Meaningful objective response rate with trastuzumab deruxtecan in HER2-associated advanced colorectal cancer: Updated results from the phase II DESTINY-CRC01 study
Updated results of the phase II DESTINY-CRC01 trial indicate that trastuzumab deruxtecan is associated with an overall response rate of 45% in heavily pre-treated metastatic colorectal cancer patients with strong HER2 overexpression. In this cohort, patients were found to have a median progression-free survival of 7 months and an overall survival exceeding 15 months.
For patients with mCRC, treatment options include fluoropyrimidine with oxaliplatin, irinotecan and anti-VEGF or anti-EGFR compounds, depending on RAS status. Interestingly, 2-3% of mCRC patients have HER2-amplified tumours and currently there is no approved HER2-targeted therapy for CRC. In the phase II, open-label, multicenter DESTINY-CRC01 study, the antibody-drug conjugate T-Dxd previously demonstrated antitumour activity in patients with HER2-overexpressing mCRC. During the 2021 ASCO Annual meeting, updated results of this trial were presented.
DESTINY-CRC01 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 3 cohorts (A: HER2 IHC3+ or IHC2+/ISH+ [N= 53]; B: IHC2+/ISH- [N= 15]; C: IHC1+ [N= 18]) and received T-Dxd (6.4 mg/kg every 3 weeks). Prior anti-HER2 treatment was permitted. 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).
Patient characteristics
Across all 3 cohorts, the median age was 58.5 years. Approximately 53.5% of patients were enrolled from Europe, 62.8% of patients having an ECOG performance status of 0. Furthermore, 90.7% of patients had a left sided primary tumour, the majority of patients (80.2%) were microsatellite stable and respectively 97.7% and 98.8% of patients had a RAS and BRAFV600E wild type 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. All patients had been previously treated with irinotecan and 30.2% of patients in cohort A also received a previous anti-HER2 treatment.
Objective response rate of 45.3%
At a median follow-up of 62.4 weeks for cohort A, an ORR of 45.3% was reported (95%CI: 31.6-59.6), all being partial responses. An additional 38% of patients experienced disease stabilization for the DCR was 83% (95%CI: 70.2-91.9]). Responses to T-Dxd were durable, with a median DoR of 7.0 months (95%CI: 5.8-9.5) in cohort A. The median treatment duration was 5.1 months (95%CI: 3.9-7.6). No ORRs were observed in cohort B or C, with a DCR of 60.0% and 22.2% respectively. IHC3-status appeared as the most evident indicator of response. Patients with a IHC3+ tumour had a better ORR (57.5%) than patients with a IHC2+/ISH+ tumour (7.7%).
In cohort A, most patients had tumour size reduction, regardless of prior anti-HER2 agent exposure. Tumour shrinkage was also maintained for the longest period of time in cohort A, compared to cohorts B and C. Cohort A had the longest median PFS at 6.9 months (95%CI: 4.1-8.7), compared to 2.1 months (95%CI: 1.4-4.1) in cohort B and 1.4 months (95%CI: 1.3-2.1) in cohort C. The median OS was longest in cohort A at 15.5 months, while this was 7.7 and 7.3 months in cohorts C and B, respectively.
All patients experienced at least one treatment-emergent adverse event (TEAE), with grade ≥3 TEAEs occurring in 65.1% of patients. The most common grade ≥3 TEAEs were anaemia (14.0%), decreased neutrophil count (22.1%), decrease platelet count (9.3%), and nausea (5.8%). Drug-related interstitial lung disease (ILD) was reported in 8 patients, with 3 cases of grade 5 ILD.
Conclusion
Longer follow-up of T-DXd in patients with HER2+ mCRC supports the continued exploration of this compound in these patients. Promising results were obtained from cohort A, although no ORR was observed in either cohorts B or C. Furthermore, the safety profile is consistent with the known safety profile of T-DXd, although close monitoring and prompt intervention is required in cases of ILD/pneumonitis.
Reference
Yoshino T 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 2021; Abstract 3505.
