Systematic Literature Review (SLR) of First-Line (1L) Treatments of Patients With Advanced or Metastatic HER2-Positive Gastroesophageal Adenocarcinoma (GEA)
Author(s)
John Bridgewater, PhD1, Javier Sabater, B. Pharm2, Junji Lin, PhD3, Wayne Su, MSc3, Tanya Madan, B. Pharm4, Paranjoy Saharia, MSc5, Michelle Smith, MSc4.
1University College London Cancer Institute, London, United Kingdom, 2Jazz Pharmaceuticals, Oxford, United Kingdom, 3Jazz Pharmaceuticals, Philadelphia, PA, USA, 4Lumanity, London, United Kingdom, 5Lumanity, Gurugram, India.
1University College London Cancer Institute, London, United Kingdom, 2Jazz Pharmaceuticals, Oxford, United Kingdom, 3Jazz Pharmaceuticals, Philadelphia, PA, USA, 4Lumanity, London, United Kingdom, 5Lumanity, Gurugram, India.
OBJECTIVES: Approximately 20% of patients with GEA, which includes gastric, gastroesophageal junction (GEJ), and esophageal cancer, have tumors that are HER2-positive. This SLR describes the efficacy and safety of regimens studied in 1L advanced/metastatic HER2-positive GEA.
METHODS: Embase®, MEDLINE® and Cochrane Library were searched on 16 August 2024 for clinical trials conducted in 1L advanced/metastatic HER2-positive GEA, supplemented by conference searches. ROBINS-I was used for quality assessment (PROSPERO ID: CRD42024581792).
RESULTS: 35 unique studies were included (22 were single-arm, 10 randomized controlled trials [RCTs], and three non-RCTs). In a phase 3 RCT, the HER2-targeted antibody trastuzumab plus chemotherapy demonstrated an overall survival (OS) benefit versus chemotherapy alone in 1L HER2-positive gastric/GEJ cancer (13.8 months vs 11.1 months). Recently, a phase 3 RCT demonstrated the anti-PD-1 antibody pembrolizumab plus trastuzumab and chemotherapy improved OS versus trastuzumab and chemotherapy alone in the subset of patients with HER2-positive gastric/GEJ cancer and a PD-L1 CPS score ≥1 (20.1 months vs 15.7 months). Dual HER2-inhibition with the introduction of pertuzumab to trastuzumab and chemotherapy did not further improve patient outcomes in the rest of the RCTs. Other immunotherapy and/or biomarker-driven combinations, such as with bevacizumab, nivolumab, and zanidatamab, were studied in small RCTs or single-arm trials. The longest OS observed in these trials was 36.5 months in a single arm trial of zanidatamab, a bispecific HER2-directed antibody, plus chemotherapy. Generally, the safety profile for most of the therapies was consistent with known safety profiles of individual component therapies.
CONCLUSIONS: There is no new HER2-targeted treatment since trastuzumab that has demonstrated OS benefits in combination regimens for 1L HER2-positive GEA. Dual blockade of HER2 and PD-L1, with the addition of immunotherapy to trastuzumab-based chemotherapy, improved survival for the subset of patients who also expressed PD-L1. Multiple trials are currently underway to investigate novel regimens like zanidatamab in 1L HER2-positive GEA.
METHODS: Embase®, MEDLINE® and Cochrane Library were searched on 16 August 2024 for clinical trials conducted in 1L advanced/metastatic HER2-positive GEA, supplemented by conference searches. ROBINS-I was used for quality assessment (PROSPERO ID: CRD42024581792).
RESULTS: 35 unique studies were included (22 were single-arm, 10 randomized controlled trials [RCTs], and three non-RCTs). In a phase 3 RCT, the HER2-targeted antibody trastuzumab plus chemotherapy demonstrated an overall survival (OS) benefit versus chemotherapy alone in 1L HER2-positive gastric/GEJ cancer (13.8 months vs 11.1 months). Recently, a phase 3 RCT demonstrated the anti-PD-1 antibody pembrolizumab plus trastuzumab and chemotherapy improved OS versus trastuzumab and chemotherapy alone in the subset of patients with HER2-positive gastric/GEJ cancer and a PD-L1 CPS score ≥1 (20.1 months vs 15.7 months). Dual HER2-inhibition with the introduction of pertuzumab to trastuzumab and chemotherapy did not further improve patient outcomes in the rest of the RCTs. Other immunotherapy and/or biomarker-driven combinations, such as with bevacizumab, nivolumab, and zanidatamab, were studied in small RCTs or single-arm trials. The longest OS observed in these trials was 36.5 months in a single arm trial of zanidatamab, a bispecific HER2-directed antibody, plus chemotherapy. Generally, the safety profile for most of the therapies was consistent with known safety profiles of individual component therapies.
CONCLUSIONS: There is no new HER2-targeted treatment since trastuzumab that has demonstrated OS benefits in combination regimens for 1L HER2-positive GEA. Dual blockade of HER2 and PD-L1, with the addition of immunotherapy to trastuzumab-based chemotherapy, improved survival for the subset of patients who also expressed PD-L1. Multiple trials are currently underway to investigate novel regimens like zanidatamab in 1L HER2-positive GEA.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
CO226
Topic
Clinical Outcomes
Topic Subcategory
Comparative Effectiveness or Efficacy
Disease
Gastrointestinal Disorders, Oncology