Trastuzumab Deruxtecan in Anti-Human Epidermal Growth Factor Receptor 2 Treatment-Naive Patients With Human Epidermal Growth Factor Receptor 2-Low Gastric or Gastroesophageal Junction Adenocarcinoma: Exploratory Cohort Results in a Phase II Trial

Abstract

Purpose: To investigate efficacy and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-low gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Methods: Patients with locally advanced or metastatic HER2-low (cohort 1, immunohistochemistry 2+/in situ hybridization-negative; cohort 2, immunohistochemistry 1+) gastric/GEJ adenocarcinoma treated with at least two prior regimens, including fluoropyrimidine and platinum, but anti-HER2 therapy naive, received T-DXd 6.4 mg/kg intravenously once every 3 weeks. The primary end point was confirmed objective response rate by independent central review.

Results: Among 21 patients enrolled in cohort 1 and 24 enrolled in cohort 2, 19 and 21 patients, respectively, had central HER2 confirmation, received T-DXd, and had measurable tumors at baseline. The confirmed objective response rate was 26.3% (95% CI, 9.1 to 51.2) from five partial responses in cohort 1 and 9.5% (95% CI, 1.2 to 30.4) from two partial responses in cohort 2. Thirteen patients (68.4%) in cohort 1 and 12 (60.0%) in cohort 2 experienced reduced tumor size. The median overall survival was 7.8 months (95% CI, 4.7 to nonevaluable) in cohort 1 and 8.5 months (95% CI, 4.3 to 10.9) in cohort 2; the median progression-free survival was 4.4 months (95% CI, 2.7 to 7.1) and 2.8 months (95% CI, 1.5 to 4.3), respectively. The most common grade ≥ 3 treatment-emergent adverse events in cohorts 1 and 2 were anemia (30.0% and 29.2%), decreased neutrophil count (25.0% and 29.2%), and decreased appetite (20.0% and 20.8%). Drug-related interstitial lung disease/pneumonitis occurred in one patient in each cohort (grade 1 or 2). No drug-related deaths occurred.

Conclusion: This study provides preliminary evidence that T-DXd has clinical activity in patients with heavily pretreated HER2-low gastric/GEJ adenocarcinoma.

Trial registration: ClinicalTrials.gov NCT03329690.

Conflict of interest statement

Kohei Shitara

Honoraria: Bristol Myers Squibb, Takeda, Janssen

Consulting or Advisory Role: Lilly, Bristol Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Boehringer Ingelheim, Amgen, Astellas Pharma, Guardant Health Japan

Research Funding: MSD (Inst), Daiichi Sankyo (Inst), Taiho Pharmaceutical (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Astellas Pharma (Inst), Eisai (Inst), Amgen (Inst)

No other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram. HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; T-DXd, trastuzumab deruxtecan.

FIG 2.

Best percentage change from baseline in tumor size by ICR in (A) cohort 1 and (B) cohort 2 (full analysis set). Dashed lines at 20% indicate progressive disease; dashed lines at –30% indicate PR. Includes patients in both cohorts who had both baseline and postbaseline target lesion assessments by ICR. One patient in each cohort was excluded because there was no baseline measurable disease by ICR. Three additional patients in the IHC 1+ cohort were excluded because there was no postbaseline assessment (n = 1) or a missing HER2 status by central laboratory (n = 2). Among the four patients in cohort 1 who received prior irinotecan, none responded to prior irinotecan (three SD and one unknown), and two had confirmed response to T-DXd (confirmed ORR = 50%). Among the four patients in cohort 2 who received prior irinotecan, one responded to prior irinotecan (PR), three did not respond to prior irinotecan (one SD, one progressive disease, and one unknown), and none had confirmed response to T-DXd (confirmed ORR = 0%). ICR, independent central review; IHC, immunohistochemistry; ISH, in situ hybridization; ORR, objective response rate; PR, partial response; SD, stable disease; T-DXd, trastuzumab deruxtecan.

FIG 3.

(A) OS and (B) PFS on the basis of ICR (full analysis set). Vertical lines show censored data: (A) eight patients (40%) in cohort 1 and five patients (23%) in cohort 2 had their data censored; (B) six patients (30%) in cohort 1 and seven patients (32%) in cohort 2 had their data censored. aTwo patients were excluded from the analysis because of a missing HER2 status by central laboratory assessment. HER2, human epidermal growth factor receptor 2; ICR, independent central review; IHC, immunohistochemistry; ISH, in situ hybridization; NE, not evaluable; OS, overall survival; PFS, progression-free survival.

FIG A1.

Time to treatment failure on the basis of independent central review (full analysis set). Two patients were excluded from cohort 2 because they had no HER2 status result in central laboratory assessment. HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization.

FIG A2.

Percentage of change in the sum of diameters for each patient. Baseline was defined as the last measurement before the first dose of study drug. Two patients were excluded from cohort 2 because they had no HER2 status result in central laboratory assessment. Dashed lines at 20% indicate progressive disease; dashed lines at –30% indicate partial response. HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization.

FIG A3.

Time to deterioration of ECOG PS ≥ 2 (full analysis set). Vertical lines represent censored data. ECOG PS, Eastern Cooperative Oncology Group performance status; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization.