In the phase 2 DESTINY-Gastric01 trial (NCT03329690), treatment with fam-trastuzumab deruxtecan-nxki (Enhertu) acheived a 40% reduction in the risk of death compared with standard chemotherapy in patients with HER2-positive gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma, according to updated survival results o presented during the 2022 Gastrointestinal Cancers Symposium.1
The updated median overall survival (OS) with trastuzumab deruxtecan remained at 12.5 months (95% CI, 10.3-15.2) compared with 8.9 months (95% CI, 6.4-10.4) with chemotherapy (HR, 0.60; 95% CI, 0.42-0.86).
“With continued follow-up after the primary analysis, trastuzumab deruxtecan demonstrated a clinically meaningful OS benefit and clinically relevant improvement in [objective response rate] compared with standard chemotherapy in HER2-positive advanced gastric or GEJ cancer,” lead study author Kensei Yamaguchi, of The Cancer Institute Hospital of the Japanese Foundation for Cancer Research in Tokyo, Japan, said in a presentation during the meeting.
In January 2021, the FDA approved trastuzumab deruxtecan for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a previous trastuzumab (Herceptin)-based regimen.2
The regulatory decision was based on primary findings from the phase 2 DESTINY-Gastric01 study, which showed that the median OS with trastuzumab deruxtecan was 12.5 months (95% CI, 9.6-14.3) compared with 8.4 months (95% CI, 6.9-10.7) with irinotecan or paclitaxel in patients with advanced, HER2-positive gastric or GEJ adenocarcinoma who had progressed following a trastuzumab-based treatment (HR, 0.59; 95% CI, 0.39-0.88; P = .0097).3
DESTINY-Gastric01 is an open-label, multicenter, randomized, phase 2 study. Investigators evaluated trastuzumab deruxtecan versus physician’s choice of standard chemotherapy in patients with HER2-expressing advanced gastric or GEJ adenocarcinoma who had received at least 2 prior regimens, including fluoropyrimidine, a platinum-based agent, and trastuzumab or approved biosimilar.
Patients who had or were suspected to have interstitial lung disease (ILD) or pneumonitis, or a history of noninfectious ILD or pneumonitis that had been treated with steroids, were excluded from enrollment.
A total 188 patients were randomized 2:1 to receive either trastuzumab deruxtecan at 6.4 mg/kg every 3 weeks (n = 126) or chemotherapy with irinotecan or paclitaxel (n = 62). Eighty-six percent of participants received a prior taxane, 71% had ramucirumab (Cyramza), and 31% received prior PD-1/PD-L1 inhibitors.
Stratification factors included by country, ECOG performance status, and HER2 status.
The primary end point of the trial was objective response rate (ORR) per independent central review (ICR), while secondary end points comprised OS, duration of response (DOR), progression-free survival, confirmed ORR, and safety.
The data cutoff date for OS was June 3, 2020, after a median follow-up of 18.5 months.
The median age was 65.5 years (range, 28.0-82.0), 24.1% of patients were female, and most patients were from Japan (79.9%). Forty-nine percent of patients had an ECOG performance of 0, and patients either had intestinal histology (66.3%), diffuse (25.7%), or other (8.1%). Three-fourths of patients (76.3%) had HER2 expression and 87.6% had gastric/GEJ as their primary site. Patients had tumors measuring at less than 5 cm (46.2%), between 5 and 10 cm (31.8%), at least 10 cm (14.9%), or missing (12.1%).
Patients had received either 2 (57.1%), 3 (28.1%), or at least 4 (14.9%) prior systemic therapies, which consisted of trastuzumab (100%), ramucirumab (70.7%), taxane (86.4%), irinotecan or another topoisomerase I inhibitor (7.3%), or an immune checkpoint inhibitor (31.3%). Patients in the trastuzumab deruxtecan group were more than twice as likely to have received 4 or more prior therapies (20.0% vs 9.7%).
Additional data with the longer follow-up showed that the ORR by ICR was 51.3% (95% CI, 41.9%-60.5%) and 14.3% (95% CI, 6.4%-26.2%) with trastuzumab deruxtecan and chemotherapy, respectively, which Yamaguchi said was a statistically significant difference. In the trastuzumab deruxtecan arm, this consisted of a 9.2% complete response (CR) rate and a 42.0% partial response (PR) rate; the stable disease (SD) rate was 35.3% and the progressive disease (PD) rate was 11.8%. Two patients (1.7%) were not evaluable for response.
The confirmed ORR was 42.0% (95% CI, 33.0%-51.4%) with trastuzumab deruxtecan and 12.5% (95% CI, 5.2%-24.1%) with chemotherapy. In the trastuzumab deruxtecan arm, the CR and PR rates were 8.4% and 33.6%, respectively; the SD and PD rates were 43.7% and 11.8%, respectively. Three patients (2.5%) were not evaluable for response.
The confirmed disease control rate was 85.7% (95% CI, 78.1%-91.5%) with trastuzumab deruxtecan compared with 62.5% (95% CI, 48.5%-75.1%) with chemotherapy. The confirmed median DOR was 12.5 months (95% CI, 5.6–not evaluable) and 3.9 months (95% CI, 3.0-4.9), respectively. The median time to response was similar between arms, at 1.5 months (95% CI, 1.4-1.7) with trastuzumab deruxtecan and 1.6 months (95% CI, 1.3-1.7) with chemotherapy.
“This presentation shows that most patients received [trastuzumab deruxtecan had a reduction in tumor size compared with approximately half of patients receiving [chemotherapy],” Yamaguchi said.
Regarding safety, grade 3 or higher adverse events (AEs) occurred in 85.6% of patients on trastuzumab deruxtecan compared with 56.5% of those on chemotherapy. The most common grade or higher AE was decreased neutrophil count (51.2% with trastuzumab deruxtecan vs 24.2% with chemotherapy), followed by anemia (38.4% vs 22.6%, respectively) and decreased white blood cell count (20.8% vs 11.3%).
Sixteen patients (12.8%) experienced ILD/pneumonitis related to trastuzumab deruxtecan as determined by an independent adjudication committee. These occurred at levels of grade 1/2 (n = 13), grade 3 (n = 2), and grade 4 (n = 1). Four ILD/pneumonitis events occurred since the primary analysis; 1 was a grade 1 event and the remaining 3 were grade 2.
The median time to first onset among the 16 overall ILD/pneumonitis events was 102.5 days (range, 36-638).
One treatment-related death from pneumonia occurred on the trastuzumab deruxtecan arm, which had been reported in the primary analysis. No ILD/pneumonitis events nor AE-related deaths occurred on the chemotherapy arm.
“This additional follow-up provides further evidence that trastuzumab deruxtecan is an effective treatment option for patients with HER2-positive advanced gastric cancer or GEJ adenocarcinoma who have progressed after 2 or more previous lines of therapy, including trastuzumab, fluoropyrimidine, and a platinum agent,” Yamaguchi concluded.
DESTINY-Gastric01 trial also has 2 exploratory cohorts focused on the HER2-low population: HER2 (immunohistochemistry [IHC] 2+/in situ hybridization —; n = 21) and HER2 (IHC 1+; n = 24).
1. Yamaguchi 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: Final overall survival (OS) results from a randomized, multicenter, open-label, phase 2 study (DESTINY-Gastric01). J Clin Oncol. 2022;40(suppl;242). doi:10.1200/JCO.2022.40.4_suppl.242
2. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. News release. FDA. January 15, 2021. Accessed January 15, 2021. http://bit.ly/35KBZ8T.
3. 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