Meaningful objective response rate with trastuzumab deruxtecan in HER2-associated advanced colorectal cancer
HER2 amplification has been identified in 2–3% of patients with colorectal cancer, although there are currently no approved HER2-targeted therapies for colorectal cancer. Final results of the phase II DESTINY-CRC01 trial confirm that trastuzumab deruxtecan at a dose of 6.4 mg/kg once every three weeks is associated with an overall response rate of 45% in heavily pre-treated metastatic colorectal cancer patients with strong HER2 overexpression.
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate of a humanised anti-HER2 antibody bound to a topoisomerase I inhibitor by a cleavable linker. In the phase II, open-label, multicentre DESTINY-CRC01 study, T-DXd previously demonstrated promising antitumour activity in patients with HER2-overexpressing mCRC. During the 2022 ASCO GI meeting, final results of this trial were presented.
Study design
In total, 86 patients with HER2-expressing RAS/BRAFV600E wild type unresectable/metastatic CRC, who had progressed on ≥2 prior regimens were split into three cohorts (cohort A: HER2+ IHC3+ or IHC2+/ISH+ [N= 53]; cohort B: IHC2+/ISH- [N= 15]; cohort C: IHC1+ [N= 18]) and received T-DXd (6.4 mg/kg every 3 weeks). Prior anti-HER2 treatment was permitted while patients with a history of or current/suspected interstitial lung disease (ILD) were excluded from the trial. The primary endpoint of this study was objective response rate (ORR) by central review in cohort A, while secondary objectives included ORR in cohorts B and C, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS).
Results
Across all three cohorts, the median age was 58.5 years and 90.7% of patients had a left sided primary tumour. In cohort A, 75.5% of patients were IHC3+ and 24.5% were IHC2+. The median number of previous treatment lines for metastatic disease was 4 (range 2-11). All patients had been previously treated with irinotecan and 30.2% of patients in cohort A also received a previous anti-HER2 treatment. In cohort A (median follow-up of 62.4 weeks, median treatment duration of 5.1 months), the confirmed ORR was 45.3% (24/53 patients), DCR was 83.0% (44/53 patients), mDOR was 7.0 months, mPFS was 6.9 months with 37 PFS events, and mOS was 15.5 months with 36 OS events. These results are consistent with the primary analysis. Subgroup analysis in cohort A demonstrated that the confirmed ORR was 43.8% (7/16 patients) for patients with prior anti-HER2 therapy, 57.5% (23/40 patients) for patients with IHC3+ status, and 7.7% (1/13 patients) for patients with IHC2+/ISH+ status. In cohorts B and C, no responses were observed (ORR of 0% in both cohorts). mPFS was 2.1 months and 1.4 months; mOS was 7.3 months and 7.7 months, for cohorts B and C respectively.
Treatment-emergent adverse events (TEAEs) of grade ≥3 occurred in 65.1% of patients. The most common TEAEs were haematologic and gastrointestinal. TEAEs leading to drug discontinuation occurred in 13 patients (15.1%). Eight patients (9.3%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (grade 2, N= 4; grade 3, N= 1; grade 5, N= 3). Median time to adjudicated onset was 61.0 days and all eight patients received corticosteroids. Four patients with grade 2 ILD recovered and one patient with grade 3 did not recover and died later on due to disease progression. In the three fatal cases adjudicated as drug-related ILD/pneumonitis, onset was from 9 to 120 days (median 22 days) and death occurred 6 to 19 days after diagnosis.
Conclusion
T-DXd monotherapy at a dose of 6.4 mg/kg every three weeks showed promising activity and durability with longer-term follow-up in patients with HER2-positive mCRC. In contrast, no responses were observed in cohorts B and C. The safety profile of T-DXd was consistent with its known safety profile. These promising results support continued exploration of T-DXd in patients with HER2-positive mCRC.
Reference
Yoshino T, Di Bartolomeo M, Raghav KPS, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). Presented at ASCO GI 2022; Abstract 119.
