DESTINY-Gastric01 Exploratory Biomarker Analysis Examines Efficacy of Trastuzumab Deruxtecan-nxki Among Patients With HER2-Positive and HER2-Low Gastric Cancer

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Trastuzumab deruxtecan-nxki demonstrated clinically meaningful benefit across specific subgroups of patients with HER2-positive and HER2-low advanced gastric cancer, according to findings from a post hoc exploratory biomarker analysis presented by Kohei Shitara, MD, and colleagues at the ESMO World Congress on Gastrointestinal Cancer 2021 (Abstract O-14).

Dr. Shitara, of the National Cancer Center Hospital East in Kashiwa, Japan, explained that trastuzumab deruxtecan-nxki is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor. The agent has shown improved objective response rates and overall survival as compared to chemotherapy in patients with HER2-positive advanced gastric cancer in the primary analysis of the DESTINY-Gastric01 study, and also showed preliminary efficacy in the exploratory cohort. Regulatory approvals were granted in the U.S. and Japan based on these data.

Kohei Shitara, MD

Kohei Shitara, MD

Dr. Shitara presented biomarker data from this study to identify the factors associated with treatment outcomes of patients enrolled based on tumor samples taken pre- and post-trastuzumab therapy.

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DESTINY-Gastric01 enrolled patients with centrally confirmed (Ventana 4B5) HER2-positive advanced gastric cancer that had experienced disease progression on two or more prior lines of therapy. HER2-positive patients were in a primary cohort where 125 patients were randomly assigned to receive trastuzumab deruxtecan-nxki and 55 patients served as the control arm; patients with HER2-low disease were included in a single-arm exploratory cohort for trastuzumab deruxtecan-nxki treatment.

Immunohistochemistry (IHC)/in situ hybridization (ISH) was done in both arms of the primary cohort. In addition, RNA sequencing analysis was done in 34 tumor biopsy samples from the trastuzumab deruxtecan-nxki arm of the primary cohort. Circulating tumor DNA (ctDNA) was detected using GuardantOMNI in 114 primary and 37 exploratory cohort sample patients, and analysis of the HER2 extracellular domain shed in blood (HER2ECD) by ELISA was done in 124 and 42 liquid biopsy samples from patients in the respective cohorts.

Exploratory cutoff values used for plasma HER2 copy number in ctDNA and HER2ECD analyses were defined as those with the smallest P value by log-rank test for overall survival.

Subgroup Analyses

The tissue-based analysis done in the in the trastuzumab deruxtecan-nxki arm of the primary cohort identified HER2 positivity in 87 patients based on tumor samples taken before trastuzumab therapy, and in 38 patients based on tissue obtained post-trastuzumab.

Both subgroups of patients with samples obtained before and after trastuzumab treatment showed a response to trastuzumab deruxtecan-nxki in an exploratory analysis; objective response rates were 48.8% and 56.8%, respectively. In patients tested prior to trastuzumab, median overall survival was 12.1 months with trastuzumab deruxtecan-nxki compared to 9.3 months in the control arm (hazard ratio [HR] = 0.76, 95% confidence interval [CI] = 0.46–1.2). In those tested after trastuzumab, median overall survival was 12.5 months vs 8.1 months (HR = 0.28, 95% CI = 0.13–0.63).

Regarding the liquid-based analysis of ctDNA among patients treated with trastuzumab deruxtecan-nxki in the primary cohort, objective response rate appeared to be correlated with baseline HER2 level in both tissue (IHC/ISH and mRNA gene expression) and liquid (plasma HER2 copy number).

In the exploratory cohort, 30 patients with baseline HER2ECD above 11.6 ng/mL had an objective response rate of 36.7%, compared with 0% in 10 patients below the 11.6 ng/mL cutoff.

In 73 patients with plasma HER2 amplification, median overall survival was 12.1 months vs 13 months in 41 patients with no HER2 amplification (HR = 1.0, 95% CI = 0.57–1.80). However, in 33 patients with plasma HER2 copy number above six, median overall survival was 21.2 months vs 12 months in 81 patients with a copy number cut-off below six (HR = 0.54, 95% CI = 0.29–1.00).  

In 67 patients with exploratory HER2ECD in primary cohort where the cut-off value was 14.4 ng/mL, median overall survival was 14.3 months vs 10 months in 57 patients with HER2ECD below the cut-off value (HR = 0.56, 95% CI = 0.33–0.95). In exploratory cohort, where the cut-off value for HER2ECD was 11.6 ng/mL, median overall survival was 10.1 months in 31 patients with HER2ECD above the cut-off value, and 4.3 months in 11 patients with HER2ECD below the cut-off value (HR = 0.37, 95% CI = 0.17–0.80).

Based upon these findings from their post hoc exploratory analysis, the investigators concluded that clinically meaningful efficacy with trastuzumab deruxtecan-nxki was demonstrated in patients with HER2-positive advanced gastric cancer, regardless of the timing of testing for HER2 status in tissue or plasma HER2 amplification in ctDNA. They further remarked that the plasma HER2 copy number or HER2ECD warrants further investigation, including exploratory cutoffs, to enrich a population of trastuzumab deruxtecan-nxki treatment responders in HER2-positive or HER2-low advanced gastric cancer.

Disclosure: For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.