T-DXd Combinations Effective in HER2+ Gastric and GEJ Cancer
Findings from the DESTINY-Gastric03 study support the further exploration of the antibody-drug conjugate trastuzumab deruxtecan for the first-line treatment of patients with advanced HER2+ gastric, esophageal, and GEJ cancers.
Microscopic image of gastric tumor cells - Generated with Google Gemini AI
First-line combinations of trastuzumab deruxtecan (T-DXd; Enhertu) and fluoropyrimidine (FP) with or without pembrolizumab (Keytruda) demonstrated notable antitumor activity for the treatment of patients with advanced HER2-positive (HER2+) esophageal, gastric, and gastroesophageal junction (GEJ) cancer, signaling a need for further research of these regimens.1
These findings come from part 2, the dose-expansion portion, of the phase 1b/2 DESTINY-Gastric03 study (NCT04379596), and were presented at the 2024 ESMO Congress by Yelena Y. Janjigian, MD, gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center in New York, NY.
In part 1 of the study, the antibody-drug conjugate T-DXd plus FP chemotherapy demonstrated tolerable safety and promising efficacy in patients with HER2+ gastric/GEJ cancer, according to results presented at the 2022 ASCO Annual Meeting.2
In part 2, a total of 229 patients aged 18 or older with unresectable, locally advanced or metastatic, HER2+ esophageal, gastric, or GEJ cancer were assigned to 1 of 6 groups:
- Cohort 1: T-DXd monotherapy at 6.4 mg/kg (n = 43)
- Cohort 2: T-DXd at 6.4 mg/kg and FP at the full dose of 1000 mg/m2 (n = 41)
- Cohort 3: T-DXd at 6.4 mg/kg, FP at the full dose of 1000 mg/m2, and pembrolizumab (n = 43)
- Cohort 4: T-DXd at 6.4 mg/kg and pembrolizumab (n = 41)
- Cohort 5: T-DXd at a reduced dose of 5.4 mg/kg, FP at a reduced dose of 750 mg/m2, and pembrolizumab (n = 32)
- Cohort 6: The standard-of-care regimen of trastuzumab (Herceptin), FP, and cisplatin/oxaliplatin (n = 29)1
The confirmed overall response rate (ORR), the study’s primary end point, for each cohort was as follows:
- 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%)
Promising Results With T-DXd and Full-Dose FP
The highest ORR was reported in cohort 2 in patients receiving full doses of T-DXd and FP. Here, the median follow-up was 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%, while it was 73% in those with a CPS of less than 1%.
Regarding progression-free survival (PFS), one of the study’s secondary end points, the highest median PFS was also observed in this cohort. The median was 20 months (95% CI, 10-28). In patients with a positive CPS, the median PFS was 14 months (range, 7-29), while it was 26 months (range, 8-not estimable [NE]) in those with a negative CPS.
Additionally, the median overall survival (OS), another secondary end point, in this cohort was 23 months (95% CI, 16-NE), with a median OS of 20 months (range, 11-NE) in patients with a positive CPS and 21 months (range, 7-NE) in patients with a negative CPS.
With a median follow-up of 21 months, 100% of patients in this group experienced any-grade adverse events (AEs), with 76% (n = 32) experiencing an AE of grade 3 or higher. Drug-related interstitial lung disease (ILD) was noted as an AE of special interest and was reported in 12% of patients in cohort 2; however, all incidences were grade 1 or 2.
Pembrolizumab Plus Full-Dose T-DXd and FP Introduces More Toxicities
In cohort 3, where patients were treated with T-DXd at the full dose of 6.4 mg/kg, FP at the full dose of 1000 mg/m2, and pembrolizumab, the ORR in patients with a positive CPS was 70% and 39% in those with a negative CPS. The median PFS of all patients in the cohort was 10 months (95% CI, 5-18), while it was 14 months (range, 5-20) in those with a positive CPS and 6 months (range, 2-11) with a negative CPS. For OS, the median was 23 months (95% CI, 13-NE) in all patients, 23 months (range, 13-NE) in patients with a positive CPS, and 16 months (range, 4-NE) in patients with a negative CPS.
Yelena Y. Janjigian, MD
While CPS did not appear to matter in cohort 2, “[in] the pembrolizumab-containing arms, CPS score did seem to matter,” Janjigian said during the presentation.
However, greater toxicities were reported in this cohort, 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). Further, 51% of patients (n = 22) had treatment-related serious AEs, and treatment-related deaths were reported in 9% (n = 4).
Due to these safety findings, “the triplet arm is being explored at lower doses, and so far, it's well tolerated,” Janjigian explained.
Reduced-Dose Triplet Shows Manageable Safety
While toxicities were higher with the full-dose triplet, safety appeared to be more manageable in the reduced-dose triplet of T-DXd at 5.4 mg/kg, FP at 750 mg/m2, and pembrolizumab. The incidence of grade 3 or higher AEs was 34% (n = 11), with 3% experiencing a treatment-related serious AE and no reports of treatment-related deaths. There were also no incidences of ILD reported in this cohort.
PFS and OS data for this cohort were immature and therefore not reported at this time.
“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,” Janjigian concluded.
