Trastuzumab Deruxtecan-nxki in HER2-Positive Metastatic Colorectal Cancer: DESTINY-CRC01

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In the phase II DESTINY-CRC01 trial reported in The Lancet Oncology, Salvatore Siena, MD, and colleagues found that trastuzumab deruxtecan-nxki produced durable responses in patients with previously treated HER2-positive metastatic colorectal cancer.

Salvatore Siena, MD

Salvatore Siena, MD

Study Details

In the trial, 78 patients from sites in Italy, Japan, Spain, the United Kingdom, and the United States were enrolled between February 2018 and July 2019 into three cohorts according to HER2 expression level: 

  • Cohort A = immunohistochemistry (IHC) 3+ or IHC2+ and in situ hybridization (ISH)-positive (n = 53)
  • Cohort B = IHC2+ and ISH-negative (n = 7)
  • Cohort C = IHC1+ (n = 18).

Patients had disease progression on two or more previous regimens (HER2-targeted therapies other than trastuzumab deruxtecan were permitted) and had RAS and BRAF V600E wild-type tumors. Treatment consisted of trastuzumab deruxtecan at 6.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was confirmed objective response rate in cohort A on independent central review.


At data cutoff (August 2019), cohorts B and C had not reached their prespecified sample size and the study was ongoing. t this time point, no confirmed objective responses had been observed in either cohort.

Among the 53 patients in cohort A, objective response was observed in 24 (45.3%, 95% confidence interval [CI] = 31.6%–59.6%; complete response in 2%) after median follow-up of 27.1 weeks (interquartile range = 19.3–40.1 weeks) and minimum follow-up of 2.7 weeks. An additional 19 patients (36%) had stable disease. Median duration of response was not evaluable (95% CI = 4.2 months–not evaluable). Objective response rates were 43.8% among 16 patients with prior HER2-directed therapy and 45.9% among those without such prior therapy.  

Median progression-free survival in cohort A was 6.9 months (95% CI = 4.1 months–not evaluable), with a 6-month rate of 53.0%. Median progression-free survival was 4.3 months (95% CI = 2.6–7.6 months) among patients with and 6.9 months (95% CI = 4.1 months–not evaluable) among patients without prior HER2-directed therapy.


  • Objective response was observed in 45% of patients with IHC3+ or IHC2+ and ISH-positive HER2 expression.
  • Interstitial lung disease or pneumonitis occurred in 6% of patients.

Adverse Events

Among all 78 patients, grade ≥ 3 adverse events that occurred in ≥ 10% were decreased neutrophil count (22%) and anemia (14%). Serious adverse events occurred in 33% of patients and were considered treatment-related in 18%; the most common treatment-related events were diarrhea (4%), interstitial lung disease (3%), pneumonitis (3%), nausea (3%), and decreased neutrophil count (3%). Interstitial lung disease or pneumonitis occurred in five patients (6%); death occurred in two patients, with both deaths considered related to treatment. No other treatment-related deaths were observed.

The investigators concluded, “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.”

Takayuki Yoshino, MD, of the National Cancer Center Hospital East, Kashiwa, Japan, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Daiichi Sankyo. For full disclosures of the study authors, visit

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