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.

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study

“…Furthermore, the data included many patients who had received fewer T-DXd administrations, including patients receiving only one administration just before the end of this expanded-access study. A comparison of SAEs with T-DXd treatment is challenging as SAE frequencies vary between trials, even among trials of patients with the same type of cancer [ 18 , 23 – 28 ]. Thus, it is difficult to reach any conclusions regarding differences in SAE frequency between this expanded-access study and other T-DXd clinical trials because of differences in T-DXd dose, treatment line, treatment duration, and cancer type [ 18 , 23 – 28 ].…”

“…A comparison of SAEs with T-DXd treatment is challenging as SAE frequencies vary between trials, even among trials of patients with the same type of cancer [ 18 , 23 – 28 ]. Thus, it is difficult to reach any conclusions regarding differences in SAE frequency between this expanded-access study and other T-DXd clinical trials because of differences in T-DXd dose, treatment line, treatment duration, and cancer type [ 18 , 23 – 28 ]. However, the results of this expanded-access study are generally consistent with the safety results as identifying recommended dose in HER2-positive gastric cancer [ 29 ].…”

Sequencing considerations in the third-line treatment of metastatic colorectal cancer

“…2 The Table summarizes the range of biomarkers that may be relevant in guiding therapy for patients with mCRC. 2,10,11 The 2024 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) for Colon Cancer (version 1.2024) include checkpoint inhibitor therapy options: nivolumab ± ipilimumab, pembrolizumab, or dostarlimab-gxly. Nivolumab + ipilimumab combination is category 2B when intensive therapy is not recommended due to toxicity concerns.…”

“…It is a small-molecule, multikinase inhibitor that targets at least 20 kinases involved in tumor activity (eg, RET, RAF1, BRAF, and VEGFR). 11 Regorafenib therapy was associated with low rates of grade 3 and 4 hematologic adverse events (AEs) in clinical trials. 11 In the ReDOS trial, the dose escalation strategy was associated with a lower rate of nonhematologic toxicities of grade 3 or higher when compared with the standard dose, with toxicities still notable as early as cycle 1 (hand-foot skin reaction [HFSR], 7.4%; fatigue, 5.6%; hypertension, 3.7%).…”

Progress of research on molecular targeted therapies for colorectal cancer

“…Trastuzumab deruxtecan (DS-8201) is a novel antibody-drug conjugate with a humanized anti-HER2 antibody, cleavable peptide linker, and potent topoisomerase I inhibitor payload that has been confirmed to be effective in multiple solid tumors, including CRC ( Tsurutani et al, 2020 ). The DESTINY-CRC01 study ( Siena et al, 2021 ; Yoshino et al, 2023 ) treated HER2-positive mCRC patients with DS-8201 after two or more prior regimens. The patients were divided into three cohorts based on HER2 expression levels: cohort A (HER2-positive, IHC 3+ or IHC 2+/ISH+), cohort B (HER2 IHC 2+/ISH-), and cohort C (HER2 IHC 1+).…”