Editor's Note: As one of the world's largest and most academically prestigious clinical oncology conferences, the 2024 European Society for Medical Oncology (ESMO) conference, held from September 13 to 17 in Barcelona, drew global attention. The conference revealed several important clinical study results in upper gastrointestinal tumors. Dr. Filippo Pietrantonio, an oncologist from the National Cancer Institute in Milan, Italy, shared his insights in an exclusive interview with Oncology Frontier.

Oncology Frontier: Could you share the research highlights from this ESMO meeting with us?

Dr. Filippo Pietrantonio: ESMO 2024 was an outstanding event, showcasing the latest phase III trials capable of changing clinical practice and trials that influence future designs and research in upper gastrointestinal cancers. Some exciting presentations emerged during the oral session on gastroesophageal cancer, including KEYNOTE-811 and the DESTINY-Gastric03 study.

In the KEYNOTE-811 trial, researchers recruited patients with pathologically confirmed HER2-positive gastroesophageal cancer and randomized them into standard treatment with chemotherapy plus trastuzumab or a combination with pembrolizumab. We conducted three interim analyses in the past, and now the final analysis has achieved its co-primary endpoint of overall survival (OS), which is crucial in oncology trials. This is a practice-changing trial, as pembrolizumab combined with trastuzumab and chemotherapy has been included in the ESMO guidelines since 2023. The median OS was extended by 3.2 months, with long-term benefits in OS, particularly in patients with a combined positive score (CPS) ≥ 1, where OS increased by an absolute 4.4 months. However, no benefit was observed in patients with PD-L1 expression of zero, aligning with current regulatory approvals for pembrolizumab in this patient group. For those with CPS ≥ 1, adding pembrolizumab to trastuzumab and chemotherapy is strongly recommended, while trastuzumab and chemotherapy remain the standard treatment for CPS < 1. KEYNOTE-811 will serve as the control arm in future first-line trials for this disease.

DESTINY-Gastric03 (DG-03) explored various combinations based on trastuzumab deruxtecan (T-DXd), gathering safety and efficacy data to select the best regimen for phase III gastric cancer studies. We know that T-DXd is the most effective drug currently approved for HER2-positive patients in advanced settings, so researchers aimed to move it to the first-line setting to improve outcomes. What did the results show? The combinations were manageable in terms of safety, but toxicity increased with more drugs added. When T-DXd was combined with fluoropyrimidines and pembrolizumab, it showed the highest patient mortality. So, will T-DXd replace trastuzumab in the first-line setting? The answer may be yes, but trial design optimization is key. By reducing T-DXd’s dose to 5.4 mg and capecitabine’s dose to 750 mg, with or without pembrolizumab, the combination seems optimal as a first-line regimen. Two ongoing phase III trials aim to redefine the current standard, and the DG-03 strategy needs to be compared with KEYNOTE-811, the current standard of care. The future of first-line treatment for HER2-positive gastric cancer looks promising and rapidly evolving, with more trials and data expected soon.

Oncology Frontier: As a speaker at this conference, you delivered a review on the significant progress in upper gastrointestinal cancers. Could you share the main takeaways from these studies?

Dr. Filippo Pietrantonio: For HER2-positive diseases, there are many directions to explore. Biomarkers are crucial, not only PD-L1 expression but also HER2 expression levels, so studying biomarkers in these trials is essential to optimally select patients and explore future strategies. Strategies like de-escalating chemotherapy can improve patients’ quality of life and adherence to other effective regimens. Collecting patient-reported quality of life data is also key.

We also saw significant data in early-stage diseases, such as the phase III TOPGEAR trial presented at the same session. This trial investigated standard perioperative chemotherapy in resectable gastroesophageal/gastric cancer patients. The key message was that adding preoperative radiotherapy to standard perioperative chemotherapy did not provide progression-free survival (PFS) or OS benefits. Does this mean radiotherapy is ineffective in these cancers? For most patients, chemotherapy is the key treatment. However, don’t overlook the importance of multidisciplinary discussions for all patients, as preoperative chemoradiotherapy can still provide clear advantages in disease downstaging and precise staging for specific cases.

Oncology Frontier: What are the key future research directions in upper gastrointestinal cancers?

Dr. Filippo Pietrantonio: Upper gastrointestinal cancers, including gastroesophageal, pancreatic, and biliary cancers, are continually evolving due to multidisciplinary management and new drugs with novel mechanisms of action, especially monoclonal antibodies and new ADC drugs. This is indeed a rapidly growing field. Investigating combination therapies, as demonstrated in today’s DG-03 study, is crucial, and we must carefully monitor the potential overlapping toxicities of these drugs. Certainly, these advancements and progress in curative-intent early disease can now let us discuss long-term survival for these highly aggressive cancer types, especially gastric cancer, which was previously unimaginable. Therefore, I am optimistic that these advances can lead to transformative changes in this field.