First-line combinations involving trastuzumab deruxtecan (T-DXd; Enhertu) have demonstrated promising antitumor activity in patients with advanced HER2-positive esophageal, gastric, and gastroesophageal junction (GEJ) cancers. These findings, signaling the need for further research, were presented at the 2024 ESMO Congress by Yelena Y. Janjigian, MD, from Memorial Sloan Kettering Cancer Center. The data comes from part 2 of the phase 1b/2 DESTINY-Gastric03 study (NCT04379596).
The DESTINY-Gastric03 study evaluated several T-DXd-based combinations. In part 2, 229 patients with unresectable, locally advanced or metastatic, HER2-positive esophageal, gastric, or GEJ cancer were assigned to one of six groups:
- T-DXd monotherapy at 6.4 mg/kg (n = 43)
- T-DXd at 6.4 mg/kg and fluoropyrimidine (FP) at 1000 mg/m2 (n = 41)
- T-DXd at 6.4 mg/kg, FP at 1000 mg/m2, and pembrolizumab (n = 43)
- T-DXd at 6.4 mg/kg and pembrolizumab (n = 41)
- T-DXd at 5.4 mg/kg, FP at 750 mg/m2, and pembrolizumab (n = 32)
- Standard-of-care trastuzumab, FP, and cisplatin/oxaliplatin (n = 29)
The primary endpoint, confirmed overall response rate (ORR), varied across the cohorts:
- Cohort 1: 49% (95% CI, 33%-65%)
- Cohort 2: 78% (95% CI, 62%-90%)
- Cohort 3: 58% (95% CI, 42%-73%)
- Cohort 4: 63% (95% CI, 46%-78%)
- Cohort 5: 59% (95% CI, 40%-77%)
- Cohort 6: 76% (95% CI, 56%-90%)
T-DXd and Full-Dose Fluoropyrimidine
Cohort 2, receiving full doses of T-DXd and FP, exhibited the highest ORR. With a median follow-up of 21 months, the median duration of response (DOR) was 20 months (95% CI, 12-28). In patients with a combined positive score (CPS) of 1% or higher, the confirmed ORR was 77%, compared to 73% in those with a CPS of less than 1%.
The highest median progression-free survival (PFS) was also observed in this cohort, reaching 20 months (95% CI, 10-28). For patients with a positive CPS, the median PFS was 14 months (range, 7-29), while it was 26 months (range, 8-NE) in those with a negative CPS. The median overall survival (OS) in this cohort was 23 months (95% CI, 16-NE).
All patients in this group experienced any-grade adverse events (AEs), with 76% (n = 32) experiencing grade 3 or higher AEs. Drug-related interstitial lung disease (ILD) was reported in 12% of patients; however, all incidences were grade 1 or 2.
Impact of Adding Pembrolizumab
In cohort 3, which included pembrolizumab, the ORR in patients with a positive CPS was 70% and 39% in those with a negative CPS. The median PFS was 10 months (95% CI, 5-18), and the median OS was 23 months (95% CI, 13-NE). Janjigian noted that the CPS score appeared to influence outcomes in the pembrolizumab-containing arms.
However, this cohort experienced greater toxicities, with grade 3 or higher AEs reported in 91% of patients (n = 39), drug-related ILD in 19% (n = 8), and grade 3 or higher drug-related ILD in 7% (n = 3). Treatment-related deaths were reported in 9% of patients (n = 4).
Reduced-Dose Triplet
The reduced-dose triplet of T-DXd at 5.4 mg/kg, FP at 750 mg/m2, and pembrolizumab showed more manageable safety. The incidence of grade 3 or higher AEs was 34% (n = 11), with no reports of treatment-related deaths or ILD. PFS and OS data for this cohort were immature at the time of reporting.
Janjigian concluded, "Based on all of this data, there are several studies now planned to evaluate the combination of T-DXd with fluoropyrimidine and immunotherapies in HER2-positive, CPS-positive tumors."
