Western Patients With HER2-Positive Gastric/GEJ Cancers Demonstrate Promising Responses to Trastuzumab Deruxtecan

Primary analysis of the phase 2 DESTINY-Gastric02 trial (NCT04014075) of fam-trastuzumab deruxtecan-nxki (Enhertu) as a second-line treatment in Western patients with HER2-positive gastric/gastroesophageal junction (GEJ) cancer resulted in a a 38% confirmed objective response rate (ORR), according to results from a primary analysis of the presented during the 2021 European Society for Medical Oncology Congress.¹

At a median follow-up of 5.7 months (range, 0.7-15.2), the antibody-drug conjugate (ADC) elicited a 38% ORR (95% CI, 27.3%-49.6%) that was comprised of 3 complete responses (3.8%) and 27 partial responses (34.2%); the stable disease rate was 43.0% and 16.5% of patients had progressive disease. Two patients were not evaluable.

Additionally, the median duration of response (DOR) with the agent was 8.1 months (95% CI, 4.1–not evaluable) and the confirmed disease control rate was 81.0% (95% CI, 70.6%-89.0%). The median progression-free survival (PFS) was 5.5 months (95% CI, 4.2-7.3) and the median time to response was 1.4 months (95% CI, 1.4-2.6).

“DESTINY-Gastric02 is the first study focused only on second-line trastuzumab deruxtecan monotherapy in Western HER2-positive patients with gastric/GEJ cancer who progressed on a trastuzumab [Herceptin]-containing regimen,” said lead study author Eric Van Cutsem, MD, PhD, full professor and division head of Digestive Oncology at University of Leuven and University Hospitals Gasthuisberg, in Leuven, Belgium, who presented the results virtually during the meeting. “Efficacy results demonstrate clinically meaningful and durable responses, and the safety profile was generally consistent with the established safety profile of trastuzumab deruxtecan.”

Trastuzumab deruxtecan was approved by the FDA in January 2021 for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a previous trastuzumab-based regimen.² The regulatory decision was based on findings from the phase 2 DESTINY-Gastric01 study, which showed that the ADC led to a median overall survival (OS) of 12.5 months compared with 8.4 months for chemotherapy (HR, 0.59; 95% CI, 0.39-0.88; P= .01).³

DESTINY-Gastric02 is the follow-up trial to the DESTINY-Gastric01 study, which investigated trastuzumab deruxtecan as a third- or later-line treatment in Asian patients.

In the open-label, multicenter, phase 2 DESTINY-Gastric02 study, investigators enrolled 79 Western patients with HER2-positive gastric/GEJ cancer who have progressed on a trastuzumab-containing regimen. Patients were treated with trastuzumab deruxtecan, which was administered at 6.4 mg/kg every 3 weeks.

To be eligible for enrollment, patients had to have pathologically documented, unresectable, or metastatic gastric or GEJ cancer, centrally confirmed HER2-positive disease (defined as immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization [ISH]+) following frontline treatment with a trastuzumab-containing regimen; and an ECOG performance status of 0 or 1.

The primary end point of the trial was confirmed ORR by independent central review (ICR). Secondary end points were PFS and DOR by ICR, as well as OS and safety and tolerability.

The data cutoff date was April 9, 2021. Patients were enrolled in Belgium, Great Britain, Italy, and Spain, as well as in the United States. The median age of the study participants was 60.7 years (range, 20.3-77.8), and 41.8% were 65 years of age or older. Moreover, 72.2% of patients were male, and 87.3% were White. Patients either had an ECOG performance status of 0 (36.7%) or 1 (63.3%). HER2 expression was reported as IHC 3+ (86.1%), IHC 2+/ISH+ (12.7%), or not evaluable (1.3%).

Most patients had unknown adenocarcinoma (72.2%) compared with 24.1% who had intestinal, 1.3% with diffuse, and 1.3% with mixed adenocarcinoma. Additionally, 65.8% of patients had GEJ cancer and 34.2% had gastric cancer. The majority of patients (93.7%) had at least 2 metastatic sites and 63.3% had liver metastasis at baseline. The median time from diagnosis was 14.2 months (range, 3.6-88.5).

The median treatment duration of treatment was 4.3 months (range, 0.7-15.9 months). Regarding safety, all-grade and grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 93.7% and 26.6% of patients, respectively; serious TRAEs occurred in 10.1% of patients. Additionally, TRAEs that were associated with discontinuation, dose reductions, and death were reported in 8.9%, 19.0%, and 1.3% of patients, respectively.

The most common TRAEs that were linked with treatment discontinuation included investigator-reported pneumonitis (3.8%) and interstitial lung disease (ILD; 2.5%). The TRAEs most commonly linked with dose reductions were nausea (7.6%) and decreased neutrophil count (5.1%).

All-grade and grade 3 or higher TRAEs that occurred in at least 15% of patients were nausea (58.2% and 3.8%, respectively), fatigue (36.7% and 3.8%), vomiting (32.9% and 1.3%), diarrhea (27.8% and 1.3%), decreased appetite (22.8% and 1.3%), alopecia (21.5% and 0%), anemia (19.0% and 7.6%), decreased platelet count (16.5% and 1.3%), and decreased neutrophil count (15.2% and 7.6%).

ILD, which occurred at any grade in 7.6% (n = 6) of patients, was also analyzed in the trial. The median time to onset adjudicated treatment-related ILD was 80.5 days (range, 53-85 days); the median duration was 38.0 days (range, 15-142 days). Eighty-three percent of adjudicated treatment-related ILD cases were grades 1 or 2; 1 grade 5 case of adjudicated treatment-related ILD was reported.

The ongoing, open-label, phase 3 DESTINY-Gastric04 trial (NCT04704934) is randomizing patients with HER2-positive metastatic and/or unresectable gastric/GEJ cancer who have progressed on, or following, a trastuzumab-containing regimen.

Trastuzumab deruxtecan also received accelerated approval for use in the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.⁴ It also has a breakthrough therapy designation from the FDA for the treatment of patients with metastatic non–small cell lung cancer whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.⁵

References

1. Van Cutsem E, di Bartolomeo M, Smyth E, et al. Primary analysis of a phase 2 single-arm trial of trastuzumab deruxtecan (T-DXd) in Western patients (Pts) with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) Cancer who progressed on or after a trastuzumab-containing regimen. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract LBA55.
2. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. News release. FDA. January 15, 2021. Accessed September 17, 2021. http://bit.ly/35KBZ8T
3. Shitara K, Bang Y-J, Iwasa S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Eng J Med. 2020;382(25):2419-2430. doi:10.1056/NEJMoa2004413
4. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. FDA. Published December 20, 2019. Accessed September 17, 2021. https://bit.ly/2tzcabv
5. ENHERTU granted breakthrough therapy designation in the US for HER2 mutant metastatic non-small cell lung cancer. News release. Daiichi Sankyo. May 18, 2020. Accessed September 17, 2021. https://bit.ly/39j3PdE