By Chumi Khurana, Senior Vice President, Oncology Franchise Head, Jazz Pharmaceuticals
For patients diagnosed with locally advanced or metastatic HER2-positive (HER2+) gastroesophageal adenocarcinoma (GEA), the first line of therapy often represents the most meaningful opportunity to alter the trajectory of disease.1 Yet despite important advances in oncology over the past decade, initial responses in this aggressive cancer are too often followed by disease progression within two years, leading to poor survival outcomes, narrowing subsequent treatment options, and underscoring an urgent need for more first-line options that extend survival.2,3
GEA, encompassing cancers of the stomach, gastroesophageal junction, and esophagus, is often diagnosed at an advanced stage and carries a poor prognosis.2,3 Most patients present with metastatic disease, and even those who initially respond to treatment frequently experience early progression.3,4 For the subset of patients with HER2+ tumors, targeted therapies introduced more than a decade ago marked a significant step forward, but durable disease control has remained difficult to achieve.4
A persistent unmet need in first-line treatment
Approximately 20% of patients with GEA have HER2+ disease.4,5,6 For more than a decade, first-line treatment strategies for this population relied on platinum-based chemotherapy combined with HER2-targeted therapy.4,6 While this approach improved outcomes compared with chemotherapy alone, responses were often transient, and most patients ultimately experienced disease progression.2,4
More recently, the integration of immunotherapy into first-line regimens has led to incremental improvements in survival for a subset of patients whose tumors express PD-L1.2,3 This progress is important and reflects continued innovation in the field. However, even with these newer approaches, and despite meaningful benefit for a subset of biomarker-defined patients, survival gains for most patients remain limited in duration, and truly durable, long-term survival remains the exception rather than the rule.
Importantly, advances have not been uniform across disease types. While HER2-directed strategies have become part of first-line care for certain gastroesophageal cancers, treatment options for patients with esophageal disease remain more limited.7 This disparity highlights ongoing gaps in care and reinforces the need for new approaches that can benefit all patients with HER2+ GEA.
Why durability matters, not just response
In metastatic GEA, response rates alone do not tell the full story. Short-lived tumor shrinkage may delay progression temporarily, but without sustained disease control, patients often face repeated relapses, cumulative toxicity, and declining quality of life.4
Durability of response is particularly critical in the first-line setting, where effective early disease control can help preserve functional status and extend the time before progression.4 When first-line therapy fails to deliver lasting benefit, patients may deteriorate quickly, limiting eligibility for subsequent treatments or clinical trials. As a result, the window to meaningfully impact long-term outcomes can narrow rapidly.4
More durable first-line options have the potential to offer benefits beyond survival alone. They may help reduce symptom burden, maintain independence, and provide patients and families with valuable time. Time that can be spent pursuing personal goals and accessing future therapeutic advances.4
Innovation at the intersection of biology and strategy
The biological complexity of GEA has long challenged progress. Tumor heterogeneity, dynamic HER2 expression, and evolving resistance mechanisms all complicate treatment decisions and contribute to limited durability of response.3,4 However, recent innovation in GEA treatment suggests the potential to move beyond the incremental advances seen previously.
Future progress in the GEA treatment landscape will depend on therapeutic strategies designed with durability in mind—approaches that more comprehensively address tumor biology and sustain disease control over time.2 Equally important is thoughtful clinical research that prioritizes outcomes most meaningful to patients, including the potential for long-term survival and the ability to maintain quality of life.2
Encouragingly, ongoing research reflects a growing recognition that first-line treatment sets the foundation for everything that follows. Improving the depth and durability of initial responses may be one of the most effective ways to change outcomes in this historically difficult-to-treat disease.2
Why the moment is now
GEA is the fifth most common cancer worldwide, and HER2+ disease is associated with high morbidity and mortality.4,5,6 Despite advances in care, the overall prognosis for patients with GEA remains poor, with a five-year survival rate of less than 10% for metastatic GEA.8,9
For patients, innovation in this space represents hope: hope for longer survival, better quality of life and more time without disease progression. For the oncology community, it is a call to continue pushing beyond modest gains and to reimagine what first-line therapy can achieve.
First-line treatment shapes the entire disease journey. In HER2+ GEA, advancing more durable and effective options at the outset could make a real difference for patients who urgently need better answers.
1 Esen, S. A., et al. First-line treatment of patients with HER2-positive metastatic gastric and gastroesophageal junction cancer. Bosnian journal of basic medical sciences,2021;22(5), 818.
2 Battaglin, F et al. Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions. Cancer Cell International, 2018; 18(1), 99.
3 Gambardella, V at al. Precision medicine to treat advanced gastroesophageal adenocarcinoma: a work in progress. Journal of clinical medicine. 2020; 9(9), 3049.
4. Stroes, C.I., et al. A systematic review of HER2 blockade for the curative treatment of gastroesophageal adenocarcinoma: Successes achieved and opportunities ahead. CancerTreatRev. 2021;99:102249.
5 Abrahao-Machado I.F., et al. HER2 testing in gastric cancer: An update WorldJGastroenterol. 2016;22(19):4619-4625.
6 Van Custem E., et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015;18(3):476-484.
7 Cowzer, D et al. Top advances in esophageal/gastroesophageal junction cancers in 2021. Cancer. 2022 128(10), 1894-1899.
8 Orditura M , GaliziaG, SforzaVet al. Treatment of gastric cancer. World J. Gastroenterol.20(7), 1635–1649 (2014).
9 Shiozaki H , SlackRS, ChenHCet al. Metastatic gastroesophageal adenocarcinoma patients treated with systemic therapy followed by consolidative local therapy: a nomogram associated with long-term survivors. Oncology91(1), 55–60 (2016).