Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study

Abstract

Background: Approximately 15-20% of advanced gastric and gastro-oesophageal junction cancers overexpress HER2. In DESTINY-Gastric01, the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan improved response and overall survival versus chemotherapy in patients from Japan and South Korea with locally advanced or metastatic HER2-positive gastric or gastro-oesophageal junction cancer whose disease progressed after two lines of previous therapy including trastuzumab. Here, we report primary and updated analyses of the single-arm, phase 2 DESTINY-Gastric02 trial, which aimed to examine trastuzumab deruxtecan in patients living in the USA and Europe.

Methods: DESTINY-Gastric02 is a single-arm, phase 2 study in adult patients from 24 study sites in the USA and Europe (Belgium, Spain, Italy, and the UK). Eligible patients were aged at least 18 years and had an Eastern Cooperative Oncology Group performance status of 0 or 1, pathologically documented unresectable or metastatic gastric or gastro-oesophageal junction cancer, progressive disease on or after first-line therapy with a trastuzumab-containing regimen, with at least one measurable lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and centrally confirmed HER2-positive disease on a postprogression biopsy. Patients were given 6·4 mg/kg of trastuzumab deruxtecan intravenously every 3 weeks until disease progression, withdrawal by patient, physician decision, or death. The primary endpoint was confirmed objective response rate by independent central review. The primary endpoint and safety were assessed in the full analysis set (ie, participants who received at least one dose of study drug). Here, we report the primary analysis of this study, with a data cutoff of April 9, 2021, and an updated analysis, with a data cutoff of Nov 8, 2021. This trial is registered with ClinicalTrials.gov, NCT04014075, and is ongoing.

Findings: Between Nov 26, 2019, and Dec 2, 2020, 89 patients were screened and 79 were enrolled and subsequently treated with trastuzumab deruxtecan (median age 60·7 years [IQR 52·0-68·3], 57 [72%] of 79 were male, 22 [28%] were female, 69 [87%] were White, four [5%] were Asian, one [1%] was Black or African American, one [1%] was Native Hawaiian or Pacific Islander, one had missing race, and three [4%] were other races). At the primary analysis (median follow-up 5·9 months [IQR 4·6-8·6 months]), confirmed objective response was reported in 30 (38% [95% CI 27·3-49·6]) of 79 patients, including three (4%) complete responses and 27 (34%) partial responses, as assessed by independent central review. As of data cutoff for the updated analysis (median follow-up 10·2 months [IQR 5·6-12·9]), a confirmed objective response was reported in 33 (42% [95% CI 30·8-53·4]) of 79 patients, including four (5%) complete responses and 29 (37%) partial responses, as assessed by independent central review. The most common grade 3 or worse treatment-emergent adverse events were anaemia (11 [14%]), nausea (six [8%]), decreased neutrophil count (six [8%]), and decreased white blood cell count (five [6%]). Drug-related serious treatment-emergent adverse events occurred in ten patients (13%). Deaths determined to be associated with study treatment occurred in two patients (3%) and were due to interstitial lung disease or pneumonitis.

Interpretation: These clinically meaningful results support the use of trastuzumab deruxtecan as second-line therapy in patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer.

Funding: Daiichi Sankyo and AstraZeneca.

Figure 1:. Patient disposition

^aThe 10 patients who failed main screening did not satisfy the inclusion/exclusion criteria of the study.

Figure 2:. (A) Best percentage change of tumour size from baseline by independent central review^a and (B) ORR across prespecified subgroups

^aThree patients were missing baseline or postbaseline target lesion assessment. Red line at 20% indicates progressive disease; black line at ‒30% indicates partial response. Analysis conducted in the full analysis set. Two-sided 95% CIs are based on the exact (Clopper-Pearson) binomial distribution. CI=confidence interval; CR=complete response; GEJ=gastroesophageal junction; HER2=human epidermal growth factor receptor 2; IHC=immunohistochemistry; ISH=in situ hybridisation; ORR=objective response rate; PR=partial response; T-DXd=trastuzumab deruxtecan.

Figure 2:. (A) Best percentage change of tumour size from baseline by independent central review^a and (B) ORR across prespecified subgroups

^aThree patients were missing baseline or postbaseline target lesion assessment. Red line at 20% indicates progressive disease; black line at ‒30% indicates partial response. Analysis conducted in the full analysis set. Two-sided 95% CIs are based on the exact (Clopper-Pearson) binomial distribution. CI=confidence interval; CR=complete response; GEJ=gastroesophageal junction; HER2=human epidermal growth factor receptor 2; IHC=immunohistochemistry; ISH=in situ hybridisation; ORR=objective response rate; PR=partial response; T-DXd=trastuzumab deruxtecan.

Figure 3:. (A) Duration of response by independent central review,^a,b (B) progression-free survival by independent central review,^c and (C) overall survival^c

^aAnalysis based on responders (n=33); 18 patients were censored (reasons: initiating new anticancer therapy, event after missing two consecutive assessments, ongoing without event, and adequate tumour assessment no longer available). ^bAnalysis conducted in the full analysis set based on 51 events (44 progressive disease, 7 deaths). ^cAnalysis conducted in the full analysis set. CI=confidence interval; NE=not evaluable; T-DXd=trastuzumab deruxtecan.

Figure 3:. (A) Duration of response by independent central review,^a,b (B) progression-free survival by independent central review,^c and (C) overall survival^c

^aAnalysis based on responders (n=33); 18 patients were censored (reasons: initiating new anticancer therapy, event after missing two consecutive assessments, ongoing without event, and adequate tumour assessment no longer available). ^bAnalysis conducted in the full analysis set based on 51 events (44 progressive disease, 7 deaths). ^cAnalysis conducted in the full analysis set. CI=confidence interval; NE=not evaluable; T-DXd=trastuzumab deruxtecan.