Trastuzumab Deruxtecan Provides Clinical Benefit in Metastatic Gastric/GEJ Cancer

Geoffrey Y. Ku, MD

Clinically meaningful results from the phase 2 DESTINY-Gastric02 study (NCT04014075) support the second-line use of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for the treatment of patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma.¹

At the primary analysis of the study with a median follow-up of 5.9 months (interquartile range [IQR] 4.6-8.6 months), a confirmed objective response was reported in 30 patients of the 79 enrolled in the trial and subsequently treated with trastuzumab deruxtecan (95% CI, 27.3-49.6). This included 3 (4%) complete responses and 27 (34%) partial responses, as assessed by independent central review.

Then, in the updated analysis with a median follow-up 0.2 months (IQR, 5.6-12.9), there were 33 patients (42%; 95% CI, 30.8-53.4) with a confirmed objective response, including 4 (5%) patients who had a complete response and 29 (37%) who had a partial response.

For safety, the most common grade 3 or worse treatment-emergent adverse events (TEAEs) consisted of anemia (14%), nausea (8%), decreased neutrophil count (8%), and decreased white blood cell count (6%). Deaths which were associated with study treatment occurred in 2 patients (3%) and were due to interstitial lung disease or pneumonitis.

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"The results confirm the safety and activity of T-DXd in this patient population. They are also similar to the results seen in DESTINY-Gastric01 [NCT03329690]. These results validate the FDA approval of T-DXd as post-trastuzumab progression in the United States. These results also help to support the approval of T-DXd in Europe. One additional important takeaway from this study is that there was about a 10% incidence of interstitial lung disease noted on this study, which unfortunately included fatal events. This interstitial lung disease rate is seen in other studies of T-DXd and highlights the need for clinicians and patients to be aware of and attentive to this toxicity," Geoffrey Y. Ku, MD, medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, told Targeted Oncology^TM.

DESTINY-Gastric02 is a single-arm, phase 2 study evaluating adult patients with HER2-positive gastric cancer from 24 study sites across the United States and Europe.

Patients were eligible for enrollment if at least 18 years of age with an ECOG performance status of 0 or 1, pathologically documented unresectable or metastatic gastric or gastro-oesophageal junction cancer, progressive disease on or after first-line therapy with a trastuzumab-containing regimen, and at least 1 measurable lesion per RECIST v1.1. Patients were also required to have centrally confirmed HER2-positive disease on a post progression biopsy.²

"The significance of DESTINY-Gastric02 is that it explored the activity of T-DXd in a Western population. It is also different than DESTINY-Gastric01, which enrolled East Asian patients, in 2 important ways. The first is that patients were treated in the second-line setting after progression on a first-line regimen containing trastuzumab. Critically, patients had to have central confirmation of persistent HER2-positive disease based on a baseline biopsy obtained after progression on trastuzumab-based therapy," said Ku.

The trial administered patients trastuzumab deruxtecan 6.4 mg/kg via intravenous infusion every 3 weeks until disease progression, withdrawal by patient, physician decision, or death. Patients were allowed 2 dose reductions of trastuzumab deruxtecan from 6.4 mg/kg to 5.4 mg/kg, and then 4.4 mg/kg. However, dose increases were not permitted after reductions.¹

Investigators assessed the primary end point of confirmed objective response and secondary end points of progression-free survival, ORR, overall survival, and duration of response.

A total of 79 patients were enrolled in the study between November 26, 2019, and December 2, 2020. Patients were treated with at least 1 dose of trastuzumab deruxtecan at this time. The median age among those enrolled was 60.7 years (IQR, 52.0-68.3). There were 57 male patients (72%), 22 (28%) female, and 69 (87%) patients were White, while 4 (5%) were Asian, 1 (1%) was Black or African American, 1 (1%) was Native Hawaiian or Pacific Islander, 1 (1%) had missing race data, and 3 (4%) were other races.

As of the data cutoff date of November 8, 2021, for the updated analysis, the median duration of treatment was 4.3 months (IQR 2.7-10.1), and all 79 patients had a TEAE. A total of 44 (56%) patients had a grade 3 or worse TEAE, and 33 (42%) had a serious TEAE. TEAEs which were drug-related occurred in 75 patients (95%). Twenty-four (30%) of these patients had a grade 3 or worse AE, and 10 (13%) had a serious AE.

Overall, grade 3 or worse TEAEs which were the most common included anemia (14%), nausea (8%), decreased neutrophil count (8%), and decreased white blood cell count (6%). Additionally, TEAEs leading to discontinuation of the study drug occurred in 15 patients, 10 of which were drug related. Then, TEAEs that led to dose reductions occurred in 17 patients, and 14 were drug related, and TEAEs which led to dose interruptions occurred in 23 patients, 8 of which were drug related.

"Ultimately, this is a single-arm phase 2 study. The phase 3 DESTINY-Gastric04 study [NCT04704934] is comparing T-DXd to ramucirumab [Cyramza]/paclitaxel to determine if T-DXd is superior. In addition, combinations of T-DXd [with chemotherapy, immunotherapy and anti-angiogenic therapy] are being evaluated in the first- and second-line settings in the DESTINY-Gastric03 study [NCT04379596]," added Ku.

REFERENCES:

1. Van Cutsem E, di Bartolomeo M, Smyth E, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol. 2023;24(7):744-756. doi:10.1016/S1470-2045(23)00215-2

2. DS-8201a in HER2-positive gastric cancer that cannot be surgically removed or has spread (DESTINY-Gastric02). ClinicalTrials.gov. Updated May 3, 2023. Accessed July 24, 2023. https://clinicaltrials.gov/study/NCT04014075?tab=table