What is the first-line treatment for a patient with ROS1 (Rearranged during Transfection) mutated metastatic Non-Small Cell Lung Cancer (NSCLC)?

First-Line Treatment for ROS1-Positive Metastatic NSCLC

Crizotinib, entrectinib, or repotrectinib are the preferred first-line treatment options for ROS1-positive metastatic NSCLC, with selection based primarily on CNS involvement and drug availability. 1

Preferred First-Line Options

The treatment landscape for ROS1-positive NSCLC has evolved with three FDA-approved targeted therapies demonstrating superior efficacy compared to chemotherapy:

Crizotinib (Preferred Option)

• FDA-approved and remains the most established first-line choice with extensive clinical validation 2, 3
• Achieves objective response rates of 70-80% with median PFS of 19.2-23.0 months 2, 4, 5
• Real-world data confirms median overall survival of 52.7-60.0 months 4, 5
• Dosing: 600 mg orally once daily until disease progression 3
• NCCN designated crizotinib as the preferred agent based on FDA approval and superior trial data 2

Entrectinib (Preferred Option, Especially for CNS Disease)

• FDA-approved with superior CNS penetration compared to crizotinib, making it particularly valuable for patients with baseline brain metastases 1, 3
• Recommended dosage: 600 mg orally once daily 3
• Can be administered as capsules or oral pellets for patients with swallowing difficulties 3

Repotrectinib (Preferred Option if Available)

• Recommended as a preferred first-line choice, particularly for patients with CNS involvement 1
• Represents the newest generation ROS1 TKI with broader resistance mutation coverage 6

Selection Algorithm

For patients WITHOUT baseline CNS metastases:

• Start with crizotinib as the most established option with longest track record 2, 4
• Consider entrectinib or repotrectinib if crizotinib is unavailable or contraindicated 1

For patients WITH baseline CNS metastases:

• Prioritize entrectinib or repotrectinib over crizotinib due to superior CNS penetration 1
• If neither is available, crizotinib remains acceptable but monitor CNS disease closely 2

Critical Prognostic Factors

Baseline metastatic organ involvement is the most important prognostic factor:

• Patients with >2 baseline metastatic organ sites have significantly worse outcomes (mPFS 4.0 months vs 24.0 months; mOS 6.0 months vs 60.0 months) 5
• This represents the only independent prognostic factor for PFS in multivariable analysis 5
• Female patients may have shorter mPFS compared to males (12.0 vs 24.0 months) 5

Testing Requirements Before Treatment

Molecular confirmation is mandatory:

• ROS1 testing should be performed using FISH or FDA-approved tests on tumor tissue 2, 1
• Plasma testing is only appropriate when tumor tissue is unavailable 1, 3
• Information on FDA-approved companion diagnostics available at www.fda.gov/CompanionDiagnostics 3

Pre-treatment evaluation required for entrectinib:

• Assess left ventricular ejection fraction (LVEF) 3
• Check serum uric acid levels 3
• Evaluate QT interval and electrolytes 3

Common Pitfalls to Avoid

Do not use immunotherapy as first-line treatment:

• Immunotherapy is less effective in tumors with actionable mutations like ROS1 rearrangements, regardless of PD-L1 expression levels 2

Do not use ceritinib as first-line:

• While ceritinib shows activity (ORR 62%, PFS 19.3 months in crizotinib-naïve patients), it is not EMA-approved and not preferred over crizotinib, entrectinib, or repotrectinib 2

Do not delay treatment for extensive molecular profiling:

• ROS1 testing alone is sufficient to initiate targeted therapy 2
• Additional resistance mutation testing should be reserved for progression 1

Safety Profile

Crizotinib demonstrates excellent tolerability:

• Most adverse events are grade 1-2 (fatigue 16.2%, elevated transaminases 13.9%, vision disorders 11.6%) 4
• No grade ≥3 adverse events reported in recent real-world cohorts 4