A phase II DESTINY-Gastric02 study shows clinically meaningful activity of trastuzumab deruxtecan, with durable responses in patients with HER2-positive gastric or gastro-oesophageal junction adenocarcinoma whose disease progressed on a trastuzumab-containing regimen; the patients included in this study are from USA and Europe. A high proportion of patients treated with trastuzumab deruxtecan reached the primary endpoint of confirmed objective response rate (ORR) by independent central review compared with studies of other second-line treatments.
The activity outcomes of second-line treatment with trastuzumab deruxtecan in this study population are particularly promising when compared with historical data. The findings are reported by Prof. Eric Van Cutsem of the University Hospitals Gasthuisberg, University of Leuven in Leuven, Belgium, and colleagues on 14 June 2023 in The Lancet Oncology.
The authors explained in the background that approximately 15-20% of advanced gastric and gastro-oesophageal junction cancers overexpress HER2. In DESTINY-Gastric01 study, 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 treatment including trastuzumab.
In the latest article published in The Lancet Oncology, the study team report primary and updated analyses of the DESTINY-Gastric02 study, which aimed to examine trastuzumab deruxtecan in patients living in the USA and Europe. DESTINY-Gastric02 is a single-arm, phase II study conducted 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 ECOG performance status 0 or 1, pathologically documented unresectable or metastatic gastric or gastro-oesophageal junction cancer, progressive disease on or after first-line treatment with a trastuzumab-containing regimen, with at least one measurable lesion per RECIST version 1.1, and centrally confirmed HER2-positive disease on a post-progression 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 ORR by independent central review. The primary endpoint and safety were assessed in the full analysis set. Data reported are from the primary analysis of this study, with a data cut-off of 9 April 2021, and an updated analysis, with a data cut-off of 8 November 2021. The study is ongoing.
Between 26 November 2019 and 2 December 2020, 89 patients were screened and 79 were enrolled and subsequently treated with trastuzumab deruxtecan. Median age was 60.7 years, 72% were male, 28% female, 87% White, 5% Asian, 1% Black or African American, 1% Native Hawaiian or Pacific Islander, one patient had missing race, and 4% were other races.
At the primary analysis with a median follow-up 5.9 months, confirmed objective response was reported in 30 of 79 patients (38%; 95% CI 27.3–49.6), including 3 complete responses (4%) and 27 partial responses (34%), as assessed by independent central review. As of data cut-off for the updated analysis with median follow-up of 10.2 months, a confirmed objective response was reported in 33 of 79 patients (42%; 95% CI 30.8–53.4), including 4 complete responses (5%) and 29 partial responses (37%), as assessed by independent central review.
The most common grade 3 or worse treatment-emergent adverse events (TRAEs) were anaemia (14%), nausea (8%), decreased neutrophil count (8%), and decreased white blood cell count (6%). Drug-related serious TRAEs occurred in 13%. Deaths determined to be associated with study treatment occurred in 3% and were due to interstitial lung disease or pneumonitis.
The authors wrote that DESTINY-Gastric02 data support clinically meaningful activity and a manageable safety profile and thus, trastuzumab deruxtecan as a valuable second-line HER2-targeted treatment option for patients from the USA or Europe, similar to the findings of DESTINY-Gastric01 for Asian patients in the third-line and later settings. Planned analyses of this study will include evaluation of circulating biomarkers including cell-free DNA.
Results from DESTINY-Gastric02 also support the ongoing randomised, phase III DESTINY-Gastric04 study, which is investigating the efficacy and safety of trastuzumab deruxtecan compared with ramucirumab and paclitaxel in patients with gastric or gastro-oesophageal junction cancer whose disease has progressed on or after a trastuzumab-containing regimen.
The study was sponsored and designed by Daiichi Sankyo in collaboration with AstraZeneca.
Reference
Van Cutsem E, di Bartolomeo M, Smyth E, et al. 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. The Lancet Oncology; Published online 14 June 2023. DOI: https://doi.org/10.1016/ S1470-2045(23)00215-2
