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.
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.
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).
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.