Daiichi Sankyo, Basking Ridge, NJ. Courtesy: Daiichi Sankyo.
Daiichi Sankyo, Basking Ridge, NJ. Courtesy: Daiichi Sankyo.

The pivotal phase II DESTINY-Gastric01 trial (NCT03329690) of known as trastuzumab deruxtecan, previously known as DS-8201, in patients with HER2+ unresectable or metastatic gastric (stomach) or gastroesophageal junction cancer that had progressed following two or more treatment regimens including trastuzumab and chemotherapy, shows positive results.

Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)* is a HER2 directed antibody-drug conjugate or ADC that delivers novel topoisomerase I inhibitor payload, via a cleavable tetrapeptide-based linker attached to a HER2 monoclonal antibody, to cancer cells. The antibody-drug conjugates uses Daiichi Sankyo’s proprietary DXd ADC technology.

Conditionally approved
In December 2019 the drug was conditionally approved by the U.S Food and Drug Administration (FDA) for the treatment of adult patients with advanced, unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based treatments in the metastatic setting.

The drug has not been approved for the treatment of patients with previously treated HER2 positive metastatic gastric cancer.

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DESTINY-Gastric01 Trial
The DESTINY-Gastric01 trial is a pivotal phase II, open-label, multi-center trial assessing the safety and efficacy of trastuzumab deruxtecan in 189 patients from Japan and South Korea with HER2 expressing advanced gastric cancer or gastroesophageal junction adenocarcinoma (defined as IHC3+ or IHC2+/ISH+) who have progressed on two or more prior treatment regimens including fluoropyrimidine (5-FU), platinum chemotherapy and trastuzumab.

The participating patients were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of chemotherapy (paclitaxel or irinotecan monotherapy). Patients were treated with trastuzumab deruxtecan 6.4 mg/kg once every three weeks or chemotherapy given on the same schedule. The primary endpoint of the study is objective response rate. Secondary endpoints include overall survival, progression-free survival, duration of response, disease control rate and time to treatment failure as well as pharmacokinetic and safety endpoints.

The study met its primary endpoint, achieving a statistically significant and clinically meaningful improvement in objective response rate (ORR), as assessed by an independent review committee, in patients treated with trastuzumab deruxtecan versus investigator’s choice of chemotherapy (irinotecan or paclitaxel monotherapy).

Trastuzumab deruxtecan also showed a statistically significant and clinically meaningful improvement in overall survival (OS), a key secondary endpoint. The safety profile observed for trastuzumab deruxtecan in DESTINY-Gastric01 was consistent with previous clinical trials.

These results confirm the activity seen in the non-randomized phase I study of trastuzumab deruxtecan in patients with HER2 positive advanced gastric cancer published in The Lancet Oncology.[1] Data from DESTINY-Gastric01 will be presented at an upcoming medical meeting.

Based on the results from the study, Daiichi Sankyo will initiate discussions with the Japan Ministry of Health, Labour and Welfare (MHLW) to determine the next steps for a regulatory submission based on the results of DESTINY-Gastric01. Both Daiichi Sankyo and AstraZenea also plan to discuss the data with other health authorities.

The overall safety and tolerability profile of trastuzumab deruxtecan in DESTINY-Gastric01 was consistent with that seen in the published phase I trial in which the most common adverse events (≥30%, any grade) were hematologic and gastrointestinal including neutrophil count decrease, anemia, nausea and decreased appetite There were cases of drug-related interstitial lung disease (ILD) and pneumonitis, the majority of which were grade 1 and 2 with two grade 3 and one grade 4. No ILD-related deaths (grade 5) occurred in gastric patients in the phase 1 trial or in the DESTINY-Gastric01 trial.

“We are excited to report positive topline results from this trial,” said Gilles Gallant, BPharm, Ph.D., FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo.

“Our development plan remains on track for gastric cancer, including an initial regulatory application in Japan where gastric cancer is highly prevalent and where SAKIGAKE designation has been granted for this indication. We are strongly committed to bringing this therapy as rapidly as possible to patients in need,” Gallant added.

“Gastric cancer is usually diagnosed in the advanced stage and patients face markedly high mortality rates, making the need for new therapies especially urgent,” said José Baselga, MD, Ph.D., Executive Vice President, Oncology R&D, AstraZeneca.

“Given the previous results seen in our HER2 positive development program and now in HER2 positive gastric cancer, we believe this antibody-drug conjugate has the potential to redefine the treatment of patients with HER2 expressing cancers,” Baselga concluded.

HER2 expression in gastric cancer
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including gastric, breast and lung cancers. HER2 overexpression is often associated with aggressive disease and poorer prognosis.[2] When a patient is diagnosed with gastric cancer, guidelines recommend evaluating HER2 expression levels by an immunohistochemistry (IHC) test.[3] A finding of IHC 3+ is considered positive. A result of IHC 2+ is considered equivocal, in which case an additional testing method of in situ hybridization (ISH) is recommended to confirm HER2 status.

Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer mortality; there were approximately one million new cases reported in 2018 and 783,000 deaths.[4] Incidence rates for gastric cancer are markedly higher in eastern Asia, where approximately half of all cases occur. [8] South Korea and Japan have the first and third highest incidence rates of gastric cancer worldwide, respectively; in 2018, the age-standardized rate in Japan was 27.5 per 100,000 and in South Korea it was 39.6 per 100,000.[5]

Approximately one in five gastric cancers are HER2 positive.[6] Gastric cancer is usually diagnosed in the advanced stage, but even when diagnosed in earlier stages of the disease the survival rate remains modest.[7] Recommended first-line treatment for HER2 positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 agent, which has been shown to improve outcomes when added to chemotherapy.[8] For gastric cancer that progresses on trastuzumab, there are no other approved HER2 targeting therapies and subsequent treatment options are limited.[9]

Clinical Development Program
A comprehensive development program for trastuzumab deruxtecan is underway globally with five pivotal trials in HER2 expressing metastatic breast and gastric cancer, including a trial in patients with metastatic breast cancer and low levels of HER2 expression (HER2 low).

Phase II trials are underway for HER2 expressing advanced colorectal cancer, as well as metastatic non-squamous HER2 overexpressing or HER2, mutated non-small cell lung cancer. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.

Note
* Fam-trastuzumab deruxtecan-nxki in the US only, trastuzumab deruxtecan outside the United States.

Prescribing information
Click here to download the full prescribing information, including Boxed WARNING, and Medication Guide. For provider and patient support, reimbursement and distribution visit the for ENHERTU in the U.S. visit the product website.

Clinical trial
DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Gastric Cancer [DESTINY-Gastric01] – NCT03329690
DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing or -Mutated Non-Small Cell Lung Cancer – NCT03505710

References
[1] Shitara K et al. Lancet Oncol. 2019;S1470-2045 (19):30088-9
[2] Iqbal and Iqbal. Mol Biol Int. 2014; 2014: 852748
[3] NCCN Guidelines® Gastric Cancer. Version 4.2019. December 20, 2019: GAST-B 3
[4] Bray F et al. GLOBOCAN CA CANCER J CLIN 2018;68:394–424
[5] World Cancer Research Fund International. Stomach Cancer Statistics. 2018. Online. Last accessed January 6, 2020:
[6] American Cancer Society. Tests for Stomach Cancer. 2017. Online. Last accessed January 6, 2020.
[7] Curea et al. Cancer Biotherapy & Radiopharmaceuticals. 2017;32 (10): Review.
[8] NCCN Guidelines® Gastric Cancer. Version 4.2019. December 20, 2019: MS-22
[9] NCCN Guidelines® Gastric Cancer. Version 4.2019. December 20, 2019: MS-36