What is the recommended first-line treatment for patients with ROS1 (Rearranged during Transfection) mutant non-small cell lung cancer (NSCLC)?

Management of ROS1-Positive Non-Small Cell Lung Cancer

First-Line Treatment

For treatment-naïve patients with ROS1-positive metastatic NSCLC, offer crizotinib or entrectinib as preferred first-line options, with repotrectinib also being a preferred choice if available. 1, 2

Preferred First-Line Agents

• 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 1
• 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 1, 2, 3
• Repotrectinib is recommended as a preferred option, especially for patients with CNS involvement 1

Alternative First-Line Options

• Ceritinib may be offered as first-line therapy but with weaker recommendation strength, showing an objective response rate of 62% with PFS of 19.3 months in crizotinib-naïve patients 1
• Lorlatinib can be considered as first-line therapy but with weak recommendation strength 1
• Standard platinum-based chemotherapy may be offered following non-driver mutation guidelines if targeted therapy is not feasible 1

Important Treatment Considerations

• Brain metastases: Entrectinib or repotrectinib are preferred over crizotinib due to superior CNS penetration 1, 2
• Performance status: All ROS1 TKIs are appropriate for patients with performance status 0-4 1
• Immunotherapy: Single-agent immunotherapy should NOT be used as first-line therapy in ROS1-positive NSCLC, as it appears less effective regardless of PD-L1 expression levels 1

Subsequent Therapy After First-Line ROS1 TKI

After Progression on Crizotinib or Ceritinib

For patients progressing on first-line crizotinib or ceritinib, the recommended approach depends on the pattern of progression:

Asymptomatic or Limited Progression

• Repotrectinib (if not previously given) or lorlatinib are recommended targeted therapy options 1
• Entrectinib can be considered if previously treated with crizotinib or ceritinib 1
• Definitive local therapy (SABR or surgery) should be considered for oligoprogression 1

CNS Progression

• Entrectinib (if previously treated with crizotinib or ceritinib), repotrectinib, or lorlatinib are recommended 1
• Stereotactic radiosurgery (SRS) with or without surgical resection should be considered for symptomatic lesions 1

Symptomatic Systemic Progression

• Repotrectinib (if not previously given) or lorlatinib are recommended targeted therapy options 1
• Platinum-based chemotherapy (e.g., carboplatin/pemetrexed for nonsquamous NSCLC) following non-driver mutation guidelines 1
• Clinical trial enrollment should be strongly considered 1

After Progression on Entrectinib or Repotrectinib

• Repotrectinib (if not previously given) or lorlatinib for subsequent targeted therapy 1
• Standard chemotherapy regimens as used for NSCLC without genetic alterations 1

Critical Pitfalls to Avoid

• Do NOT use alectinib in ROS1-positive NSCLC after crizotinib resistance, as no trial data support efficacy in this setting 1
• Avoid immunotherapy after progression on targeted therapy, as it appears less effective in patients with oncogenic drivers regardless of PD-L1 levels 1
• Perform molecular testing via broad molecular profiling at progression (plasma or tissue-based) to identify genomic resistance mechanisms and guide subsequent therapy selection 1

Testing and Monitoring Recommendations

• ROS1 testing should be performed using FISH or FDA-approved tests on tumor tissue; plasma testing is only appropriate when tumor tissue is unavailable 1, 2
• Before initiating ROS1 TKI therapy, evaluate left ventricular ejection fraction, serum uric acid levels, QT interval, and electrolytes 2
• At progression, strongly consider rebiopsy with tissue-based testing if plasma testing is negative to identify resistance mechanisms 1

Special Populations

• TP53 co-mutations: Patients with ROS1-positive/TP53-mutant tumors have significantly shorter median PFS (7.0 months vs 24.1 months) compared to TP53 wild-type patients when treated with crizotinib 4
• Oligometastatic disease: Consider definitive local therapy (SABR or surgery) as consolidation after initiating ROS1 TKI therapy 1