, 9

ROS1 testing should be performed using FISH or FDA-approved tests on tumor tissue; plasma testing is only appropriate when tumor tissue is unavailable 7, 8
At progression, strongly consider rebiopsy with tissue-based testing if plasma testing is negative to identify resistance mechanisms 6

For patients with oligometastatic disease, consider definitive local therapy (SABR or surgery) as consolidation after initiating ROS1 TKI therapy 6