Proffered paper session 2: GI upper digestive

In this video, Prof Dr Karen Geboes discusses and comments on the data of some interesting studies that were presented at ESMO 2024 during the proffered paper session on upper digestive gastrointestinal tumours. 

The first study discussed the final results of the TOPGEAR trial, offering insights into the comparison between chemotherapy and chemoradiation in gastric cancer. The trial, which enrolled around 600 patients and followed them for approximately 60 months, concluded with a negative result. Specifically, pre-operative chemoradiation therapy consisting of 45 grey with 5FU did not demonstrate any survival benefit for patients with gastric cancer. This finding aligns with previous studies like the CRITICS and ARTIST trials, which also showed no survival advantage for postoperative chemoradiation. During the discussion of the TOPGEAR results, the speaker suggested that radiotherapy may no longer hold a place in the treatment of oesophageal and gastric cancers. They also referenced the recent ESOPEC trial, which favoured FLOT chemotherapy over chemoradiotherapy for oesophageal adenocarcinoma. However, there are some distinctions between the TOPGEAR and ESOPEC trials. While two-thirds of the patients in the TOPGEAR trial received the older ECF chemotherapy regimen and only one-third received FLOT, the median overall survival for the chemotherapy-alone group was around 50 months, which is comparable to the current standard based on the FLOT trial. Notably, the patients in the TOPGEAR trial mainly had advanced disease (T3, T4, and node-positive tumours), making the results robust. In contrast, the ESOPEC trial’s control arm, which used chemoradiotherapy, performed less favourably than previous trials like the CROSS trial. This raised questions about the quality and consistency of the radiotherapy arm in ESOPEC. While the ESOPEC trial leans toward FLOT chemotherapy, further analysis is needed to understand the radiotherapy arm’s underperformance in that study fully.

The second study discussed was the MOONLIGHT study, which compared various combinations of chemotherapy and immunotherapy in gastric and gastroesophageal cancers. Specifically, it evaluated Folfox alone, Folfox with a combination of ipilimumab and nivolumab (Ipi/Nivo), Folfox with sequential Ipi/Nivo, and FLOT with nivolumab. The trial included smaller cohorts, with each arm consisting of 60 to 90 patients and relatively few patients with PD-L1 positivity. Overall, the trial yielded largely negative results. None of the arms demonstrated significant benefit, except for the FLOT plus nivolumab arm, which was enriched with PD-L1 positive patients. This suggests that PD-L1 status might have played a role in the modest success seen in that specific group. One key finding from the study was the high toxicity associated with the Folfox plus nivolumab arm, which raised concerns about its feasibility as a treatment option. While the study doesn’t contribute much new information regarding the combination of chemotherapy and immunotherapy in gastric or gastroesophageal cancers, it does suggest that FLOT plus nivolumab could be a potential therapy worth exploring further, especially in patients with PD-L1 positive tumours. However, further trials will be necessary to clarify its role in treatment.

The third trial discussed was the KEYNOTE-811 study, previously reported in 2023, which led to the approval and reimbursement of the combination of trastuzumab, pembrolizumab, and chemotherapy for HER2-positive gastric cancers by the European Medicines Agency (EMA) for patients with a Combined Positive Score (CPS) of 1 or higher. Now, the final survival analysis of the trial has been presented. It confirmed a two-month survival benefit with the addition of pembrolizumab to trastuzumab and chemotherapy in HER2-positive gastric cancers. Importantly, the benefit was more pronounced in patients with CPS scores of 1 or higher, reinforcing the association between higher CPS scores and improved outcomes in this patient population. During the presentation, the discussant raised an interesting point about the magnitude of the benefit and how it scales with CPS levels. While the results support the notion that higher CPS scores correspond to greater treatment benefit, this continuum of benefit differs from the clear binary outcome observed with treatments like anti-EGFR therapies in colorectal cancer, where patients with RAS mutations are harmed by treatment and only RAS wild-type patients benefit. In HER2-positive gastric cancer, there appears to be a more gradual increase in benefit as CPS increases rather than a stark cutoff. This observation invites further reflection on how biomarkers like CPS should be used to assess and weigh the value of treatment benefits in different patient populations.

The final study discussed in the session was the DESTINY GASTRIC-03 trial, which explored the use of trastuzumab deruxtican (now reimbursed in Belgium as a second-line treatment) in the first-line setting for HER2-positive gastric cancer. The trial investigated trastuzumab deruxtican at a dose of 6.4 mg/kg as a standalone treatment, in combination with 5-FU or capecitabine, and in combination with chemotherapy plus pembrolizumab.

The main findings were that trastuzumab deruxtican plus chemotherapy was superior to trastuzumab deruxtican monotherapy. Additionally, when combining trastuzumab deruxtican with pembrolizumab, the dose of trastuzumab deruxtican needed to be reduced to avoid excessive toxicity.

An interesting point raised during the discussion was the importance of biomarkers, particularly immunohistochemistry, for HER2 status. Patients with IHC 3+ HER2 expression performed better than those with lower HER2 expression, suggesting that IHC could be a valuable tool in identifying patients who will benefit most from trastuzumab deruxtican treatment.

The takeaway from this session is the evolving focus on tailoring treatments based on biomarker profiles to ensure the right treatment reaches the right patients, reinforcing a more personalised approach to cancer care.