HER-2 targeting in gastric cancer has not occurred to the same magnitude as in breast cancer, with one of the reasons being a lower patient population that overexpresses HER-2 in this indication. While existing approved drugs in this setting, such as Herceptin, only cause the tumour-cell death of HER-2 overexpressing cells, novel treatments are looking to use HER-2 as a guide towards the tumour where a payload can be released and affect neighbouring cancer cells not overexpressing HER-2. This is especially beneficial in indications such as gastric cancer which exhibit heterogeneous HER-2 overexpression. During the virtual ASCO 2020 conference, an update on DESTINY-Gastric01 Phase II trial provided a positive outlook for the future treatment of gastric cancer patient with Enhertu (trastuzumab deruxtecan).
Enhertu is an antibody-drug conjugate, which is composed of the HER-2 targeting trastuzumab antibody attached to a topoisomerase inhibitor payload. This novel drug is able to target HER-2 overexpressing cells and implement the inhibitor properties of trastuzumab, meanwhile delivering a cytotoxic payload to the cell and surrounding tumour environment to increase overall tumour-cell death. The DESTINY-Gastric01 Phase II trial yielded promising results for patients with metastatic HER-2 gastric cancer, had met its primary and secondary endpoints. Patients randomised to the Enhertu treatment group reported a significantly higher ORR of 51.3% in comparison to 14.3% in the physician-choice chemotherapy group. The secondary endpoints, PFS and OS were also significantly improved.
Enhertu is approved in Japan and the US for use in breast cancer and Daiichi Sankyo and AstraZeneca have recently submitted the latest trial data to the MHLW. Enhertu already had Sakigake designation in Japan and has recently received breakthrough therapy designation and orphan drug status with the FDA, therefore GlobalData expects imminent filling in the US. It remains to be determined how Enhertu will compete with Herceptin in gastric cancer given that a retrospective head-to-head comparison based on current trials cannot be made due to the dissimilarity in their respective clinical trial designs. Enhertu has the potential to be used as a monotherapy for patients that do not tolerate the existing standard of care (SOC), Herceptin plus chemotherapy, but it is unlikely positioned to overtake trastuzumab as the SOC for this patient population. GlobalData expects a head-to-head comparative trial of Enhertu versus Herceptin plus chemo will be planned to determine whether Enhertu can rival trastuzumab as the new SOC for HER2 positive patients.