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Trastuzumab Deruxtecan Demonstrates Efficacy in HER2-positive and HER2-low Advanced Gastric Cancer

Findings from a post-hoc exploratory biomarker analysis of DESTINY-Gastric01 study
06 Jul 2021
Gastrointestinal cancers;  Personalised medicine

Trastuzumab deruxtecan 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 at the ESMO World Congress on Gastrointestinal Cancer 2021, which was held from 30 June to 3 July.

Dr. Kohei Shitara of the National Cancer Center Hospital East in Kashiwa, Japan explained that trastuzumab deruxtecan is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor that has shown improved objective response rates (ORR) and overall survival (OS), as compared with chemotherapy in patients with HER2-positive advanced gastric cancer in the primary analysis of the DESTINY-Gastric01 study (NCT03329690) and also showed preliminary efficacy in the exploratory cohort.1,2 Regulatory approvals were granted in the US and Japan based on these data.

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

DESTINY-Gastric01 enrolled patients with centrally confirmed (Ventana 4B5) HER2-positive advanced gastric cancer showing progression on ≥2 prior lines of therapy. HER2-positive patients were in a primary cohort where 125 patients were randomised to receive trastuzumab deruxtecan and 55 patients served as controls; patients with HER2-low disease were included in a single-arm exploratory cohort for trastuzumab deruxtecan treatment.

Immunohistochemistry (IHC)/in situ hybridisation (ISH) was done in both arms of the primary cohort. In addition, RNA sequencing analysis was done in 34 tumour biopsy samples in the trastuzumab deruxtecan arm of the primary cohort. Circulating tumour DNA (ctDNA) was detected using GuardantOMNI in 114 primary and 37 exploratory cohort samples 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 cut-off values used for plasma ERBB2 copy number in ctDNA and HER2ECD analyses were defined as those with the smallest p-value by log-rank test for OS.

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

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

Regarding the liquid-based analysis of ctDNA among patients treated with trastuzumab deruxtecan in the primary cohort, ORR appears to be correlated with baseline HER2 level in both tissue (IHC/ISH and mRNA gene expression) and liquid (plasma ERBB2 copy number).

In the exploratory cohort, 30 patients with baseline HER2ECD above 11.6 ng/mL had ORR 36.7%, compared with ORR 0% in 10 patients below the 11.6 ng/mL cut-off.

In 73 patients with plasma ERBB2 amplification, median OS was 12.1 month versus 13 month in 41 patients with no ERBB2 amplification (HR 1.0; 95% CI 0.57-1.80). However, in 33 patients with plasma ERBB2 copy number above 6.0, median OS was 21.2 month versus 12 month in 81 patients with copy number cut-off below 6 (HR 0.54; 95% CI 0.29-1.00).  

In 67 patients with exploratory HER2ECD in primary cohort where cut-off value was 14.4 ng/mL, median OS was 14.3 month versus 10 month in 57 patients with HER2ECD below 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 OS was 10.1 month in 31 patients with HER2ECD above cut-off value and 4.3 month in 11 patients with HER2ECD below 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 was demonstrated in patients with HER2-positive advanced gastric cancer regardless of the timing of testing for HER2 status in tissue or plasma ERBB2 amplification in ctDNA. They further remarked that the plasma ERBB2 copy number or HER2ECD warrants further investigation, including exploratory cut-offs, as a mean to enrich a population of trastuzumab deruxtecan treatment responders in HER2-positive or HER2-low advanced gastric cancer.

Funding from Daiichi Sankyo and AstraZeneca was disclosed.

Prof. Yelena Y. Janjigian of the Memorial Sloan Kettering Cancer Center in New York, NY, US who discussed the study data said that DESTINY-Gastric01 was a practice changing study. Data from the biomarker analysis show that only 30% of new tumour samples were obtained after/during trastuzumab therapy. The ORR was slightly higher in patients with HER2-positive tumours after/during first trastuzumab group; the ORR was 57% versus 48%. The OS was confounded by small sample size.

High level of ERBB2 (in mRNA or plasma) predicts high ORR. In case of tissue mRNA >9.7, the ORR was 81% versus 23%, but the sample size was small. Plasma ERBB2 was detected in 64% of patients by Guardant360. In ERBB2 ctDNApositive cases, the ORR was better (76% versus 40%). There was nearly doubled OS in case of ctDNA ERBB2 >6 copy (21 versus 12 months median OS).

Having co-occurring EGFR/MET amplifications is associated with worse outcome. Prof. Janjigian commented that FDA urges to biopsy all patients after trastuzumab progression as loss of HER2 occurs in 20% of patients with oesophago-gastric cancer. Based on this analysis we can consider ctDNA if biopsy is not feasible.   

Citations

  1. Shitara K, et al. Trastuzumab Deruxtecan in Previously Treated HER2- Positive Gastric Cancer.  N Engl J Med 2020;382:2419-2430.
  2. Yamaguchi K, et al. ESMO 2020 Virtual Congress, Abstract 1422MO.

Reference

O14 – Shitara K, Bang Y, Iwasa S, et al. Exploratory Biomarker Analysis of Trastuzumab Deruxtecan in DESTINY-Gastric01, A Randomized, Phase 2, Multicenter, Open-Label Study in Patients With HER2-positive or -low Advanced Gastric or Gastroesophageal Junction Adenocarcinoma. ESMO World Congress on Gastrointestinal Cancer 2021 (30 June - 3 July).

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