AZ/Daiichi Sankyo Announce Positive Phase 2 DESTINY-Gastric01 Trial Results for Enhertu in HER2-Positive Advanced Gastric Cancer

Detailed results from the positive, registration-enabling, randomized controlled Phase II clinical trial DESTINY-Gastric01 demonstrated that Enhertu (trastuzumab deruxtecan, also known as DS-8201), jointly developed by AstraZeneca and Daiichi Sankyo Company Limited, achieved statistically significant and clinically meaningful improvements in objective response rate (ORR) and overall survival (OS)—a key secondary endpoint—compared with chemotherapy.

This trial is conducted in patients with HER2-positive, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have progressed after two or more prior treatment regimens, including trastuzumab and chemotherapy.

Gastric cancer is the third leading cause of cancer-related mortality, with a five-year survival rate of only 5% for patients with metastatic disease; approximately one-fifth of gastric cancer cases are HER2-positive.

As assessed by the Independent Review Committee (IRC), the confirmed objective response rate (ORR) in the DS-8201 monotherapy group (6.4 mg/kg) was 42.9%, compared with 12.5% in the investigator’s choice chemotherapy control group (paclitaxel or irinotecan). Among patients treated with DS-8201, 10 achieved a complete response (CR) and 41 achieved a partial response (PR); whereas in the chemotherapy control group, no patients achieved a CR and 7 achieved a PR.

Results from a prespecified interim analysis showed that, compared with the chemotherapy control group, patients in the DS-8201 treatment group had a 41% reduction in the risk of death (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.39–0.88; p=0.0097). The median overall survival was 12.5 months in the DS-8201 treatment group versus 8.4 months in the control group. The estimated one-year survival rate was 52.1% in the DS-8201 treatment group and 28.9% in the chemotherapy control group.

Dr. Kohei Shitara, Director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Chiba, Japan, and principal investigator of the Phase II DESTINY-Gastric01 trial, stated, “Once HER2-positive metastatic gastric cancer patients progress after initial anti-HER2 therapy, subsequent treatment options are very limited, and there are currently no approved HER2-targeted therapies for gastric cancer. Based on the superior results of the DESTINY-Gastric01 trial, DS-8201 has the potential to become a new standard of care for these patients.”

José Baselga, Executive Vice President of Oncology R&D at AstraZeneca, stated, “The results from the DESTINY-Gastric01 trial demonstrated that the objective response rate in the DS-8201 group was more than three times higher than that in the chemotherapy control group. Furthermore, over half of the patients treated with DS-8201 were still alive one year later, compared to less than one-third in the chemotherapy control group. Previously, in the DESTINY-Breast01 trial, DS-8201 also showed impressive results in the treatment of HER2-positive metastatic breast cancer. These trial results in gastric cancer may further establish the role of DS-8201 in improving patient outcomes across multiple HER2-targeted tumor indications.”

Antoine Yver, Executive Vice President and Global Head of Oncology R&D at Daiichi Sankyo, stated, “DS-8201 is the first HER2-targeted therapy to significantly improve overall survival in patients with HER2-positive, previously treated metastatic gastric cancer. These trial data are highly encouraging and of great significance, as mortality rates rise markedly and treatment options remain very limited for patients with advanced gastric cancer once disease progression occurs. We are currently collaborating with regulatory authorities worldwide to make DS-8201 available to patients with metastatic gastric cancer as soon as possible.”

The trial results showed that the confirmed disease control rate (DCR) in the DS-8201 treatment group was 85.7%, compared to 62.5% in the control group; the confirmed median duration of response (DoR) was 11.3 months, whereas it was 3.9 months in the chemotherapy control group.

SD, Stable Disease

1. Data cutoff date: November 8, 2019

2. DS-8201 6.4 mg/kg

3. Assessed by an Independent Central Review Committee

4. Objective Response Rate (ORR) = (Complete Response [CR] + Partial Response [PR])

5. Confirmed objective response rate (ORR) refers to responses confirmed by follow-up scans performed 4 weeks or more after the initial determination of complete response (CR) or partial response (PR); unconfirmed ORR was the primary endpoint of the trial (51.3% [95% CI 41.9–60.5] vs. 14.3% [95% CI 6.4–26.2]; p < 0.0001). Both confirmed and unconfirmed ORRs were assessed by an independent central review committee.

6. Disease Control Rate (DCR) = (Complete Response [CR] + Partial Response [PR] + Stable Disease [SD])

The safety and tolerability profile of DS-8201 in the DESTINY-Gastric01 trial was consistent with that observed in the Phase I gastric cancer trial and previously reported DS-8201 trials.5 The most common grade 3 or higher treatment-related adverse events included decreased neutrophil count (51.2%), anemia (37.6%), decreased white blood cell count (20.8%), and decreased appetite (16.8%). An independent review committee determined that 12 patients (9.6%) experienced treatment-related interstitial lung disease (ILD) and pneumonitis, which were mostly grade 1 or 2, with two cases of grade 3 and one case of grade 4; no grade 5 events (ILD-related deaths) occurred.

These study results were presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting (virtual conference) and simultaneously published online in The New England Journal of Medicine.

Based on the results of the DESTINY-Gastric01 trial, DS-8201 was recently granted Breakthrough Therapy Designation (BTD) by the U.S. FDA for the treatment of patients with HER2-positive unresectable or metastatic gastric cancer; it also received Orphan Drug Designation (ODD) for the treatment of gastric cancer, including gastroesophageal junction adenocarcinoma.

References

1. Bray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018; 68:394-424.

2. American Cancer Society. Stomach Cancer: Early Detection, Diagnosis, and Staging. Available at: https://www.cancer.org/cancer/stomach-cancer/detection-diagnosis-staging/survival-rates.html.

3. American Cancer Society. Stomach Cancer: Treating Stomach Cancer. Available at: https://www.cancer.org/cancer/stomach-cancer/treating/targeted-therapies.html.

4. Iqbal N. et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;2014:852748. doi:10.1155/2014/852748.

5. Shitara, K, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Lancet Oncol. 2019; 20:827–36.

6. Shitara, K et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. DOI: 10.1056/NEJMoa2004413.

7. Curea F.G, et al. Current Targeted Therapies in HER2-Positive Gastric Adenocarcinoma. Cancer Biotherapy & Radiopharmaceuticals. 2017;32 (10).

8. NCCN Guidelines® Gastric Cancer. Version 4.2019. December 20, 2019: MS-22-36.

9. ClinicalTrials.Gov. NCT03329690. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03329690

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