Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer

Abstract

DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH-), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC.

Fig. 1. Antitumor activity of trastuzumab deruxtecan.

A Waterfall plot showing the greatest percentage change from baseline in the sum of diameters of measurable tumors in patients with HER2-positive mCRC (cohort A). Each bar represents a patient. The line at 20% indicates progressive disease. The line at −30% indicates partial response. B Spider plot showing change over time from baseline in the sum of diameters of measurable tumors in cohorts A, B, and C. ^aFour patients from the full analysis set were excluded; 1 patient had no measurable target lesion and 3 patients had no postbaseline data. ^bBy local assessment. ^cOne patient from cohort B and 5 patients from cohort C had missing postbaseline data. HER2 human epidermal growth factor receptor 2, IHC immunohistochemistry, ISH in situ hybridization.

Fig. 2. Progression-free survival and overall survival in patients with HER2-positive and HER2-low mCRC receiving trastuzumab deruxtecan.

Kaplan–Meier curves representing (A) progression-free survival and (B) overall survival. Marks indicate where data were censored. HER2 human epidermal growth factor receptor 2, IHC immunohistochemistry, ISH in situ hybridization, NE not evaluable.

Fig. 3. Objective response rate and progression-free survival by patient subgroups in patients with HER2-positive (cohort A) mCRC receiving trastuzumab deruxtecan.

A, B Forest plot of subgroups for (A) objective response rate^a. Data are presented as the point estimate of ORR with its exact 95% CI. The dotted line represents the ORR of patients in the HER2 + cohort A (45.3%). Forest plot of subgroups for (B) progression-free survival. Data are presented as median PFS with its exact 95% CI. The dotted line represents the median PFS of patients in the HER2 + cohort A (6.9 months). ^aReprinted from ref. , with permission from Elsevier. ^bLeft: rectum, sigmoidal, descending; right: cecum, ascending, transverse. ECOG PS Eastern Cooperative Oncology Group performance status, HER2 human epidermal growth factor receptor 2, IHC immunohistochemistry, ISH in situ hybridization, mCRC metastatic colorectal cancer.