ENHERTU (T-DXd; AstraZeneca and Daiichi Sankyo) is a HER2-directed antibody-drug conjugate (ADC). DESTINY-Gastric04 was a global Phase III trial comparing T-DXd (6.4 mg/kg every 3 weeks) to ramucirumab plus paclitaxel in 494 patients with HER2-positive gastric/GEJ cancer after trastuzumab progression. Patients with active or prior interstitial lung disease were excluded. The primary endpoint was overall survival (OS), with key secondary endpoints including progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety.

In the DESTINY-Gastric04 trial, T-DXd showed a significant survival advantage over ramucirumab plus paclitaxel in patients with HER2-positive gastric or GEJ cancer. At a median follow-up of 16.8 months (T-DXd) and 14.4 months (ram/pac), the median OS was 14.7 vs 11.4 months, respectively, translating to a 30% reduction in the risk of death. Six-, 12-, and 24-month OS rates favored T-DXd (83.5%, 57.6%, 29.0%) over ram/pac (74.4%, 48.9%, 13.9%).

PFS was also longer with T-DXd (6.7 vs 5.6 months), with higher six- and 12-month PFS rates (52.6% and 22.9%) compared to ram/pac (41.5% and 13.6%). T-DXd produced a higher confirmed ORR (44.3% vs 29.1%) and a longer DOR (7.4 vs 5.3 months). Disease control rate (DCR) was also superior with T-DXd (91.9% vs 75.9%).

In terms of safety, grade ≥3 treatment-emergent adverse events (TEAEs) were seen in 50.0% of T-DXd patients and 54.1% of those on ram/pac, with neutropenia being the most common severe AE in both arms. Interstitial lung disease (ILD)/pneumonitis occurred more frequently with T-DXd (13.9%) than with ram/pac (1.3%). Despite the higher incidence of ILD and associated treatment modifications, the overall safety profile of T-DXd was manageable and supports its use as a new second-line standard of care in this setting.

KOL insights

T-DXd demonstrated a statistically significant and clinically meaningful improvement in OS compared with ramucirumab plus paclitaxel in patients with HER2-positive metastatic GC/GEJ in the second line setting, DESTINY-Gastric04 confirmed T-DXd as the global second line standard-of-care therapy for patients with HER2-positive metastatic GC/GEJ. – Expert Opinion

Gastric cancer is particularly challenging to treat, especially in the advanced stages where the five-year survival rate remains low, the superior overall survival demonstrated in DESTINY-Gastric04 confirms that ENHERTU could become the global standard of care in the second-line metastatic setting of HER2 positive gastric cancer or gastroesophageal junction cancer.– Expert Opinion

“Trastuzumab deruxtecan is approved for patients with metastatic HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma who received a prior trastuzumab-based regimen based on previous Phase II studies. The improvement in overall survival with trastuzumab deruxtecan compared to ramucirumab with paclitaxel seen in this study validates the role of trastuzumab deruxtecan in the second-line setting."– Expert Opinion

Conclusion

In 2024, approximately 29,000 cases (DelveInsight’s estimates) of gastric cancer, including gastroesophageal junction (GEJ) cancer, were reported in the United States, with a higher prevalence in males and stage IV being the most common at diagnosis. Among these cases, 20-25% are HER2-positive. It is worth noting that Gastric Cancer is more prevalent in Asian countries. 

As second-line treatment options, paclitaxel with CYRAMZA (ramucirumab) (Eli Lilly & Co.) and ENHERTU have both received approval. The DESTINY-Gastric04 trial's findings validate ENHERTU's position as the second-line, global standard of care for patients with HER2-positive metastatic GC/GEJA.  These findings further justify the development in an earlier line setting. Building on DESTINY-Gastric04 findings, future clinical trials, such as DESTINY-Gastric05, DESTINY-Gastric03, and ARTEMIDE-Gastric01, will examine ENHERTU's safety and effectiveness in the first-line HER2-positive gastric cancer. KEYTRUDA (pembrolizumab), an anti–PD–1 monoclonal antibody, is currently the only marketed first-line treatment for HER2-positive advanced GC/GEJA, with regulatory approvals in the US (2021), EU (2023), and Japan (2024). 

Several promising investigational therapies are in development, aiming to expand treatment options in HER2-positive GC/GEJA space. These include ZIIHERA, Rilvegostomig, HLX22, Evorpacept, TUKYSA (tucatinib), BAY2927088, and MRG002. These candidates reflect a growing pipeline focused on enhancing efficacy and overcoming resistance in HER2-positive gastric and GEJ cancers.