Proffered paper session: GI lower digestive

In this video, Prof Dr Marc Van den Eynde discusses and comments on the data of some interesting studies that were presented at ESMO 2024 during the proffered paper session on lower digestive gastrointestinal tumours, especially in the adjuvant and neo-adjuvant setting. 

In the adjuvant setting, one of the communications focused on the LEANOX phase 2 trial investigating a new approach for dosing oxaliplatin in patients with stage III colorectal cancer. Traditionally, oxaliplatin is dosed based on a patient’s body surface area (BSA), but this trial explored whether adjusting the dose according to lean body mass (LBM) could reduce the side effect of oxaliplatin-induced peripheral neuropathy, which is a significant issue in this setting. The study specifically looked at patients with reduced lean body mass, often seen after surgery, and compared the effects of the traditional BSA-based method with the LBM-adjusted dosing. The study’s primary endpoint was the occurrence of peripheral neuropathy three months after the patients completed six cycles of FOLFOX chemotherapy. The findings showed that the LBM-based dosing led to a significant reduction in neuropathy, with a 20-fold decrease in grade 2 neuropathy compared to the traditional method. This reduction in neuropathy persisted over time, even after patients had completed their chemotherapy. Interestingly, patients in the LBM-adjusted arm also received a higher dose intensity of oxaliplatin than those in the BSA group, suggesting that the new method allowed for better chemotherapy delivery while minimising toxic side effects. The study also looked at DFS and OS, though it was not designed to definitively prove non-inferiority in these outcomes. However, no significant difference in survival between the two groups was observed, indicating that adjusting the dose based on lean body mass did not negatively affect treatment efficacy.

Another communication, the SAKK 41/13 trial, focused on the role of aspirin in the adjuvant setting, particularly for patients with colorectal cancer who carry a PIK3CA mutation. This mutation is present in about 15% of patients, and previous retrospective studies have suggested that taking aspirin or COX-2 inhibitors postoperatively, alongside chemotherapy for three years, might provide some benefit to these patients. However, this communication was the first prospective trial to directly assess whether giving aspirin during and after chemotherapy could benefit patients with PIK3CA-mutant tumours. The study was an international collaboration, screening over 1,000 patients and enrolling over 100 into the trial. Unfortunately, the trial was underpowered, making it difficult to draw definitive conclusions. Despite this, the study did report on the included patients, showing a non-significant but clinically meaningful reduction in the risk of relapse for those who took aspirin in the adjuvant setting. The primary endpoint was 3-year DFS. While the results were not statistically significant, the hazard ratio of 0.6 in favour of patients treated with aspirin suggested a numerical reduction in relapse risk. Although the study was underpowered, this trend is intriguing and points to the potential benefit of aspirin. OS was also reported, but the interpretation was challenging, as there appeared to be a short-term detrimental effect on survival, for which there is no clear explanation. This is the first prospective trial to evaluate aspirin in this context, and while it is not practice-changing, it opens the door for further investigation. Other ongoing trials, such as the ASPIC trial, are expected to report results soon, possibly next year. Combining the results from this and future trials could offer more definitive evidence about aspirin’s role in the adjuvant setting for PIK3CA-mutant colorectal cancer patients, potentially leading to more precise clinical guidance.

The NICHE-2 trial, which has already garnered significant attention for its impressive pCR rates, was presented during ESMO 2024  new data on DFS. The trial demonstrated the benefits of a short-duration preoperative treatment regimen consisting of one dose of ipilimumab and two doses of nivolumab over eight weeks. The results were initially groundbreaking, showing a 68% rate of pCR and a 95% rate of MPR. What was communicated at ESMO was even more striking: the study reported a 100% 3-year DFS. While the median follow-up is still relatively short and further confirmation is needed, these early results are auspicious, suggesting an effective pathological response and significant long-term survival benefits. 

Another critical aspect of the NICHE-2 trial is the analysis of ctDNA as a potential biomarker. With such high rates of pathological response, there is growing interest in whether surgery could be spared for some patients. Although all patients in NICHE-2 underwent surgery, the researchers found a strong correlation between ctDNA clearance and pathological response. Specifically, 92% of patients achieved preoperative ctDNA clearance, which is highly associated with a major or complete pathological response. Postoperatively, all patients had cleared ctDNA. This suggests that ctDNA might become a valuable tool for identifying patients who could avoid surgery based on their response to immunotherapy. The findings raise the possibility of moving toward non-operative management in select patients with complete responses, a question that will likely be explored in future studies.

The NICHE-3 trial follows a similar design to NICHE-2 but replaces ipilimumab (anti-CTLA-4) with relatlimab, an anti-LAG-3 antibody, in combination with nivolumab. Like NICHE-2, patients received two monthly doses of relatlimab and nivolumab and were operated on eight weeks after starting treatment. The efficacy outcomes in NICHE-3, including pCR and MPR, are comparable to those seen in NICHE-2. However, the critical difference between the trials is the side effect profiles. NICHE-3 reported a higher incidence of immune-related side effects, particularly grade 3 and 4 toxicities, with a notable increase in cases of endocrinopathies.

The IMHOTEP trial, a multicenter French phase II study, evaluated pembrolizumab in a neoadjuvant setting for colorectal cancer. Patients received one or two pre-operative cycles of pembrolizumab at 400 mg every six weeks. The trial was a basket study, and the results communicated were specific to the colorectal cancer cohort. The trial met its primary endpoint with an impressive 55% of patients achieving a pCR. Interestingly, patients who received two cycles of pembrolizumab showed a higher pCR rate—close to 70%—compared to those who only received one cycle. This suggests that extending the duration of neoadjuvant immunotherapy may enhance efficacy. Regarding safety, immune-related adverse events were as expected, around 13%. However, some post-operative deaths were reported, potentially related to the frailty and age of some participants. This highlights the importance of careful patient selection when considering neoadjuvant immunotherapy, especially in elderly or vulnerable populations.

A key takeaway from the discussion around neoadjuvant immunotherapy is that combining anti-PD-1 or PD-L1 with additional immune checkpoint inhibitors like anti-CTLA-4 or anti-LAG-3 increases pCR rates compared to monotherapy. Additionally, extending the duration of neoadjuvant immunotherapy, as seen in the IMHOTEP trial, further improves pCR rates. Long-term survival data from these trials, particularly the NICHE-2 trial, are eagerly awaited to understand the survival impact of these approaches better.