First-Line T-DXd Combinations Show Early Antitumor Activity in HER2+ Gastric/GEJ Cancers

Yelena Y. Janjigian, MD

Treatment with first-line fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) alone or in combination with fluoropyrimidine with or without pembrolizumab (Keytruda) demonstrated antitumor activity and a manageable safety profile in patients with advanced HER2-positive esophageal, gastric, and gastroesophageal junction (GEJ) cancer, according to findings from part 2 of the phase 1b/2 DESTINY-Gastric03 study (NCT04378596) presented at the 2024 ESMO Congress.¹

In part 1 of the study, the antibody-drug conjugate T-DXd plus fluoropyrimidine chemotherapy demonstrated tolerable safety and promising efficacy in patients with HER2-positive 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-positive 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 fluoropyrimidine at the full dose of 1000 mg/m2 (n = 41)
• Cohort 3: T-DXd at 6.4 mg/kg, fluoropyrimidine 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, fluoropyrimidine 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 Fluoropyrimidine

The highest ORR was reported in cohort 2 in patients receiving full doses of T-DXd and fluoropyrimidine. 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 Fluoropyrimidine Introduces More Toxicities

In cohort 3, where patients were treated with T-DXd at the full dose of 6.4 mg/kg, fluoropyrimidine 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.

While CPS did not appear to matter in cohort 2, “[in] the pembrolizumab-containing arms, CPS score did seem to matter,” lead study author Yelena Y. Janjigian, MD, a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center in New York, stated 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

Although 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.

References

1. Janjigian YY, van Laahoven H, Rha SY, et al. Trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2-positive (HER2+) esophageal, gastric or gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03 (DG-03). Presented at: 2024 ESMO Congress; September 13-17, 2024; 2024; Barcelona, Spain. Abstract 1401O.
2. Janjigian YY, Oh D-Y, Rha SY, et al. Dose-escalation and dose-expansion study of trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2+ gastric cancer (GC)/gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03. J Clin Oncol. 2022;40(4). doi: 10.1200/JCO.2022.40.4_suppl.295