Efficacy and Safety of Trastuzumab Deruxtecan in Gastrointestinal Malignancies: A Systemic Review and Meta-Analysis

Ali Hussain^1*Qamar Iqbal¹Sangeetha Isaac¹Faisal Shariff²Ezza Tariq²Hassan Awais¹Nayan Mainkar¹Heidi Lynn Reis¹Aakriti Arora¹Akshay Deotare¹Azka Tasleem¹Srijan Valasapalli¹Munizay Paracha¹Maya Hashmi¹Hamdi Battah¹Mahvish Muzaffar^1*

• ¹East Carolina University, Greenville, United States
• ²University of Toledo, Toledo, Ohio, United States

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that is effective in treating gastrointestinal (GI) cancers. However, significant variability in its reported efficacy and safety profiles is likely due to differences in trial designs, patient populations, and clinical settings. This systematic review and meta-analysis aimed to consolidate current evidence on the efficacy and safety of T-DXd in human epidermal growth factor receptor 2 (HER2)-positive GI malignancies. We conducted a systematic review and meta-analysis following PRISMA guidelines, utilizing the Medline, Embase, Cochrane Central, and ClinicalTrials.gov databases. Out of 5,594 articles reviewed, ten studies were ultimately included after both primary and secondary screenings, providing data on the outcomes and safety of T-DXd in HER2 positive GI malignancies. The NIH quality assessment tool was employed to evaluate the quality of the studies. Pooled analyses were performed using the 'meta' package (Schwarzer et al., R programming language), and proportions with 95% confidence intervals (CIs) were calculated. We identified 653 patients treated with T-DXd for HER2 positive GI malignancies in ten studies. The median age of the patients was 64.5 years (27-85), with 53% being male. The median follow-up duration was 5.9 months(0.5-30.5). The median overall survival and progression-free survival were 11.15 (1.4-20.8) and 5.6 months (2.6-8.7), respectively. The pooled objective response rate (ORR) was 36.9% (95% CI:31.5%-42.5%, I² = 41%, n = 589), with partial response and complete response rates of 35.2% (95% CI:31.1%-39.5%, I² = 0%, n = 516) and 1.3% (95% CI: 0.0%-4.7%, I² = 73%, n = 516), respectively. The median duration of response (DoR) was seven months (0.7-22.3). Reported adverse events included anemia, febrile neutropenia, thrombocytopenia, diarrhea, nausea, interstitial lung disease/pneumonitis, heart failure, and hepatitis. For the 5.4 mg/kg dose, grade 3/4 adverse events were reported in 67 patients. For the 6.4 mg/kg dose, 146 grade 3/4 adverse events were reported. This meta-analysis supports the efficacy of T-DXd in patients with HER2 positive GI malignancies with moderate ORR, even in patients who have experienced disease progression after multiple lines of therapy. These findings validate existing research and underscore the need for further clinical trials, particularly in earlier lines of treatment.