The first patient has received treatment with fam-trastuzumab deruxtecan-nxki in the phase 2 DESTINY-CRC02 trial, which is exploring the safety and efficacy of the antibody-drug conjugate in patients with HER2-overexpressing, BRAF wild-type, RAS-mutant or wild-type or mutant locally advanced, unresectable or metastatic colorectal cancer who have progressed following treatment with standard chemotherapy.
The first patient has received treatment with fam-trastuzumab deruxtecan-nxki (Enhertu) in the phase 2 DESTINY-CRC02 (NCT04744831) trial, which is exploring the safety and efficacy of the antibody-drug conjugate in patients with HER2-overexpressing, BRAF wild-type, RAS-mutant or wild-type or mutant locally advanced, unresectable or metastatic colorectal cancer (CRC) who have progressed following treatment with standard chemotherapy.1
"Patients with metastatic colorectal cancer often have limited treatment options following progression on standard-of-care therapy, making it important to understand new ways to treat these patients. Identifying patients with HER2 overexpression is an important area of research to further explore," Gilles Gallant, BPharm, PhD, FOPQ, senior vice president and global head of oncology development, Oncology R&D, Daiichi Sankyo, the developer of the ADC.
"Based on the encouraging data from the DESTINY-CRC01 phase 2 trial, we have initiated this second phase 2 study to further evaluate the potential of targeting HER2 with Enhertu at the 5.4-mg/kg and 6.4-mg/kg doses in patients with HER2-overexpressing advanced colorectal cancer."
Trastuzumab deruxtecan is a HER2-directed ADC that consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.
In the global, phase 2 DESTINY-CRC02 trial, which will be conducted in 2 stages, is expected to enroll 120 patients from sites across North and South America, Asia, and Europe. In stage 1 of the study, 80 patients will be randomized 1:1 to receive trastuzumab deruxtecan at a dose of either 5.4 mg/kg or 6.4 mg/kg every 3 weeks. In stage 2, 40 additional patients will be enrolled to the 5.4-mg/kg cohort.
The primary end point is confirmed objective response rate (ORR), which will be assessed by blinded independent central review, while secondary end points include duration of response (DOR), disease control rate (DCR), clinical benefit ratio, investigator-assessed ORR, progression-free survival (PFS), overall survival (OS), pharmacokinetics, patient reported outcomes, and safety.
To be eligible for enrollment, patients must have pathologically documented, unresectable, recurrent, or metastatic CRC with HER2 overexpression and be either BRAF wild-type, RAS wild-type, or RAS-mutant.2 Additionally, patients must have received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan; targeted therapies, such as EGFR-targeted therapy if RAS wild-type; VEGF treatment; or a PD-1/PD-L1 inhibitor if the tumor is microsatellite instability–high, mismatch repair deficient, or has high tumor mutational burden.
Additionally, trastuzumab deruxtecan was evaluated in the open-label, multicenter, phase 2 DESTINY-CRC01 (NCT03384940) trial in patients with HER2-expressing, RAS/BRAF wild-type, unresectable, and/or metastatic CRC, who had previously received 2 or more lines of treatment.
Patients were treated with trastuzumab deruxtecan at a dose of 6.4 mg/kg every 3 weeks and were stratified into 3 cohorts. Cohort A included 53 patients with HER2-positive disease as defined by immunohistochemistry (IHC) 3+ or IHC 2+, cohort B included 7 patients with HER2-positive and fluorescence in situ hybridization (FISH)—negative tumors, and cohort C included 18 patients with HER2-positive disease as defined by IHC 1+.
Patients who had received prior anti-HER2 therapies were permitted to enroll permitted, while those who had a history of interstitial lung disease (ILD) were ineligible.
Of the 78 patients enrolled and treated, the median age was 58.5 years (range, 27-79), a majority were male (52.6%), and a significant percentage had left colon or rectum cancer (89.7%). The median number of prior therapies was 4 (range, 2-11), and the median treatment duration in all patients was 3.5 months.
Treatment with the trastuzumab deruxtecan resulted in an ORR of 45.3% (95% CI, 31.6%-59.6%), a DCR of 83.0% (95% CI, 70.2%-91.9%), and the median DOR was not reached (95% CI, 4.2–not evaluable [NE]). The median PFS was 6.9 months (95% CI, 4.1–NE), and the median OS was not reached.3
In terms of safety, grade 3 or higher treatment-emergent adverse events (TEAEs) were observed in 61.5% of all patients (n=48/78).
In January 2021, trastuzumab deruxtecan was approved for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a previous trastuzumab (Herceptin)-based regimen. Prior to that, in December 2019, the agent was approved for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.