New Trials in GI Cancers: Could Your Patient Benefit?

Several new clinical studies on non-colorectal gastrointestinal cancers have started recruiting. Maybe one of your patients might benefit from enrolling?

Unresectable hepatocellular carcinoma. Adult patients with this type of liver cancer who have not received any systemic treatment may be interested in an open-label, single-group phase 2 study testing a sequence of proven therapies. Patients in the study will undergo transarterial radioembolization with TheraSphere, followed by intravenous (IV) bevacizumab (Avastin, Alymsys, Mvasi, Zirabev) monotherapy, then a combination of bevacizumab and IV durvalumab (Imfinzi).

TheraSphere is a highly targeted radiation treatment approved by the US Food and Drug Administration that delivers radioactive yttrium-90 microspheres directly to the liver. Bevacizumab, an antiangiogenic drug, is indicated in the United States for first-line treatment of unresectable/metastatic liver cancer in combination with atezolizumab (Tecentriq). Durvalumab is a programmed death ligand 1 inhibitor immunotherapy approved in Europe, although not yet in the United States, for the same indication.

Study centers across Colorado, Florida, Missouri, New Jersey, New York, North Carolina, Ohio, Pennsylvania, and Wisconsin started recruiting for the trial’s 100 participants in February 2024. Sites in Georgia, Massachusetts, Michigan, Oregon, Virginia, and Washington are also planned. Progression-free survival over approximately 3 years is the primary outcome measure. Overall survival is a secondary measure, and quality of life (QoL) won’t be measured. More details at clinicaltrials.gov

When asked about this trial, John Marshall, MD, chief of the Division of Hematology-Oncology at Georgetown University and clinical director of oncology for Georgetown University Hospital, Washington, DC, said that although the approach was not new, “[it] might help a bit.”

Previously treated, locally advanced unresectable/metastatic gastric, esophageal, pancreatic, or gastroesophageal junction cancer. Adults with one of these cancers who will not be receiving radiation are sought for an open-label, single-group “proof-of-concept” phase 2 study testing an experimental antibody-drug conjugate called patritumab deruxtecan (HER3-DXd). The two-in-one conjugate consists of patritumab, a monoclonal antibody to HER3 — a receptor tyrosine kinase found on many epidermal growth factor receptor-mutated tumor cells — bonded to a cytotoxic payload of DXd, a topoisomerase I inhibitor that disrupts DNA replication. For up to approximately 27 months, participants in the trial will receive an IV infusion of HER3-DXd every 3 weeks. The study opened in February 2024 in California, Missouri, Tennessee, Texas, Taiwan, and Japan looking for 400 participants with one of several solid cancers. The objective response rate is the primary outcome. Overall survival is the secondary outcome, and the researchers will not track QoL. More details at clinicaltrials.gov

Marshall viewed the study as, “A little new.”

Previously treated advanced or metastatic gastric or gastroesophageal junction cancer expressing claudin 18.2. People in this clinical situation can join a randomized, controlled phase 3 trial of another antibody-drug conjugate, this time targeting membrane protein claudin 18.2, to see if the therapy (AZD0901) slows the progression of the disease and improves survival. Claudin 18.2 is frequently overexpressed on the surface of gastric tumor cells and thus acts as a biomarker for potential new treatments for this type of cancer, which typically has a poor outcome. The study will also evaluate an assay called Ventana CLDN18.2 that will be used to test future patients for the presence of tumors that express claudin 18.2, making them eligible for therapy with AZD0901.

Participants will be assigned to one of three groups and treated for up to approximately 3 years. The two experimental groups will receive differing doses of AZD0901 by IV infusion. Individuals in the active comparator group will be treated with the investigator’s choice of local standard-of-care chemotherapy or targeted therapy.

Sites in China, Taiwan, and Japan opened their doors in March 2024 seeking the first of 589 participants. They will soon be joined by other research centers across Asia, Canada, Europe, the United Kingdom, 15 US states, and the District of Columbia. Progression-free survival and overall survival in participants who received two or more previous lines of therapy are the primary outcomes. Overall survival is a secondary measure, and QoL is not being assessed. More details at clinicaltrials.gov

Marshall said that current treatment for gastric cancer is “slow to evolve,” but this trial could change the standard of care eventually.

Advanced and unresectable or metastatic gastric, esophageal, or gastroesophageal carcinoma. Adults with one of these types of cancer who have tried at least two prior chemotherapy and/or immunotherapy regimens may be eligible for a randomized, open-label phase 3 trial determining whether the antibody-drug conjugate sacituzumab tirumotecan is better than “physician’s choice” at improving survival. Sacituzumab tirumotecan homes in on trophoblast cell surface antigen 2 (TROP2), a transmembrane glycoprotein that is highly expressed in gastrointestinal tumors and predictive of aggressive disease. Once attached to TROP2, the conjugate discharges its toxic payload: A topoisomerase I inhibitor that crosses the cell membrane and disrupts DNA replication.

One group of people in the study will receive an IV infusion of sacituzumab tirumotecan every 2 weeks for up to approximately 4 years. The other individuals will get a physician’s choice of standard chemotherapy, such as oral trifluridine-tipiracil, or an IV drug, such as irinotecan, paclitaxel, or docetaxel. Sites in Georgia, Tennessee, Israel, South Korea, and Taiwan started recruiting 450 participants in May 2024. The primary outcome is overall survival, and QoL won’t be measured. More details at clinicaltrials.gov

This approach could work and “maybe” change the standard of care, said Marshall, although the idea was “not new,” he added.

Advanced and unresectable or metastatic pancreatic cancer. Individuals facing one of these scenarios may be eligible to participate in a randomized, open-label, controlled phase 2b/3 trial to see whether adding an investigational treatment called trabedersen (OT-101) to modified chemotherapy improves survival. Trabedersen blocks the transforming growth factor (TGF) beta receptor 2, preventing the production of a cytokine called TGF-beta 2 that is often overexpressed in cancer and is implicated in the growth, progression, and migration of tumor cells. Every 2 weeks for up to 2.5 years, all participants will receive chemotherapy with a modified regimen of FOLFIRINOX (folinic acid, 5-FU, irinotecan, oxaliplatin). One group will also be treated with IV trabedersen on days 4-7 of the 2-week cycle.

The Karmanos Cancer Center in Detroit, opened its doors to the first of the study’s 455 participants in May 2024. Overall survival is a primary outcome; QoL is not measured. More details at clinicaltrials.gov

Marshall felt that the combination of modified FOLFIRINOX and trabedersen was “unlikely to work” or change the standard of care.

Unresectable, locally advanced or metastatic hepatocellular carcinoma with Child-Pugh B7 or B8 cirrhosis. Adults with this diagnosis who have not received systemic treatment for this stage of their disease can join a nonrandomized, open-label phase 2 trial examining how the antiangiogenic drug bevacizumab plus immunotherapy atezolizumab (Tecentriq) performs in patients with moderately severe cirrhosis. The combination is already approved in the United States for first-line treatment of unresectable or metastatic liver cancer. For up to approximately 3 years, or until unacceptable toxicity or loss of clinical benefit, whichever happens first, one group of participants will receive IV atezolizumab plus bevacizumab every 3 weeks. The other people will receive atezolizumab alone, on the same schedule. Centers in 13 states and Puerto Rico began welcoming the planned 120 participants in May 2024. The primary outcome is the percentage of patients with adverse events; overall survival over approximately 3 years and QoL are secondary outcomes. More details at clinicaltrials.gov

All trial information is from the National Institutes of Health and the US National Library of Medicine (online at clinicaltrials.gov).

Marshall is a Medscape Medical News contributor and was not involved in any of these trials.