Trastuzumab Deruxtecan Slated for Study in HER2+ Gastric/GEJ Cancer

Axel Grothey, MD

Fam-trastuzumab deruxtecan-nxki (Enhertu) is under study alone and in combination for the treatment of patients with HER2-overexpressing locally advanced, unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma in the ongoing phase 1b/2 DESTINY-Gastric03 trial (NCT04379596).^1,2

“Trastuzumab deruxtecan is an active agent that is [sort of a] targeted chemotherapy, which makes it so exciting,” said Axel Grothey, MD, a medical oncologist and director of Gastrointestinal Cancer Research at West Cancer Center and Research Institute, in an interview with OncLive^®.

Trastuzumab (Herceptin) plus chemotherapy is currently a standard frontline treatment for patients with HER2-overexpressing metastatic gastric cancer but possesses a modest survival advantage compared with chemotherapy alone.

Trastuzumab deruxtecan is an antibody-drug conjugate (ADC) comprised of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload.

“Trastuzumab deruxtecan is interesting because it can kill cancer cells by its bystander effect of its payload. When trastuzumab homes in on the HER2-protein expression, the drug complex is internalized and releases the chemotherapy payload. This can then diffuse to the neighboring cancer cells to cause a bystander effect, which, theoretically, can affect the surrounding cells that do not express HER2,” said Daniel H. Ahn, DO, an oncologist, internist, and assistant professor of medicine at Mayo Clinic, in an interview with OncLive^®.

In a phase 1 trial, the agent demonstrated a confirmed objective response rate (ORR) of 43.2% in patients with heavily pretreated HER2-positive metastatic gastric cancer who received a dose of 5.4 mg/kg or 6.4 mg/kg.³

“Trastuzumab had been the only agent that really worked in gastric cancer, but now we have data with trastuzumab deruxtecan, which can provide benefit in patients who have had prior trastuzumab in gastric cancer,” said Grothey.

On January 15, 2021, the FDA approved trastuzumab deruxtecan for the treatment of patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen.⁴

The regulatory decision was based on data from the phase 2 DESTINY-Gastric01 trial (NCT04014075), which demonstrated that treatment with the ADC resulted in an improvement in overall survival (OS) compared with irinotecan or paclitaxel, at 12.5 months (95% CI, 9.6-14.3) versus 8.4 months (95% CI, 6.9-10.7), respectively, in patients with advanced, HER2-positive gastric or GEJ adenocarcinoma who had progressed following a trastuzumab-based regimen (HR, 0.59; 95% CI, 0.39-0.88; P = .0097).⁵

To be eligible for enrollment in the 2-part, open-label, multicenter, DESTINY-Gastric03 study, patients have to be at least 18 years of age, or at least 20 years of age in Japan; have diagnosed locally advanced, unresectable or metastatic gastric/GEJ adenocarcinoma; measurable disease per RECIST v1.1 criteria; adequate organ function, including cardiac, renal, and hepatic function; and HER2 overexpression, defined by immunohistochemistry (IHC) of 3+ or IHC 2+ and in situ hybridization positivity.

In the dose-escalation portion of the study (part 1), patients who have received prior trastuzumab-containing therapy will be randomized to 1 of 5 arms: trastuzumab deruxtecan plus 5-fluorouracil (5-FU); trastuzumab deruxtecan plus capecitabine (Xeloda); trastuzumab deruxtecan plus durvalumab (Imfinzi); trastuzumab deruxtecan plus 5-FU or capecitabine plus oxaliplatin; or trastuzumab deruxtecan plus 5-FU or capecitabine plus durvalumab.

In the dose-expansion phase (part 2), patients who have not received any prior therapy for metastatic disease will be randomized to 1 of 4 arms: trastuzumab deruxtecan; trastuzumab plus 5-FU/capecitabine plus oxaliplatin/cisplatin; trastuzumab deruxtecan plus 5-FU or capecitabine, and oxaliplatin; or trastuzumab deruxtecan plus 5-FU or capecitabine plus durvalumab.

“[DESTINY-Gastric03] should help us have a better understanding of ADCs in the frontline setting,” said Ahn.

In part 2, patients will be stratified by HER2 status. Safety, determination of recommended phase 2 doses in part 1, and the investigator-assessed confirmed ORR from part 2 per RECIST v1.1 criteria will serve as primary end points of the study.

Secondary end points, all per investigator assessment, will include the confirmed ORR from part 1, disease control rate, duration of response, progression-free survival, OS, the safety from part 2, pharmacokinetics, and immunogenicity.

Safety will be of particular importance to evaluate since approximately 9% to 10% of patients developed pneumonitis-related toxicities and cytopenias in the DESTINY-Gastric01 trial, said Ahn.

“Cytopenias are expected from ADCs, but pneumonitis-related toxicities are unique [to trastuzumab deruxtecan] compared with other ADCs. We haven’t seen these types of adverse effects with agents such as T-DM1 [ado-trastuzumab emtansine; Kadcyla],” Ahn stated.

The study launched on June 3, 2020 and will continue to recruit patients across the following countries and territories: United States, Canada, Brazil, Italy, Spain, United Kingdom, The Netherlands, Germany, Poland, Russian Federation, Japan, Republic of Korea, China, and Taiwan.

References

1. Janjigian YY, Viglianti N, Liu F, et al. A phase Ib/II, multicenter, open-label, dose-escalation, and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd, DS-8201) monotherapy and combinations in patients with HER2-overexpressing gastric cancer (DESTINY-Gastric03). J Clin Oncol. 2021(suppl 3):TPS261. doi:10.1200/JCO.2021.39.3_suppl.TPS261
2. Phase1b/2 study of the safety and efficacy of T-DXd combinations in advanced HER2+ gastric cancer (DESTINY-Gastric03) (DG-03). ClinicalTrials.gov. Posted May 7, 2020. Updated January 22, 2021. Accessed February 10, 2021. https://clinicaltrials.gov/ct2/show/NCT04379596
3. Shitara K, Iwata H, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Lancet Oncol. 2019;20(6):827-836. doi:10.1016/S1470-2045(19)30088-9
4. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. News release. FDA. January 15, 2021. Accessed February 10, 2021. http://bit.ly/35KBZ8T.
5. Shitara K, Bang Y-J, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: a randomized, phase II, multicenter, open-label study (DESTINY-Gastric01). J Clin Oncol. 2020;38(suppl 15):4513. doi:10.1200/JCO.2020.38.15_suppl.4513