Clinical Benefit of Trastuzumab Deruxtecan Sustained in Metastatic Gastric/GEJ Cancer

Fam-trastuzumab deruxtecan-nxki (Enhertu) resulted in clinical benefit and acceptable safety in patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a trastuzumab (Herceptin)–based regimen, according to longer-term follow-up data from the phase 2 DESTINY-Gastric02 study (NCT04014075) presented at the 2022 European Society for Medical Oncology Congress (ESMO).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.

References

1. Ku G, di Bartolomeo M, Smyth E, et al; DESTINY-Gastric02 Investigators. Updated analysis of DESTINY-Gastric02: A phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive (HER2+) unresectable/metastatic gastric/gastroesophageal junction (GEJ) cancer who progressed on or after trastuzumab-containing regimen. Presented at: European Society for Medical Oncology Congress 2022; September 9-13, 2022; Paris, France.
2. van Cutsem E, di Bartolomeo M, Smyth E, et al. Primary analysis of a phase II 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. Ann Oncol. 2021;32(suppl 5):S1332. doi:10.1016/j.annonc.2021.08.2135
3. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. FDA. January 15, 2021. Accessed September 10, 2022. bit.ly/3qttyss