Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer
Copyright © 2024 Massachusetts Medical Society..
BACKGROUND: The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R.
METHODS: In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2.
RESULTS: On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events.
CONCLUSIONS: Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:390 |
|---|---|
| Enthalten in: |
The New England journal of medicine - 390(2024), 2 vom: 11. Jan., Seite 118-131 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Drilon, Alexander [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
08O3FQ4UNP |
|---|
| Anmerkungen: |
Date Completed 12.01.2024 Date Revised 12.01.2024 published: Print ClinicalTrials.gov: NCT03093116 Citation Status MEDLINE |
|---|
| doi: |
10.1056/NEJMoa2302299 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM366884077 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM366884077 | ||
| 003 | DE-627 | ||
| 005 | 20240114234846.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240114s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1056/NEJMoa2302299 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1258.xml |
| 035 | |a (DE-627)NLM366884077 | ||
| 035 | |a (NLM)38197815 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Drilon, Alexander |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.01.2024 | ||
| 500 | |a Date Revised 12.01.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT03093116 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Massachusetts Medical Society. | ||
| 520 | |a BACKGROUND: The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R | ||
| 520 | |a METHODS: In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2 | ||
| 520 | |a RESULTS: On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events | ||
| 520 | |a CONCLUSIONS: Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.) | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Protein-Tyrosine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins |2 NLM | |
| 650 | 7 | |a repotrectinib |2 NLM | |
| 650 | 7 | |a 08O3FQ4UNP |2 NLM | |
| 650 | 7 | |a ROS1 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 700 | 1 | |a Camidge, D Ross |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Jessica J |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Sang-We |e verfasserin |4 aut | |
| 700 | 1 | |a Solomon, Benjamin J |e verfasserin |4 aut | |
| 700 | 1 | |a Dziadziuszko, Rafal |e verfasserin |4 aut | |
| 700 | 1 | |a Besse, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Goto, Koichi |e verfasserin |4 aut | |
| 700 | 1 | |a de Langen, Adrianus Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Wolf, Jürgen |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Ki Hyeong |e verfasserin |4 aut | |
| 700 | 1 | |a Popat, Sanjay |e verfasserin |4 aut | |
| 700 | 1 | |a Springfeld, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Nagasaka, Misako |e verfasserin |4 aut | |
| 700 | 1 | |a Felip, Enriqueta |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Nong |e verfasserin |4 aut | |
| 700 | 1 | |a Velcheti, Vamsidhar |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Shun |e verfasserin |4 aut | |
| 700 | 1 | |a Kao, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Dooms, Christophe |e verfasserin |4 aut | |
| 700 | 1 | |a Krebs, Matthew G |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Wenxiu |e verfasserin |4 aut | |
| 700 | 1 | |a Beg, Muhammad Shaalan |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Xiufeng |e verfasserin |4 aut | |
| 700 | 1 | |a Moro-Sibilot, Denis |e verfasserin |4 aut | |
| 700 | 1 | |a Cheema, Parneet |e verfasserin |4 aut | |
| 700 | 1 | |a Stopatschinskaja, Shanna |e verfasserin |4 aut | |
| 700 | 1 | |a Mehta, Minal |e verfasserin |4 aut | |
| 700 | 1 | |a Trone, Denise |e verfasserin |4 aut | |
| 700 | 1 | |a Graber, Armin |e verfasserin |4 aut | |
| 700 | 1 | |a Sims, Gregory |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Cho, Byoung Chul |e verfasserin |4 aut | |
| 700 | 0 | |a TRIDENT-1 Investigators |e verfasserin |4 aut | |
| 700 | 1 | |a Kao, Steven |e investigator |4 oth | |
| 700 | 1 | |a Karapetis, Christos |e investigator |4 oth | |
| 700 | 1 | |a Solomon, Benjamin |e investigator |4 oth | |
| 700 | 1 | |a Dooms, Christopher |e investigator |4 oth | |
| 700 | 1 | |a Prenen, Prenen |e investigator |4 oth | |
| 700 | 1 | |a Cheema, Parneet |e investigator |4 oth | |
| 700 | 1 | |a Chu, Quincy |e investigator |4 oth | |
| 700 | 1 | |a Liu, Geoffrey |e investigator |4 oth | |
| 700 | 1 | |a Wheatley-Price, Paul |e investigator |4 oth | |
| 700 | 1 | |a Cheng, Ying |e investigator |4 oth | |
| 700 | 1 | |a Dong, Xiaorong |e investigator |4 oth | |
| 700 | 1 | |a Fang, Jian |e investigator |4 oth | |
| 700 | 1 | |a He, Yong |e investigator |4 oth | |
| 700 | 1 | |a Hu, Chunhong |e investigator |4 oth | |
| 700 | 1 | |a Hu, Xiufeng |e investigator |4 oth | |
| 700 | 1 | |a Jiang, Liyan |e investigator |4 oth | |
| 700 | 1 | |a Li, Junling |e investigator |4 oth | |
| 700 | 1 | |a Lin, Gen |e investigator |4 oth | |
| 700 | 1 | |a Lu, Shun |e investigator |4 oth | |
| 700 | 1 | |a Luo, Feng |e investigator |4 oth | |
| 700 | 1 | |a Miao, Liyun |e investigator |4 oth | |
| 700 | 1 | |a Shi, Huaqiu |e investigator |4 oth | |
| 700 | 1 | |a Su, Haichuan |e investigator |4 oth | |
| 700 | 1 | |a Sun, Meili |e investigator |4 oth | |
| 700 | 1 | |a Wang, Xiang |e investigator |4 oth | |
| 700 | 1 | |a Wu, Jingxun |e investigator |4 oth | |
| 700 | 1 | |a Yang, Jinji |e investigator |4 oth | |
| 700 | 1 | |a Yang, Nong |e investigator |4 oth | |
| 700 | 1 | |a Yao, Wenxiu |e investigator |4 oth | |
| 700 | 1 | |a Ying, Kejing |e investigator |4 oth | |
| 700 | 1 | |a Yu, Yan |e investigator |4 oth | |
| 700 | 1 | |a Zhang, Yiping |e investigator |4 oth | |
| 700 | 1 | |a Zhou, Jianying |e investigator |4 oth | |
| 700 | 1 | |a Rohrberg, Kristoffer |e investigator |4 oth | |
| 700 | 1 | |a Besse, Benjamin |e investigator |4 oth | |
| 700 | 1 | |a Hervieu, Alice |e investigator |4 oth | |
| 700 | 1 | |a Moro-Sibilot, Denis |e investigator |4 oth | |
| 700 | 1 | |a Grohe, Christian |e investigator |4 oth | |
| 700 | 1 | |a Springfeld, Christoph |e investigator |4 oth | |
| 700 | 1 | |a Wermke, Martin |e investigator |4 oth | |
| 700 | 1 | |a Wolf, Jurgen |e investigator |4 oth | |
| 700 | 1 | |a Ho, James |e investigator |4 oth | |
| 700 | 1 | |a Li, Jacky |e investigator |4 oth | |
| 700 | 1 | |a Loong, Herbert |e investigator |4 oth | |
| 700 | 1 | |a Muller, Veronika |e investigator |4 oth | |
| 700 | 1 | |a Bearz, Alessandra |e investigator |4 oth | |
| 700 | 1 | |a Bracarda, Sergio |e investigator |4 oth | |
| 700 | 1 | |a Cappuzzo, Federico |e investigator |4 oth | |
| 700 | 1 | |a Prelaj, Arsela |e investigator |4 oth | |
| 700 | 1 | |a Pagano, Maria |e investigator |4 oth | |
| 700 | 1 | |a Goto, Koichi |e investigator |4 oth | |
| 700 | 1 | |a Kato, Terufumi |e investigator |4 oth | |
| 700 | 1 | |a Nogami, Naoyuki |e investigator |4 oth | |
| 700 | 1 | |a Sakakibara, Jun |e investigator |4 oth | |
| 700 | 1 | |a Tamiya, Motohiro |e investigator |4 oth | |
| 700 | 1 | |a de Langen, Adrianus |e investigator |4 oth | |
| 700 | 1 | |a Van der Wekken, Anthonie |e investigator |4 oth | |
| 700 | 1 | |a Dziadziuszko, Rafal |e investigator |4 oth | |
| 700 | 1 | |a Kowalski, Dariusz |e investigator |4 oth | |
| 700 | 1 | |a Krawczyk, Pawel |e investigator |4 oth | |
| 700 | 1 | |a Lim, Darren |e investigator |4 oth | |
| 700 | 1 | |a Soo, Ross Andrew |e investigator |4 oth | |
| 700 | 1 | |a Cho, Byoung Chul |e investigator |4 oth | |
| 700 | 1 | |a Hong, Jung Yong |e investigator |4 oth | |
| 700 | 1 | |a Kang, Jin-Hyoung |e investigator |4 oth | |
| 700 | 1 | |a Kim, Dong-Wan |e investigator |4 oth | |
| 700 | 1 | |a Kim, Sang-We |e investigator |4 oth | |
| 700 | 1 | |a Lee, Ki Hyeong |e investigator |4 oth | |
| 700 | 1 | |a Aguilar, Andres |e investigator |4 oth | |
| 700 | 1 | |a Felip, Enriqueta |e investigator |4 oth | |
| 700 | 1 | |a Grande, Enrique |e investigator |4 oth | |
| 700 | 1 | |a Guerrero, Angel |e investigator |4 oth | |
| 700 | 1 | |a Moreno, Irene |e investigator |4 oth | |
| 700 | 1 | |a Moreno, Victor |e investigator |4 oth | |
| 700 | 1 | |a Yang, Chih-Hsin |e investigator |4 oth | |
| 700 | 1 | |a Yen, Chia-Jui |e investigator |4 oth | |
| 700 | 1 | |a Fontana, Elisa |e investigator |4 oth | |
| 700 | 1 | |a Krebs, Matthew |e investigator |4 oth | |
| 700 | 1 | |a Pinato, David |e investigator |4 oth | |
| 700 | 1 | |a Popat, Sanjay |e investigator |4 oth | |
| 700 | 1 | |a Adhami, Faisal |e investigator |4 oth | |
| 700 | 1 | |a Anderson, Ian |e investigator |4 oth | |
| 700 | 1 | |a Anderson, Peter |e investigator |4 oth | |
| 700 | 1 | |a Awad, Mark |e investigator |4 oth | |
| 700 | 1 | |a Baik, Christina |e investigator |4 oth | |
| 700 | 1 | |a Bauman, Jessica |e investigator |4 oth | |
| 700 | 1 | |a Bazhenova, Lyudmila |e investigator |4 oth | |
| 700 | 1 | |a Bestvina, Christine |e investigator |4 oth | |
| 700 | 1 | |a Camidge, Ross |e investigator |4 oth | |
| 700 | 1 | |a Creelan, Ben |e investigator |4 oth | |
| 700 | 1 | |a Drilon, Alexander |e investigator |4 oth | |
| 700 | 1 | |a Dudek, Arkadiusz |e investigator |4 oth | |
| 700 | 1 | |a Elamin, Yasir |e investigator |4 oth | |
| 700 | 1 | |a Gadgeel, Shirish |e investigator |4 oth | |
| 700 | 1 | |a Gerstner, Greg |e investigator |4 oth | |
| 700 | 1 | |a Kasbari, Samer |e investigator |4 oth | |
| 700 | 1 | |a Kazmi, Syed |e investigator |4 oth | |
| 700 | 1 | |a Lammers, Philip |e investigator |4 oth | |
| 700 | 1 | |a Levy, Benjamin |e investigator |4 oth | |
| 700 | 1 | |a Lin, Jessica |e investigator |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t The New England journal of medicine |d 1945 |g 390(2024), 2 vom: 11. Jan., Seite 118-131 |w (DE-627)NLM000008184 |x 1533-4406 |7 nnns |
| 773 | 1 | 8 | |g volume:390 |g year:2024 |g number:2 |g day:11 |g month:01 |g pages:118-131 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1056/NEJMoa2302299 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 390 |j 2024 |e 2 |b 11 |c 01 |h 118-131 | ||