Long-Term Efficacy and Safety of Entrectinib in ROS1 Fusion–Positive NSCLC
Open accessAbstract
Introduction Entrectinib is an approved tyrosine kinase inhibitor (TKI) for ROS1 fusion–positive NSCLC. An updated integrated analysis of entrectinib from the ALKA-372-001, STARTRK-1, and STARTRK-2 trials is presented, with substantially longer follow-up, more patients, and the first description of the median overall survival (OS). An exploratory analysis of entrectinib in ROS1 fusion–positive NSCLC with the central nervous system (CNS)–only progression post-crizotinib is reported. Methods Adults with ROS1 fusion–positive, locally advanced or metastatic NSCLC who received at least one dose of entrectinib and had 12 months or longer of follow-up were included in the analysis. Co-primary end points were confirmed objective response rate (ORR) and duration of response (DoR) by blinded independent central review. The data cutoff was on August 31, 2020. Results The efficacy-assessable population comprised 168 ROS1 TKI–naïve patients. The median survival follow-up was 29.1 months (interquartile range, 21.8–35.9). The ORR was 68% (95% confidence interval [CI]: 60.2–74.8); the median DoR was 20.5 months. The median progression-free survival (PFS) was 15.7 months and the median OS was 47.8 months. In the 25 patients with measurable baseline CNS metastases, the intracranial ORR was 80% (95% CI: 59.3–93.2), median intracranial DoR was 12.9 months, and median intracranial PFS was 8.8 months. Among 18 patients with CNS-only progression on previous crizotinib treatment, two achieved a partial response (11%) and four had stable disease (22%). In seven patients with measurable CNS disease from this cohort, the intracranial ORR was 14% (1 partial response). Conclusions Entrectinib is active and achieves prolonged survival in ROS1 TKI–naïve patients with ROS1 fusion–positive NSCLC. Modest activity is seen in patients with CNS-only progression post-crizotinib.
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Entrectinib was designed to cross the blood-brain barrier, but overall responses were marginal in patients with previous CNS progression (IC-ORR: 11%) and against G2032R.
“Entrectinib was designed to cross the blood-brain barrier, but overall responses were marginal in patients with previous CNS progression (intracranial [IC]-ORR: 11%) and against the most common acquired resistance mutation after crizotinib treatment, G2032R, which occurs in 30% to 40% of patients.8,14,15”
From Taletrectinib in <i>ROS1</i> + Non–Small Cell Lung Cancer: TRUST (2025) · cites this paper as [15]
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- Authors
- Drilon, A., Chiu, C.-H., Fan, Y., Cho, B. C., Lu, S., Ahn, M.-J., Krebs, M. G., Liu, S. V., John, T., Otterson, G. A., Tan, D. S. W., Patil, T., Dziadziuszko, R., Massarelli, E., Seto, T., Doebele, R. C., Pitcher, B., Kurtsikidze, N., Heinzmann, S., & Siena, S.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Taipei Veterans General Hospital (TW)
- Zhejiang Cancer Hospital (CN)
- Yonsei Cancer Hospital (KR)
- Samsung Medical Center (KR)
- Manchester Academic Health Science Centre (GB)
- Georgetown University (US)
- Peter MacCallum Cancer Centre (AU)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- National University of Singapore (SG)
- University of Colorado Anschutz (US)
- City Of Hope National Medical Center (US)
- National Hospital Organization Kyushu Cancer Center (JP)
- Roche (Canada) (CA)
- F. Hoffmann-La Roche AG (CH)
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- University of Milan (IT)
- Corresponding author
- Siena, Salvatore
- ORCID
- Venue
- JTO Clinical and Research Reports
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 3
- Issue
- 6
- Pages
- 100332
- ISSN
- 2666-3643 (ISSN-L)
- PMC
- PMC9160474
- OpenAlex
- W4225123144
- Cited by
- 113
- References
- 25
- Citations by year
- 2026: 7 · 2025: 36 · 2024: 41 · 2023: 25 · 2022: 4
- FWCI
- 17.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JTO Clinical and Research Reports (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-nd)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Funders
- Takeda Pharmaceutical Company
- Novartis Pharma
- AbbVie
- F. Hoffmann-La Roche
- Boehringer Ingelheim
- Amgen
- Exelixis
- Bristol-Myers Squibb
- Eli Lilly and Company
- National Institute for Health and Care Research
- Janssen Pharmaceuticals
- Daiichi-Sankyo
- Merck KGaA
- Merck Sharp and Dohme
- Taiho Pharmaceutical
- Kyowa Hakko Kirin
- Ono Pharmaceutical
- NIHR Leicester Clinical Research Facility
- Bayer
- Society for Academic Continuing Medical Education
- Genentech
- GlaxoSmithKline
- Pfizer Japan
- Chugai Pharmaceutical
- Pfizer
- Eli Lilly Japan
- AstraZeneca
- Manchester Biomedical Research Centre
- Kissei
- Boehringer Ingelheim Japan
- Yuhan
- EMD Serono
- Gilead Sciences
- Merck
- Novartis
- Roche
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- entrectinib, tyrosine kinase inhibitors, central nervous system metastasis, crizotinib resistance, intracranial response, overall survival, progression-free survival, drug safety
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