Salvatore Siena1, Maria Di Bartolomeo2, Kanwal Raghav3, Toshiki Masuishi4, Fotios Loupakis5, Hisato Kawakami6, Kensei Yamaguchi7, Tomohiro Nishina8, Marwan Fakih9, Elena Elez10, Javier Rodriguez11, Fortunato Ciardiello12, Yoshito Komatsu13, Taito Esaki14, Ki Chung15, Zev Wainberg16, Andrea Sartore-Bianchi1, Kapil Saxena17, Eriko Yamamoto18, Emarjola Bako17, Yasuyuki Okuda18, Javad Shahidi17, Axel Grothey19, Takayuki Yoshino20. 1. Department of Oncology and Hemato-Oncology, Università degli Studi di Milano and Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. 2. Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 3. The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 4. Aichi Cancer Center Hospital, Aichi, Japan. 5. Oncology Institute Veneto IOV-IRCCS, Padua, Italy. 6. Kindai University Hospital, Osaka, Japan. 7. The Cancer Institute Hospital of JFCR, Tokyo, Japan. 8. National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan. 9. City of Hope Medical Center, Philadelphia, PA, USA. 10. Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 11. Department of Medical Oncology, Gastrointestinal Oncology Unit, Clínica Universidad de Navarra, University of Navarra, Navarra, Spain. 12. Università degli Studi della Campania Luigi Vanvitelli, Caserta, Italy. 13. Hokkaido University Hospital, Hokkaido, Japan. 14. National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. 15. Prisma Health Cancer Institute, Greenville, SC, USA. 16. UCLA Medical Center, Los Angeles, CA, USA. 17. Daiichi Sankyo, Basking Ridge, NJ, USA. 18. Daiichi Sankyo Co, Ltd, Tokyo, Japan. 19. West Cancer Center, Germantown, TN, USA. 20. National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: tyoshino@east.ncc.go.jp.
Abstract
BACKGROUND: HER2 amplification has been identified in 2-3% of patients with colorectal cancer, although there are currently no approved HER2-targeted therapies for colorectal cancer. We aimed to study the antitumour activity and safety of trastuzumab deruxtecan (an antibody-drug conjugate of humanised anti-HER2 antibody with topoisomerase I inhibitor payloads) in patients with HER2-expressing metastatic colorectal cancer. METHODS: DESTINY-CRC01 is an open-label, phase 2 study that recruited patients from 25 clinics and hospitals in Italy, Japan, Spain, the UK, and the USA. Eligible patients had centrally confirmed HER2-expressing metastatic colorectal cancer that had progressed on two or more previous regimens (HER2-targeted therapies other than trastuzumab deruxtecan permitted), were aged 18 years or older (≥20 years in Japan), had an Eastern Cooperative Oncology Group score of 0 or 1, and had RAS and BRAFV600E wild-type tumours. Patients were enrolled into one of three cohorts by HER2 expression level: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC2+ and in-situ hybridisation [ISH]-positive), cohort B (IHC2+ and ISH-negative), or cohort C (IHC1+). Patients received 6·4 mg/kg trastuzumab deruxtecan intravenously every 3 weeks until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate in cohort A by independent central review which was assessed in the full analysis set and safety was assessed in the safety analysis set. Both the full analysis set and the safety analysis set included all patients who received one or more doses of trastuzumab deruxtecan. This ongoing trial is registered with ClinicalTrials.gov, number NCT03384940. FINDINGS: Between Feb 23, 2018, and July 3, 2019, 78 patients were enrolled in the study (53 in cohort A, seven in cohort B, and 18 in cohort C), all of whom received at least one dose of study drug. For the 53 (68%) patients with HER2-positive tumours (cohort A), a confirmed objective response was reported in 24 (45·3%, 95% CI 31·6-59·6) patients after a median follow-up of 27·1 weeks (IQR 19·3-40·1). Grade 3 or worse treatment-emergent adverse events that occurred in at least 10% of all participants were decreased neutrophil count (17 [22%] of 78) and anaemia (11 [14%]). Five patients (6%) had adjudicated interstitial lung disease or pneumonitis (two grade 2; one grade 3; two grade 5, the only treatment-related deaths). INTERPRETATION: Trastuzumab deruxtecan showed promising and durable activity in HER2-positive metastatic colorectal cancer refractory to standard treatment, with a safety profile consistent with that reported in previous trastuzumab deruxtecan trials. Interstitial lung disease and pneumonitis are important risks requiring careful monitoring and prompt intervention. FUNDING: Daiichi Sankyo.
BACKGROUND:HER2 amplification has been identified in 2-3% of patients with colorectal cancer, although there are currently no approved HER2-targeted therapies for colorectal cancer. We aimed to study the antitumour activity and safety of trastuzumabderuxtecan (an antibody-drug conjugate of humanised anti-HER2 antibody with topoisomerase I inhibitor payloads) in patients with HER2-expressing metastatic colorectal cancer. METHODS: DESTINY-CRC01 is an open-label, phase 2 study that recruited patients from 25 clinics and hospitals in Italy, Japan, Spain, the UK, and the USA. Eligible patients had centrally confirmed HER2-expressing metastatic colorectal cancer that had progressed on two or more previous regimens (HER2-targeted therapies other than trastuzumabderuxtecan permitted), were aged 18 years or older (≥20 years in Japan), had an Eastern Cooperative Oncology Group score of 0 or 1, and had RAS and BRAFV600E wild-type tumours. Patients were enrolled into one of three cohorts by HER2 expression level: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC2+ and in-situ hybridisation [ISH]-positive), cohort B (IHC2+ and ISH-negative), or cohort C (IHC1+). Patients received 6·4 mg/kg trastuzumabderuxtecan intravenously every 3 weeks until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate in cohort A by independent central review which was assessed in the full analysis set and safety was assessed in the safety analysis set. Both the full analysis set and the safety analysis set included all patients who received one or more doses of trastuzumabderuxtecan. This ongoing trial is registered with ClinicalTrials.gov, number NCT03384940. FINDINGS: Between Feb 23, 2018, and July 3, 2019, 78 patients were enrolled in the study (53 in cohort A, seven in cohort B, and 18 in cohort C), all of whom received at least one dose of study drug. For the 53 (68%) patients with HER2-positive tumours (cohort A), a confirmed objective response was reported in 24 (45·3%, 95% CI 31·6-59·6) patients after a median follow-up of 27·1 weeks (IQR 19·3-40·1). Grade 3 or worse treatment-emergent adverse events that occurred in at least 10% of all participants were decreased neutrophil count (17 [22%] of 78) and anaemia (11 [14%]). Five patients (6%) had adjudicated interstitial lung disease or pneumonitis (two grade 2; one grade 3; two grade 5, the only treatment-related deaths). INTERPRETATION:Trastuzumabderuxtecan showed promising and durable activity in HER2-positive metastatic colorectal cancer refractory to standard treatment, with a safety profile consistent with that reported in previous trastuzumabderuxtecan trials. Interstitial lung disease and pneumonitis are important risks requiring careful monitoring and prompt intervention. FUNDING: Daiichi Sankyo.
Authors: Chan Shen; Daniel Tannenbaum; Robert Horn; Jane Rogers; Cathy Eng; Shouhao Zhou; Benny Johnson; Scott Kopetz; Van Morris; Michael Overman; Christine Parseghian; George J Chang; Maria A Lopez-Olivo; Raghav Kanwal; Lee M Ellis; Arvind Dasari Journal: JAMA Netw Open Date: 2022-05-02
Authors: M José Ortiz-Morales; Marta Toledano-Fonseca; Rafael Mena-Osuna; M Teresa Cano; Auxiliadora Gómez-España; Juan R De la Haba-Rodríguez; Antonio Rodríguez-Ariza; Enrique Aranda Journal: Cancers (Basel) Date: 2022-06-21 Impact factor: 6.575
Authors: Changhee Kang; Chin-Hee Song; Nayoung Kim; Ryoung Hee Nam; Soo In Choi; Jeong Eun Yu; Heewon Nho; Jin A Choi; Jin Won Kim; Hee Young Na; Ha-Na Lee; Young-Joon Surh Journal: Front Oncol Date: 2021-07-08 Impact factor: 6.244