Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial
Mené sur 78 patients atteints d'un cancer colorectal métastatique HER2+, cet essai multicentrique de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du trastuzumab déruxtécan (un conjugué anticorps-médicament anti-HER2)
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 (anantibody–drug conjugate of humanised anti-HER2 antibody with topoisomerase I inhibitorpayloads) in patients with HER2-expressing metastatic colorectal cancer.
Methods : DESTINY-CRC01 is an open-label, phase 2 study that recruited patients from 25 clinic sand hospitals in Italy, Japan, Spain, the UK, and the USA. Eligible patients had centrallyconfirmed HER2-expressing metastatic colorectal cancer that had progressed on twoor more previous regimens (HER2-targeted therapies other than trastuzumab deruxtecanpermitted), were aged 18 years or older (≥20 years in Japan), had an Eastern CooperativeOncology Group score of 0 or 1, and had RAS and BRAFV600E wild-type tumours. Patients were enrolled into one of three cohorts by HER2 expressionlevel: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC2+ and in-situhybridisation [ISH]-positive), cohort B (IHC2+ and ISH-negative), or cohort C (IHC1+).Patients received 6·4 mg/kg trastuzumab deruxtecan intravenously every 3 weeks untildisease progression, unacceptable adverse events, withdrawal of consent, or death.The primary endpoint was confirmed objective response rate in cohort A by independentcentral review which was assessed in the full analysis set and safety was assessedin the safety analysis set. Both the full analysis set and the safety analysis setincluded all patients who received one or more doses of trastuzumab deruxtecan. Thisongoing trial is registered with ClinicalTrials.gov, number NCT03384940.
Findings : Between Feb 23, 2018, and July 3, 2019, 78 patients were enrolled in the study (53in cohort A, seven in cohort B, and 18 in cohort C), all of whom received at leastone dose of study drug. For the 53 (68%) patients with HER2-positive tumours (cohortA), a confirmed objective response was reported in 24 (45·3%, 95% CI 31·6–59·6) patientsafter a median follow-up of 27·1 weeks (IQR 19·3–40·1). Grade 3 or worse treatment-emergentadverse events that occurred in at least 10% of all participants were decreased neutrophilcount (17 [22%] of 78) and anaemia (11 [14%]). Five patients (6%) had adjudicatedinterstitial lung disease or pneumonitis (two grade 2; one grade 3; two grade 5, theonly treatment-related deaths).
Interpretation : Trastuzumab deruxtecan showed promising and durable activity in HER2-positive metastaticcolorectal cancer refractory to standard treatment, with a safety profile consistentwith that reported in previous trastuzumab deruxtecan trials. Interstitial lung diseaseand pneumonitis are important risks requiring careful monitoring and prompt intervention.
The Lancet Oncology , résumé, 2020