Having recently gained approval in metastatic breast cancer, fam-trastuzumab deruxtecan-nxki (T-DXd) is now proving its worth in metastatic colorectal cancer, according to results of the phase II DESTINY-CRC01 study in patients with HER2-positive disease.¹

T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor.

Positive results for T-DXd, including an overall survival benefit, were recently shown in gastric cancer in the DESTINY-Gastric01 trial, as reported in The New England Journal of Medicine.² In the open-label nonrandomized DESTINY-CRC01 trial, 45% of heavily pretreated patients with HER2-positive (3+ IHC) colorectal cancer responded to this single agent, and 83% achieved disease control.

Salvatore Siena, MD

Michael S. Lee, MD

“In our opinion, these data demonstrate the potential of T-DXd as a treatment option for patients with advanced HER2-positive colorectal cancer,” said Salvatore Siena, MD, of Niguarda Cancer Center and Università degli Studi di Milano, Milan, Italy, who presented the study during the ASCO20 Virtual Scientific Program.

Although there remain some unanswered questions regarding the use of T-DXd in patients with HER2-expressing metastatic colorectal cancer, “these data are promising for subsequent anti-HER2 therapy in HER2-positive metastatic colorectal cancer,” said study discussant Michael S. Lee, MD, Assistant Professor of Medicine at Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.

DESTINY-CRC01 Details

The trial was conducted in 78 patients with previously treated unresectable and/or metastatic colorectal cancer that was HER2-expressing and RAS/BRAF wild-type. Patients had received at least two prior regimens, which in 30% included prior anti-HER2 treatment. The median number of prior regimens was four (range, 2–11). Patients with current or suspected interstitial lung disease (a known toxicity of T-DXd) were excluded.

Three cohorts were based on the degree of HER2 positivity: HER2-positive with immunohistochemistry (IHC) scoring 3+ or IHC 2+/in situ hybridization (ISH)+ (cohort A, n = 53); HER2 IHC 2+/ISH– (cohort B, n = 7); or HER2 IHC 1+ (cohort C, n = 18).

All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was objective response by blinded central review in cohort A, who had the highest HER2 expression.

In cohort A, objective responses were observed in 45.3%, with one patient demonstrating a complete response. Responses were seen equally for patients with or without prior anti-HER2 treatment (43.8% vs 45.9%). The median duration of response was not reached. Stable disease was also achieved by 37.7% of patients in cohort A, yielding a disease control rate of 83.0%. Median progression-free survival was 6.9 months in cohort A, and median overall survival was not reached. There were no confirmed responses in cohorts B and C, who had lower HER2 expression.

Interstitial Lung Disease in 6.4%

The median treatment exposure was 4.8 months. Over that time, the safety profile was consistent with what has been seen in other tumor types, with most adverse events being low grade. Interstitial lung disease, however, occurred in five patients (6.4%). Of these cases, two were grade 2, one was grade 3, and two were grade 5; the median time to reported onset was 80 days.

“Of note, the study protocol recommendations included monitoring for symptoms of interstitial lung disease and to halt T-DXd and start corticosteroids if it is suspected,” explained Dr. Siena. All five patients, therefore, received steroids; two recovered, two died, and one did not recover and later died of progressive disease.

“Interstitial lung disease is an important risk [with T-DXd] and requires careful monitoring and proper intervention,” Dr. Siena emphasized.

Approximately half the patients in cohort A and also in the overall study population
experienced a treatment-related adverse event; they were considered serious in 23% and 18%, respectively. The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite. 

DISCLOSURE: The study was funded by Daiichi Sankyo. Dr. Siena reported owning stock and other interests with Guardant Health and Myriad Genetics; has served as a consultant or advisor to Amgen, Bayer, Bristol Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, and Seattle Genetics; has received institutional research funding from MSD Oncology; has patents, royalties, and other intellectual property from Amgen; and has received travel accommodations and expenses from Amgen, Bayer, and Roche. Dr. Lee has received travel support from Genentech/Roche and institutional research support from several companies.

REFERENCES

1. Siena S, Di Bartolomeo M, Raghav KPS, et al: A phase II, multicenter, open-label study of trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer: DESTINY-CRC01. ASCO20 Virtual Scientific Program. Abstract 4000. Presented May 29, 2020.

2. Shitara K, Bang YJ, Iwasa S, et al: Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 382:2419-2430, 2020.