The ESMO 2024 conference is set to present groundbreaking data in the realm of Gastrointestinal cancers, with a focus on gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, colorectal cancer, pancreatic cancer, and neuroendocrine tumors.

Colorectal cancer takes center stage at the conference, with the majority of abstracts focused on this area. This year’s ESMO meeting is highly anticipated for the introduction of new therapeutic classes and the release of data on innovative molecules in colorectal cancer space, including Innovent Biologics’ Phase I first-in-class PD-1/IL-2 bispecific antibody fusion protein (IBI363) for advanced colorectal cancer, Merck/Inspirna’s Phase I/II SLC6A8 inhibitor (ompenaclid) in RAS mutated mCRC, and NextCure’s  Phase I/II LAIR-2 Fc protein (NC410) in MSS/MSI-L colorectal cancer patients. Pfizer and Amgen are also presenting updates on their treatments for mutation-specific colorectal cancer, focusing on BRAF and KRAS mutations, respectively.

Within, gastric or gastroesophageal junction adenocarcinoma, Keymed Biosciences and AstraZeneca are revealing data on their ADC molecules, SHR-A1904 (CLDN18.2 targeted ADC) and Trastuzumab deruxtecan (HER2 targeted ADC), respectively. Merck’s KEYNOTE-811 final overall survival results is a much-awaited abstract. 

Pancreatic cancer will see fresh insights from early-stage players like Immuneering Corporation and FutureGen Biopharmaceutical with their first-in-class drugs, IMM-1-104 and FG-M108, respectively, in patients with unresectable or metastatic pancreatic cancer. 

In addition, Exelixis is poised to disclose the final results from the Phase III pivotal CABINET trial in neuroendocrine tumors. 

Unveiling the latest in Gastrointestinal Cancers treatment landscape

• Abstract Number – 1141O
• Abstract Type – Proffered paper session
• Indication - Neuroendocrine Tumors (NET)

Title: Exelixis’s Cabozantinib's Progression-Free Survival Gains Set the Stage for New Treatment Era in NET

Executive Summary: Exelixis’s CABOMETYX shows promising potential in treating advanced neuroendocrine tumors, with CABINET pivotal trial results demonstrating significant progression-free survival benefits.

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As per DelveInsight, there were approximately 29,500 cases of Neuroendocrine Tumors (NET) in the United States, in 2023. It has been observed that gastrointestinal NET are the most common type accounting for approximately. 60% of NET diagnoses, whereas 25% are Lung NET, 7% are PNET.  The current NET treatment landscape is dominated by first-line therapies such as somatostatin analogs (octreotide, lanreotide), with targeted therapies like everolimus and sunitinib representing the next options in line. However, once patients progress on these agents, treatment options are limited, creating a significant unmet need for therapies that can extend PFS and provide meaningful clinical benefits.

Exelixis’s CABOMETYX (cabozantinib), a multi-targeted tyrosine kinase inhibitor (TKI) with activity against VEGFR, MET, and AXL, might have the potential to fill this gap, as the drug has already shown efficacy in other tumor types like renal cell carcinoma and hepatocellular carcinoma, making its role in neuroendocrine tumors highly anticipated. The drug is currently being evaluated in a Phase III CABINET trial in patients with advanced neuroendocrine tumors (NET) who have progressed on prior therapies. In July, Ipsen opted into this Phase III CABINET trial, expanding the collaboration and license agreement with Exelixis and permitting Ipsen to seek potential marketing authorizations for CABOMETYX in advanced pNET and epNET from regulatory authorities outside of the US and Japan. The decision to expand the existing agreement was based on detailed results from the CABINET trial, which were first presented at the ESMO Congress 2023.

As previously announced, CABINET was stopped early due to a dramatic improvement in progression-free survival (PFS) observed at an interim analysis in both cohorts. The study demonstrated a statistically significant and clinically meaningful improvement in PFS with cabozantinib versus placebo. At ESMO 2024, updated results from this Phase III study will be presented, with a focus on progression-free survival (PFS) as evaluated by Blinded Independent Central Review (BICR) and further insights into key subgroup analyses. 

Exelixis recently revealed that the FDA has accepted its supplemental New Drug Application (sNDA) for cabozantinib, targeting patients with previously treated advanced pancreatic and extra-pancreatic neuroendocrine tumors. The FDA has set a standard review timeline, with a PDUFA target action date of April 3, 2025, marking a key milestone in potentially expanding cabozantinib's reach in treating these challenging cancers.

• Abstract Number – 575P
• Abstract Type – Poster 
• Indication - Advanced/metastatic colorectal cancer (mCRC)

Title:  Inspirna’s First-in-class SLC6A8 Inhibitor, Ompenaclid’s Promise in Combating RAS-Mutated Advanced CRC

Executive Summary: Ompenaclid, a novel oral SLC6A8 inhibitor, shows promise in enhancing efficacy in RAS-mutated advanced mCRC when combined with FOLFIRI and bevacizumab, potentially transforming second-line treatment options, with updated results expected at the upcoming ESMO 2024.

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RAS mutations, prevalent in approximately 45% of CRC patients, have posed a challenge in clinical settings due to their association with resistance to EGFR inhibitors, making treatment options for these patients more limited. There is a high unmet need for a safe and effective pan-RASm treatment in the advanced or metastatic CRC setting. The RASmt mCRC treatment space is mainly dominated by chemotherapy regimens and VEGF inhibitors, with limited targeted therapies beyond the second line. Ompenaclid, a first-in-class oral inhibitor of the creatine transport channel SLC6A8, targeting a previously untapped metabolic pathway, positions it as a potential game-changer in this niche but highly challenging market.

The drug is being evaluated in a Phase Ib/II study in combination with FOLFIRI and bevacizumab in RAS-mutated advanced or metastatic CRC. Early data from the trial, also previously presented at the ESMO 2023 conference, have shown encouraging signals, with the combination demonstrating manageable safety profiles and promising efficacy markers, including objective response rates (ORR) and progression-free survival (PFS). Inspirna is expected to present the updated results from this trial at the ESMO 2024, which will likely delve deeper into the efficacy data, demonstrating the potential of ompenaclid to improve on the standard of care for advanced CRC. The competitive landscape will likely intensify, but ompenaclid’s distinct MoA offers a competitive edge that could drive its adoption in the second-line mCRC setting.

• Abstract Number – 1400O
• Abstract Type – Proffered paper session 
• Indication - HER2+ advanced, unresectable or metastatic G/GEJ adenocarcinoma

Title:  Merck’s KEYNOTE-811 Trial Final Overall Survival Results Poised to Impact HER2+ G/GEJ Cancer Treatment

Executive Summary: Merck is set to reveal the final overall survival results from the Phase III KEYNOTE-811 trial at ESMO 2024, highlighting pembrolizumab's efficacy with trastuzumab and chemotherapy in HER2-positive advanced gastric/gastroesophageal junction cancer

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Merck is set to present the highly anticipated final overall survival results from the Phase III KEYNOTE-811 trial at ESMO 2024, shedding light on the efficacy of combining pembrolizumab with trastuzumab and chemotherapy as first-line treatment in HER2-positive advanced, unresectable, or metastatic gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. 

Based on findings from the Phase III KEYNOTE-811 interim analysis of objective response rate (ORR) and duration of response (DOR), the combination received accelerated approval from the FDA in May 2021 for use in patients with locally advanced unresectable or metastatic HER2-positive G/GEJ cancer regardless of PD-L1 expression. 

The co-primary endpoints of the trial were overall survival (OS) and progression-free survival (PFS). In June 2023, Merck announced that the trial had met one of the primary endpoints, demonstrating a statistically significant improvement in PFS with the addition of pembrolizumab. However, the benefit was limited to patients with PD-L1–positive tumors. These results were previously presented at the ESMO 2023, further strengthening the combination regimen as a potentially new standard of care. 

Recently in May 2024, Merck announced that in the final analysis of this trial, KEYTRUDA in combination with trastuzumab and chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS compared to placebo in combination with trastuzumab and chemotherapy in the intention-to-treat (ITT) study population, with the greatest benefit observed in patients whose tumors expressed PD-L1 (CPS ≥1). These final overall survival results from the KEYNOTE-811 study are scheduled to be presented at ESMO 2024, with outcomes expected to influence potential full approval and reshape treatment standards in this challenging cancer landscape. Existing HER2+ therapies include trastuzumab and combinations with chemotherapy. 

Top 10 Key Abstracts for Gastrointestinal cancers