Mini Oral Session: GI upper

In this video Dr Ana-Maria Bucalau discusses and comments on the data of some interesting studies that were presented at ESMO 2024 during the mini-oral session on upper digestive gastrointestinal tumours.

The first study presented today was a phase 3 randomised trial evaluating the combination of a new drug, SHR-1701, alongside chemotherapy versus placebo with chemotherapy in first-line treatment for patients with HER2-negative gastric or gastroesophageal junction adenocarcinoma. SHR-1701 is a novel dual inhibitor of PD-L1 and TGF-β, targeting two critical pathways. The rationale for this combination stems from only about 20% of tumours exhibiting a sustained response to PD-L1 therapies alone. TGF-β signalling within the tumour microenvironment is associated with resistance to PD-L1 blockade. By inhibiting both pathways, the combination aims to enhance therapeutic efficacy. Patients in the trial were randomised 1:1 to receive either the new drug combined with chemotherapy or a placebo with chemotherapy (Capox regimen). The study’s primary endpoint was OS in the PD-L1 combined positive score (CPS) of ≥5 and in the ITT population. Secondary endpoints included PFS, ORR, duration of response, and safety outcomes. The study successfully met its primary endpoint, demonstrating a survival benefit in the overall ITT population and in patients with PD-L1 CPS ≥5. Additionally, the study showed a trend towards improved PFS and ORR, and the safety profile of the combination was acceptable. While the results for this new molecule are promising, it would have been informative to include a comparison arm of chemotherapy combined with an anti-PD-1 agent, which is currently the standard of care for patients with PD-L1 CPS ≥1. This would have provided a clearer understanding of SHR-1701’s relative efficacy in this setting.

The second study highlighted is the SPACE-FLOT study, which examined whether the pathological response to neoadjuvant FLOT chemotherapy could guide its use in the adjuvant setting for patients with gastroesophageal cancer. This international study utilised real-world data from more than 1,800 patients across 12 countries. Patients with locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma typically receive perioperative FLOT chemotherapy, consisting of four cycles before surgery and four cycles after surgery. However, prescribing the recommended four cycles of FLOT after surgery is often challenging, and many patients are unable to complete this regimen. In the study, patients were grouped into minimal, partial, and complete responders based on their pathological response to FLOT chemotherapy, as determined by tumour regression grading (TRG). The researchers then compared survival outcomes between patients who did and did not receive adjuvant FLOT after surgery. The results showed that only patients with a partial response to neoadjuvant FLOT benefited from continuing FLOT chemotherapy in the adjuvant setting. However, it is important to note that this was a retrospective study with real-world data and no randomisation, and there were some imbalances in prognostic factors. Therefore, while the findings are significant, they should be interpreted cautiously Moreover, other studies, such as the VESTIGE study, have demonstrated that patients with poor prognostic factors can still benefit from adjuvant FLOT, suggesting that it may not be appropriate to dismiss its use in certain cases entirely.

The third study to highlight is the POLAR study, a phase II trial investigating the combination of pembrolizumab and olaparib as maintenance treatment in selected patients with metastatic pancreatic cancer. To place POLAR in context, revisiting the 2019 phase III POLO trial is necessary. The POLO trial demonstrated that PFS was longer with maintenance olaparib compared to placebo for patients with a germline BRCA mutation and metastatic pancreatic cancer who had not progressed during platinum-based chemotherapy. The POLAR study builds on this premise, exploring whether adding a PD-1 inhibitor like pembrolizumab to olaparib can improve survival outcomes in certain immunogenic metastatic pancreatic cancers. The study population was divided into three cohorts based on genotypes and treatment responses. The first cohort included patients with germline or somatic BRCA or PALB2 mutations who had responded well to platinum-based chemotherapy. The second cohort consisted of patients with other non-core HRD mutations, also responsive to platinum. The third cohort comprised patients without any HRD mutations but who had shown a good response to platinum therapy. Primary endpoints included ORR and PFS at 6 months. While the data remains immature, early results suggest a favourable trend, particularly in the first cohort, indicating that precision immunotherapy for pancreatic cancer may be a viable and effective approach.

The last two studies focus on the treatment of hepatocellular carcinoma. The first is the CheckMate 9DW trial, initially presented at ASCO earlier this year, which demonstrated that first-line treatment with the combination of ipilimumab and nivolumab improved survival compared to sorafenib or lenvatinib for patients with unresectable and untreated HCC. At ESMO 2024, additional data on immune-mediated AEs were shared. Any-grade immune-mediated AEs occurred in 58% of patients, while 28% experienced grade 3 or 4 events. Despite these AEs, the majority were manageable and did not result in treatment discontinuation. These findings further bolster the use of this combination in HCC treatment, with the CheckMate 9DW trial currently showing the highest median OSl and ORR in this patient population.

The five-year update of the Himalaya phase 3 trial also focuses on hepatocellular carcinoma. Previously published results from this trial demonstrated that the STRIDE regimen, a combination of tremelimumab and durvalumab, significantly improved overall survival compared to sorafenib in patients with unresectable and untreated HCC. The latest update revealed an unprecedented five-year survival rate, with one in five patients still alive at five years.

Currently, three key combination therapies are available for the treatment of HCC, with more in development, including combinations involving systemic treatments and locoregional intra-arterial therapies. The challenge moving forward will be navigating the growing range of therapeutic options in this evolving landscape.