In a statement earlier today, Daiichi Sankyo confirmed that it has submitted a supplemental New Drug Application (sNDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for trastuzumab deruxtecan, previously known as DS-8201, a HER2 directed antibody-drug conjugate (ADC), for the treatment of patients with HER2 positive metastatic gastric cancer.

Trastuzumab deruxtecan, which is approved and commercially available in the United States and marketed as Enhertu® (formerly known as trastuzumab deruxtecan outside the U.S.; fam-trastuzumab deruxtecan-nxki in the U.S. only) for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting, has previously received SAKIGAKE designation for this second potential indication and will receive an expedited review time of six months.

Trastuzumab deruxtecan is the lead antibody-drug conjugate (ADC) in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC Scientific platform.

HER2 positive
HER2 is a cell growth-promoting tyrosine kinase receptor protein expressed on the surface of many types of tumors including gastric, breast, and lung cancers. Overexpression of HER2 is associated with a specific HER2 gene alteration known as HER2 amplification which is often associated with aggressive disease and poorer prognosis.[1]

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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.[2] The incidence rates for gastric cancer are markedly higher in eastern Asia, where approximately half of all cases occur.[6] For example, 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.[3]

Approximately one in five gastric cancers are HER2 positive.[4] Gastric cancer is usually diagnosed in the advanced stage, but even when diagnosed in earlier stages of the disease the survival rate remains modest.[5] Recommended first-line treatment for HER2 positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab (Herceptin®; Genentech/Roche), an anti-HER2 medicine, which has been shown to improve outcomes when added to chemotherapy.[6] However, for gastric cancer that progresses on first-line treatment, trastuzumab has not shown any further benefit and there are no other approved HER2 targeting medicines.[6]

Unmet medical needs
Currently, there are no HER2 directed treatment options approved for patients with HER2 positive metastatic gastric cancer who have progressed after trastuzumab.

“Today’s submission by Daiichi Sankyo brings us closer to bringing trastuzumab deruxtecan to a population of patients with unmet medical needs in Japan,” noted Wataru Takasaki, Ph.D., Executive Officer, Head of R&D Division in Japan, Daiichi Sankyo.

“If approved, trastuzumab deruxtecan has the potential to meaningfully advance the treatment of patients with HER2 positive metastatic gastric cancer as the first-ever antibody-drug conjugate approved to treat this type of cancer.”

Significant and meaningful
The Japanese sNDA is based on data from the pivotal phase II DESTINY-Gastric01 trial and phase I trial published in The Lancet Oncology.

In the non-randomized, open-label, multiple-dose study investigators looked at the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing advanced solid tumors. In the dose-escalation phase of the trial they established doses for expansion of 5·4 mg/kg or 6·4 mg/kg Q3W.

In this study, patients treated with trastuzumab deruxtecan demonstrated a statistically significant and clinically meaningful improvement in objective response rate (ORR) as assessed by an independent review committee as well as in overall survival (OS) compared to patients treated with investigator’s choice of chemotherapy (irinotecan or paclitaxel monotherapy).

The full results of DESTINY-Gastric01 will be presented at the 2020 virtual annual meeting of the American Society of Clinical Oncology (ASCO) later this year.

Safety and tolerability
The overall safety and tolerability profile of trastuzumab deruxtecan in the pivotal phase II DESTINY-Gastric01 trial (NCT03329690) was consistent with that seen in the 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 patients with gastric cancer in the phase I trial or in the DESTINY-Gastric01 trial.

Trastuzumab deruxtecan has not been approved in the EU, or countries outside of Japan and the United States, for any indication. It is an investigational agent globally for various indications. Safety and effectiveness have not been established for the subject proposed use.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Clinical trials
DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-expressing Gastric Cancer (DESTINY-Gastric01) – NCT03329690
DS-8201a in HER2-positive Gastric Cancer That Cannot Be Surgically Removed or Has Spread (DESTINY-Gastric02) – NCT04014075
Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2+ Gastric Cancer (DESTINY-Gastric03) (DG-03) – NCT04379596

[1] Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;2014:852748. doi:10.1155/2014/852748
[2] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394‐424. doi:10.3322/caac.21492
[3] World Cancer Research Fund International. Stomach Cancer Statistics. 2018.
[4] American Cancer Society. Tests for Stomach Cancer. 2017.
[5] Curea FG, Hebbar M, Ilie SM, et al. Current Targeted Therapies in HER2-Positive Gastric Adenocarcinoma. Cancer Biother Radiopharm. 2017;32(10):351‐363. doi:10.1089/cbr.2017.2249
[6] NCCN Guidelines® Gastric Cancer. Version 4.2019. December 20, 2019: MS-22-36.

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