Trastuzumab Deruxtecan Has Promising Activity in Advanced Colorectal Cancer

By Reuters Staff

May 14, 2021

NEW YORK (Reuters Health) - Trastuzumab deruxtecan, an antibody-drug conjugate, showed "promising and durable activity" in HER2-positive metastatic colorectal cancer (CRC) refractory to standard treatment in an open-label phase-2 trial.

HER2 amplification is seen in 2% to 3% of colorectal tumors, but there are currently no approved HER2-targeted therapies for colorectal cancer.

The DESTINY-CRC01 trial evaluated trastuzumab deruxtecan in 78 patients with HER2-expressing metastatic CRC that had progressed on two or more previous regimens, including HER2-targeted therapies other than trastuzumab deruxtecan.

Patients were grouped by HER2-expression level: cohort A (HER2-positive, immunohistochemistry (IHC) 3+ or IHC2+ and in-situ hybridization (ISH)-positive; 53 patients); cohort B (IHC2+ and ISH-negative, seven patients); cohort C (IHC1+, 18 patients).

They received 6.4 mg/kg trastuzumab deruxtecan intravenously every three weeks until disease progression, unacceptable side effects, withdrawal of consent, or death.

After median follow up of 27 weeks, the objective response rate in cohort A (the primary endpoint) was 45.3% (24 of 53 patients). There was one (2%) complete response (2%) and 23 partial responses (43%), Dr. Salvatore Siena of the University of Milan, in Italy, and colleagues report in The Lancet Oncology.

Within cohort A, a greater proportion of patients with high levels of HER2 expression (IHC3+) had an objective response than did patients with IHC2+ and ISH-positive tumors (57.5% vs. 7.7%). "However, due to the low number of patients enrolled with IHC2+ and ISH-positive tumors, further studies are needed," the investigators say.

"Although trastuzumab deruxtecan has shown antitumour activity in HER2-low breast tumors, no responses were seen among patients with HER2-low metastatic colorectal cancer tumors (cohort B, IHC2+ and ISH-negative; cohort C, IHC1+)," they note.

Regression of target lesions and lasting responses were seen in most patients with HER2-positive tumors, resulting in progression-free-survival and overall-survival benefits. In the HER2-positive cohort, median progression-free survival and overall survival were not reached, due to the relatively short follow-up.

The safety profile for trastuzumab deruxtecan was consistent with previous studies, with no new safety signals. All patients reported a treatment-emergent adverse event; most were low grade and non-serious.

The "notable adverse event" was interstitial lung disease or pneumonitis which occurred in five patients (6%) and accounted for the two drug-related deaths.

"This study paves the way for further clinical investigation of trastuzumab deruxtecan as a potential treatment option for HER2-positive refractory metastatic colorectal cancer," Dr. Siena and colleagues conclude.

The authors of a linked comment note that responses to trastuzumab deruxtecan "appeared to be durable and were seen irrespective of previous HER2-targeted therapy, suggesting a degree of non-overlapping resistance."

"However, no responses with trastuzumab deruxtecan were observed in HER2 moderately-expressing, without gene amplification, metastatic colorectal cancer or HER2 low-expressing metastatic colorectal cancer, suggesting that in these subgroups, response and disease control was not adequate," writes Dr. Ian Chau of Royal Marsden Hospital, in Surrey, U.K.

"These results echo, and might even surpass, other recent studies with combinations of trastuzumab with lapatinib, pertuzumab and tucatinib, and pertuzumab plus trastuzumab emtansine, but together they herald HER2 as a clinically meaningful target in metastatic colorectal cancer," Dr. Chau notes.

"The benefit of trastuzumab deruxtecan needs to be balanced carefully with the risk of life-threatening toxicities such as pneumonitis," Dr. Chau adds.

This study was sponsored by Daiichi Sankyo and AstraZeneca. Several authors have declared financial relationships with the companies.

SOURCE: and Lancet Oncology, online May 4, 2021.