DESTINY-CRC01: What the Colorectal Cancer Trial Found

The 2% problem

HER2 is a protein that sits on the surface of some cancer cells and pushes them to grow. In breast and stomach cancer, drugs aimed at HER2 have been standard for years.

In colorectal cancer, HER2 is amplified in only 2% to 3% of people. That is small enough that for a long time nobody had an approved HER2 drug for bowel cancer at all. DESTINY-CRC01 was built to test one.

What the drug is

Trastuzumab deruxtecan is an antibody-drug conjugate. The antibody half recognizes HER2 and sticks to cells carrying it. Attached to that antibody is a chemotherapy payload, a topoisomerase I inhibitor, which is released once the package is pulled inside the cell.

The point of the design is delivery. The chemotherapy is meant to reach HER2-bearing cells rather than circulate freely through the body.

Who was in the trial

The trial recruited from 25 clinics and hospitals in Italy, Japan, Spain, the United Kingdom, and the United States. It ran from February 23, 2018 to July 3, 2019, and enrolled 78 people.

Everyone had metastatic colorectal cancer with confirmed HER2 expression that had already progressed on two or more previous treatment regimens. Everyone was well enough to be fully active or nearly so. Tumors had to be normal for RAS and BRAF V600E, since changes in those genes point treatment elsewhere. Our page on KRAS G12C in colorectal cancer covers why those genes are checked first.

People were sorted into three groups by how much HER2 their tumors carried. Cohort A, the main group, had the strongest expression: 53 people. Cohort B had 7. Cohort C, the weakest, had 18.

Everyone received the drug by infusion every three weeks until the disease grew, side effects became unacceptable, or they chose to stop.

What it found

The main measure was the share of people in cohort A whose tumors shrank enough to count as a confirmed response, judged by reviewers outside the trial team.

Twenty-four of the 53 responded. That is 45.3%, with a confidence interval running from 31.6% to 59.6%. Median follow-up was 27.1 weeks, a little over six months.

For a group whose cancer had already outgrown two or more lines of treatment, close to half responding is a substantial result.

The safety finding that matters most

Severe side effects reported in at least 10% of all 78 participants were a low neutrophil count, the white cells that fight bacteria, in 22%, and anemia in 14%.

The one that defines this drug is different. Five people, 6% of the trial, developed interstitial lung disease or pneumonitis — inflammation and scarring in the lung tissue. Two of those cases were fatal, and they were the only treatment-related deaths in the trial.

This is not a footnote. The current prescribing information for the drug carries a boxed warning for interstitial lung disease at the very top of the label. It instructs clinicians to investigate cough, breathlessness, and fever promptly, and to stop the drug permanently in anyone with grade 2 or worse lung inflammation.

What happened after

DESTINY-CRC01 had no comparison group, so it could not settle anything by itself. What it did was justify larger trials.

The drug is now approved in the United States for adults with unresectable or metastatic HER2-positive solid tumors, defined as immunohistochemistry 3+, who have had prior systemic treatment and have no satisfactory alternative. That indication is not limited by organ, so it can cover bowel cancer. It was granted under accelerated approval based on response rate and how long responses lasted, which means continued approval depends on a confirmatory trial. Our page on colorectal cancer treatment sets out the standard options this sits behind.

What this trial cannot tell you

• It was single-arm. With no control group, there is no way to know how the same people would have done on something else.
• The headline number rests on 53 people, followed for a median of about six months. Response rate is not survival.
• Severe lung inflammation occurred in 6% and killed two participants. That risk travels with the drug.
• Everyone enrolled had RAS and BRAF V600E normal tumors and was well enough to be nearly fully active. Results from that group may not carry over to everyone.
• Accelerated approval is provisional by design. It can be withdrawn if the confirmatory evidence does not arrive.

When to get checked

HER2 testing only matters once colorectal cancer has been found, and most of it is found late. SEER reports that 23% of colorectal cancers are already distant at diagnosis, and another 37% have reached regional lymph nodes.

Screening from age 45 is the main defense. Between screenings, NCI lists these as reasons to check with a doctor at any age:

• Blood in the stool, bright red or very dark
• A change in bowel habits that does not settle
• A feeling that the bowel does not empty fully
• Stools that are narrower than usual
• Ongoing gas pains, bloating, fullness, or cramps
• Weight loss for no known reason, fatigue, or vomiting

Anyone already in treatment with this drug should act on a new cough, breathlessness, or fever rather than waiting to see. Breathlessness needs emergency care. So does a fever during treatment that lowers blood counts — call the care team immediately, at any hour, and say you are on cancer treatment. A new cough on its own warrants a same-day call.

Sources

• Siena S et al., Trastuzumab deruxtecan in HER2-expressing metastatic colorectal cancer (DESTINY-CRC01), Lancet Oncology 2021 — https://pubmed.ncbi.nlm.nih.gov/33961795/
• ClinicalTrials.gov v2 API record, NCT03384940 — https://clinicaltrials.gov/api/v2/studies/NCT03384940
• DailyMed, ENHERTU (fam-trastuzumab deruxtecan-nxki) prescribing information — https://dailymed.nlm.nih.gov/dailymed/services/v2/spls/7e67e73e-ddf4-4e4d-8b50-09d7514910b6.xml
• NCI PDQ, Colon Cancer Treatment (Patient Version) — https://www.cancer.gov/types/colorectal/patient/colon-treatment-pdq
• SEER Cancer Stat Facts, Colorectal Cancer — https://seer.cancer.gov/statfacts/html/colorect.html

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.

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