Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): Primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study.

Abstract

3501 Background: T-DXd (6.4 mg/kg, every 3 weeks [Q3W]) demonstrated antitumor activity in pts with HER2+ mCRC in DESTINY-CRC01 (Siena et al. Lancet Oncol. 2021). We present primary results of DESTINY-CRC02 (NCT04744831), which assessed the efficacy and safety of T-DXd (5.4 and 6.4 mg/kg) in pts with HER2+ mCRC. Methods: This was a multicenter phase 2 study. Eligible pts had centrally confirmed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) mCRC. Pts with RAS wild-type (wt) or mutant (m) mCRC were eligible. Pts had received prior standard therapy, unless contraindicated; prior anti-HER2 therapy was allowed. In stage 1, 80 pts were randomized 1:1 to 5.4 (n = 40) or 6.4 (n = 40) mg/kg T-DXd Q3W. In stage 2, an additional 42 pts received 5.4 mg/kg T-DXd. Primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: At data cutoff (Nov 1, 2022), most pts in the 5.4 and 6.4 mg/kg T-DXd arms had HER2 IHC 3+ (78.0% and 85.0%), RAS wt tumors (82.9% and 85.0%), and a median of 3 and 4 prior lines of therapy, respectively. cORR was 37.8% (95% CI, 27.3-49.2%) in the 5.4 mg/kg arm and 27.5% (95% CI, 14.6-43.9%) in the 6.4 mg/kg arm (all partial responses in both arms). Key efficacy data are shown in the Table: Grade ≥3 treatment-emergent adverse events (AEs) were observed in 41/83 pts (49.4%) and 23/39 pts (59.0%) in the 5.4 and 6.4 mg/kg T-DXd arms, respectively. Serious AEs were observed in 20/83 pts (24.1%) and 12/39 pts (30.8%) in the 5.4 and 6.4 mg/kg arms, respectively. Independently adjudicated drug-related interstitial lung disease occurred in 7/83 pts (8.4%) with 5.4 mg/kg T-DXd and 5/39 pts (12.8%) with 6.4 mg/kg T-DXd, and most events were grade 1/2 (1 grade 5 in the 6.4 mg/kg arm). Conclusions: T-DXd showed promising antitumor activity in pts with HER2+ mCRC at both 5.4 and 6.4 mg/kg doses. Antitumor efficacy was observed irrespective of RAS mutation status at 5.4 mg/kg T-DXd, and in those with prior anti-HER2 therapy. Overall, safety was consistent with the known safety profile of T-DXd and favored the 5.4 mg/kg dose. Clinical trial information: NCT04744831 . [Table: see text]

Temporal and spatial heterogeneity of HER2 status in metastatic colorectal cancer

“…The aim of this study was to analyze the concordance of HER2 status between primary CRC and their corresponding liver metastases. Indeed, the precise evaluation of this biomarker is mandatory, as the expansion of new treatments targeting HER2 in this location has recently led to promising results, mainly in RAS wild-type tumors [ 7 – 13 ].…”

“…However, this clinical efficacy was optimal in patients without RAS mutations [ 7 ]. More recently, a clinical trial evaluating trastuzumab conjugated to deruxtecan, a topoisomerase inhibitor, has shown promising activity in mCRC, irrespective of RAS mutation status [ 12 , 13 ]. In these trials, patient recruitment is mainly based on immunohistochemistry and in situ hybridization.…”

Target-Driven Tissue-Agnostic Drug Approvals; a New Path of Drug Development

“…The most common cancer types were endometrial cancer (n=143, ORR=45.5%) and colorectal cancer (n=115, ORR = 43.5%). Patients also demonstrated a promising mPFS of 6.9 months (Andre et al, 2023). The most common all-grade adverse reactions were fatigue, anemia, and gastrointestinal side effects.…”

“…The first 15 patients with pancreatic cancer did not respond and recruitment was consequently discontinued. Similarly, patients with HER2-positive metastatic CRC (DESTINY-CRC02) had poor ORR (<40%), including a 0% complete response rate [45]. Patients with HER2-overexpressed metastatic NSCLC (DESTINY-Lung01) received either 6.4 mg/kg (cohort 1) or 5.4 mg/kg (cohort 1A).…”

Treatment Options in Late-Line Colorectal Cancer: Lessons Learned from Recent Randomized Studies

“…Table 5 summarizes studies, primarily phase 2, investigating the efficacy of HER2 targeted therapy, often dual targeted therapy, in patients with HER2 positive (HER2+) mCRC [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ]. Patients with HER2+ mCRC benefit from anti-HER2 treatment, with RR ranging from 10 to 55% and PFS and OS outcomes spanning 2.9–6.9 months and 10.6–24.1 months, respectively.…”