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Trastuzumab deruxtecan continued to demonstrate a clinical benefit and tolerable safety profile for patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a trastuzumab-based regimen.
Longer follow-up data from the phase 2 DESTINY-Gastric02 study (NCT04014075) showed that fam-trastuzumab deruxtecan-nxki (Enhertu) continued to demonstrate a clinical benefit and tolerable safety profile for patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a trastuzumab (Herceptin)-based regimen.1
At a median follow-up of 10.2 months (range, 0.7-22.1), the confirmed objective response rate (ORR) was 41.8% (95% CI, 30.8%-53.4%) among the 79 patients treated. Complete response was reported in 4 patients (5.1%) and partial response was reported in 29 patients (36.7%). The median duration of response was 8.1 months (95% CI, 5.9-not estimable). The disease control rate was maintained from the primary analysis at 81.0% (95% CI, 70.6%-89.0%).
“The primary results of DESTINY-Gastric02 were based on a data cutoff of April 9, 2021, and it demonstrated at the time a confirmed ORR of 38.0% [95% CI, 27.3%-49.5],” Geoffrey Y. Ku, MD, said in a presentation of the findings. The primary end point of confirmed ORR was met in the primary analysis.2
He highlighted that compared with the previously reported data the clinical benefit of the agent was maintained. “Responses tended to be durable…and to occur quickly with a median time to response of 1.4 months [95% CI, 1.4-2.6].” Ku is a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.
Updated survival data showed that patients who received trastuzumab deruxtecan had a median overall survival of 12.1 months (95% CI, 9.4-15.4) and a median progression-free survival of 5.6 months (95% CI, 4.2-8.3).
“The safety profile remains generally consistent with the established profile of trastuzumab deruxtecan,” Ku said. The median treatment duration was 4.3 months (range, 0.7-22.1) and the most common treatment-emergent adverse events (TEAEs) were nausea (67.1%), vomiting (44.3%), and fatigue (41.8%).
Grade 3 or higher TEAEs were reported in 55.7% of patients and 30.4% were drug related. The rate of serious TEAEs was 41.8% with 12.7% being related to trastuzumab deruxtecan. Rates of TEAEs leading to drug discontinuation, dose reduction, or death were 19.0%, 21.5%, and 13.9%, respectively. Drug-related TEAEs that led to treatment discontinuation in 10 patients, dose reduction in 14 patients, and death in 2 patients. Both deaths were associated with adjudicated interstitial lung disease (ILD)/pneumonitis with 1 death occurring 171 days after drug initiation and the second after 353 days.
Grade 1 adjudicated drug-related ILD/pneumonitis occurred in 2 patients, grade 2 in 4 patients. The median time to onset was 80.5 days (range, 42-344) with a median duration of 36 days (range, 15-142).
Patient-reported outcomes were presented for the first time at the 2022 ESMO Congress and were assessed using the European Organization for Research and Treatment of Cancer 5-dimensional (EQ-5D) survey and the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) measure. Results were presented through cycle 7, which Ku noted was approximately 5 months into treatment. “These [data] correlate well with duration of treatment, which was 4.8 months, many patients were treated up through the first 7 cycles,” he said. “Based on patient-reported outcomes, quality of life did not worsen through cycle 7.”
DESTINY-Gastric02 was a nonrandomized study that enrolled patients with pathologically documented gastric or GEJ cancer who had centrally confirmed HER2-positive disease defined as immunohistochemistry (IHC) 3+ or IHC 2+/in situ hybridization–positive. Patients must have had disease progression on a trastuzumab-containing regimen and an ECOG performance status of 0 or 1. Participants received trastuzumab deruxtecan at 6.4 mg/kg intravenously once every 3 weeks.
Previously reported baseline characteristics for the 79 enrolled patients showed that the population had a median age of 60.7 years (range, 20.3-77.8) and a majority had an ECOG performance status of 1 (63.3%). HER2 expression was primary IHC 3+ (86.1%) with 12.7% having IHC 2+/ISH+ disease and 1.3% not evaluable. In terms of histology, 34.2% of patients had gastric cancer and 65.8% has GEJ.2 Most patients had 2 or more metastatic sites (93.7%). The median time since diagnosis was 14.2 moths (range, 3.6-88.5).
The trial was a confirmatory study initiated for Western patients following positive data from the phase 2 DESTINY-Gastric01 (NCT03329690), a randomized study which evaluated trastuzumab deruxtecan vs physician’s choice of chemotherapy in patients who had progressed on at least 2 prior regimens, including trastuzumab, a fluoropyrimidine- and a platinum-containing chemotherapy. The trial enrolled patients in Japan and South Korea. The results supported the FDA approval of trastuzumab deruxtecan for patients who had received a prior trastuzumab-containing regimen in January 2021.3
DESTINY-Gastric04 (NCT04704934), a phase 3 trial has been initiated to compare comparing trastuzumab deruxtecan vs ramucirumab (Cyramza) plus paclitaxel in patients with HER2-positive gastric or GEJ cancer with progression on or after a trastuzumab-containing regimen.