The 2025 ASCO Gastrointestinal Cancers Symposium once again delivered a slate of high-impact studies spanning esophageal, gastric, hepatocellular, pancreatic, biliary tract, and colorectal malignancies. Experts in the field offered fresh perspectives on evolving standards of care, and investigators shared cutting-edge results that promise to shape future treatment strategies.
In addition to The ASCO Post’s comprehensive coverage of landmark trials and plenary sessions, we spotlight here four noteworthy studies, each shedding new light on emerging therapeutic approaches for patients with advanced gastric, hepatocellular, and colorectal cancers.
Evorpacept Combination in HER2-Positive Gastric Cancer
Adding the CD47 blocker evorpacept to trastuzumab, ramucirumab, and paclitaxel (TRP) significantly increased the objective response rate from 26.6% to 41.3% among patients with second- or third-line HER2-positive gastric or gastroesophageal junction cancer. A pronounced benefit was seen in those who maintained strong HER2 expression.1
“Although evorpacept plus TRP did not significantly exceed the historical 30% objective response rate threshold, the 14.7% difference between the two arms suggested a meaningful component contribution from evorpacept,” said lead study author, Kohei Shitara, MD, Director of the Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Japan.
Kohei Shitara, MD
In the phase II portion of the ASPEN-06 study, a total of 127 patients with HER2-positive gastric and gastroesophageal junction cancers were randomly assigned to receive evorpacept plus TRP or TRP alone. All participants had experienced disease progression on at least one prior anti-HER2 therapy, with approximately 60% receiving second-line treatment.
Median duration of response was longer with evorpacept plus TRP—15.7 months vs 9.1 months. Progression-free survival medians were similar, but evorpacept plus TRP demonstrated a favorable hazard ratio (HR) of 0.77, indicating a potential progression-free survival benefit beyond the median time point, he said.
Of note, subgroup analyses revealed that patients who retained HER2 positivity on a fresh biopsy—performed in about 40% of participants—derived particular benefit from evorpacept. In this subset, the objective response rate reached 59% with evorpacept plus TRP vs 23% with TRP alone.
Similar enrichment occurred when combining data on fresh biopsy HER2 status with circulating tumor DNA (ctDNA)-based HER2 amplification (detected in approximately 65% of patients), yielding response rates up to 49% in the group given evorpacept plus TRP (HR = 0.62–0.64).
Toxicity profiles between the two arms were generally comparable. Neutropenia and anemia were slightly higher with evorpacept plus TRP, but differences remained under 10%, and the rate of febrile neutropenia did not increase. One treatment-related death was reported in each arm.
“Overall, these findings highlight the potential of evorpacept to enhance trastuzumab-based therapy for patients with HER2-positive gastric/gastroesophageal junction tumors, particularly in those who maintain strong HER2 expression as confirmed by a fresh biopsy or ctDNA analysis,” Dr. Shitara concluded. “The phase II data underscore evorpacept’s acceptable safety and support its continued development in this setting, with the aim of improving outcomes in a historically challenging disease population.”
TACE Plus Camrelizumab and Rivoceranib in Unresectable Liver Cancer
Combining transarterial chemoembolization (TACE) with the monoclonal anti–PD-1 antibody camrelizumab and the small-molecule tyrosine kinase inhibitor rivoceranib more than tripled progression-free survival vs TACE alone in unresectable hepatocellular carcinoma.2
The open-label, randomized, phase II CARES-005 study enrolled 200 patients with advanced disease, many of whom had a high tumor burden or vascular invasion (Vp3/Vp4 portal vein thrombus). Participants were randomly assigned equally to receive TACE plus camrelizumab and rivoceranib or TACE alone.
At data cutoff, Gao-Jun Teng, MD, of Zhongda Hospital, Southeast University, Nanjing, China, reported a median progression-free survival of 10.8 months in the combination arm, significantly longer than the 3.2 months observed with TACE alone (HR = 0.34; P < .0001).
Gao-Jun Teng, MD
Although overall survival data remain immature—fewer than half the required overall survival events had occurred—an early trend seemed to favor TACE plus camrelizumab and rivoceranib, with a median overall survival of 24.0 months vs 21.5 months with TACE alone. However, Dr. Teng noted, continued follow-up is required to confirm any potential overall survival benefit.
Regarding secondary endpoints, objective tumor response rates were higher in the combination arm, reaching approximately 61% to 65% by different radiologic criteria, vs lower rates with TACE alone. Disease control rates likewise improved with TACE plus camrelizumab and rivoceranib.
Subgroup analyses across Barcelona Clinic Liver Cancer stages showed a consistent advantage in progression-free survival for the combination therapy, underscoring its potential for broad applicability in intermediate- and advanced-stage disease settings.
Safety findings indicated that grade ≥ 3 adverse events were more common with TACE plus camrelizumab and rivoceranib (74%) than with TACE alone (22%). However, these events were described as manageable and consistent with known profiles of TACE, camrelizumab, and rivoceranib in advanced hepatocellular carcinoma. The most frequent toxicities included hepatic enzyme elevation and abdominal pain, with no new safety signals emerging.
“TACE combined with immunotherapy and targeted therapy appears to offer an effective new option for patients with unresectable hepatocellular carcinoma, potentially filling an unmet need in later-stage disease and aligning with other trials that also support a role for combination strategies in hepatocellular carcinoma,” Dr. Teng concluded.
Single-Cycle Pembrolizumab in Localized dMMR Colorectal Cancer
A single cycle of high-dose pembrolizumab (a PD-1 inhibitor) produced a 44% pathologic complete response rate in localized mismatch repair–deficient (dMMR) colon cancer, suggesting a more abbreviated immunotherapy regimen may maintain high efficacy while potentially reducing toxicity.3
In the RESET-C study, Camilla Qvortrup, MD, PhD, Clinical Associate Professor, Copenhagen University Hospital-Rigshospitalet, and colleagues investigated the efficacy and safety of a single-cycle, double-dose strategy of neoadjuvant pembrolizumab (one cycle of pembrolizumab at 4 mg/kg [maximum 400 mg]) in patients with localized dMMR colon cancer. Motivated by the growing body of evidence showing responses to neoadjuvant checkpoint inhibition—often involving longer treatment courses or combination regimens—the investigators sought to assess whether a shorter, single-agent approach might offer comparable benefits while minimizing toxicity and costs.
From February 2022 to early 2023, 85 patients with stage I to III dMMR colon cancer were enrolled. Of them, 84 proceeded to surgical resection and were included in the efficacy analysis. The treatment protocol entailed one cycle of double-dose pembrolizumab, followed by restaging with a computed tomography scan and colonoscopy (including rebiopsies) within 3 to 5 weeks prior to surgery. Blood samples were also collected for future ctDNA analysis at baseline, restaging, and after surgery.
Overall, 44% of patients achieved a pathologic complete response, and 57% attained a major pathologic response. Of note, response varied by clinical stage: those with stage I or II disease achieved a pathologic complete response rate of 61%, compared with 33% for those with stage III disease.
“Despite the shorter immunotherapy interval, these pathologic complete response rates are aligned with or exceed outcomes from earlier, more prolonged regimens in dMMR colorectal cancer,” said Dr. Qvortrup.
Regarding safety, 8% of patients treated with the single-cycle approach experienced grade 3 adverse events, with a small subset (n = 4) having immune-related events such as hepatitis or colitis. No grade 4 or 5 immune-related toxicities were observed, and two postoperative deaths were reported in patients older than age 80; neither one was attributed to immunotherapy. No recurrences have been reported thus far, and no patients have died of disease progression, said Dr. Qvortrup.
Moving forward, the RESET-C team plans to combine endoscopic findings, rebiopsy pathology, and ctDNA results into a standardized response assessment tool. Such a composite strategy may pave the way for organ preservation in patients with colon cancer, similar to evolving approaches in rectal cancer, by identifying those who could forgo radical resection without compromising oncologic outcomes.
Active Surveillance vs Surgery in Rectal Cancer
A watch-and-wait strategy in patients with locally advanced rectal cancer who achieved a complete or near-complete response to total neoadjuvant therapy resulted in similar oncologic outcomes as those treated with total neoadjuvant therapy followed by mandatory total mesorectal excision, according to a pooled analysis of the OPRA and CAO/ARO/AIO-12 trials.4
Presented by Hannah Williams, MD, of Memorial Sloan Kettering Cancer Center, the pooled analysis of the CAO/ARO/AIO-12 and OPRA trials explored survival outcomes among patients with locally advanced rectal cancer treated with total neoadjuvant therapy followed by a selective watch-and-wait strategy (OPRA) or total mesorectal excision (CAO/ARO/AIO-12).
Hannah Williams, MD
As Dr. Williams explained, a watch-and-wait strategy has become an accepted alternative to total mesorectal excision for patients with an excellent response to total neoadjuvant therapy. However, concerns remain about its oncologic safety, particularly among patients with a near-complete response to neoadjuvant treatment who are more likely to experience local tumor regrowth. Although these concerns would be best addressed through a randomized control trial, a head-to-head comparison is impractical because of the potential for patient crossover.
Although there were some differences in baseline tumor characterstics and total neoadjuvant therapy regimens, survival endpoints—disease-free survival, distant recurrence–free survival, local recurrence–free survival, and overall survival—were equivalent between the two trials. The authors also stratified survival based on paired clinical response (complete, near-complete, and incomplete grades; OPRA trial) and pathologic tumor regression (complete, intermediate, and poor grades; CAO/ARO/AIO-12 trial). Oncologic outcomes were similar across each paired tumor response grade.
These findings are particularly notable for the comparison between patients with a near-complete response (OPRA trial) and intermediate tumor regression (CAO/ARO/AIO-12 trial). More than 80% of patients with a near-complete response entered watch-and-wait surveillance in the OPRA trial. Although nearly half of these patients experienced local regrowth, delaying total mesorectal excision did not appear to have any adverse oncologic effects when compared with a similar group of patients who had intermediate tumor regression after surgical resection. The remaining patients with a near-complete response who developed a sustained clinical complete response were able to successfully preserve the rectum.
Dr. Williams emphasized that adding 2.5 more months of systemic chemotherapy in the OPRA trial did not yield improved survival, suggesting there may be opportunities to de-escalate total neoadjuvant therapy regimens. Dr. Williams and colleagues concluded that a selective watch-and-wait strategy is oncologically safe for complete and near-complete responders, allowing for potential organ preservation without detrimental effects on long-term survival. However, “close surveillance remains critical—especially for near-complete responders—as nearly half ultimately develop a sustained clinical complete response, expanding the pool of patients who may successfully avoid major surgery and its associated morbidity,” Dr. Williams said.
DISCLOSURE: Dr. Shitara has received personal fees for consulting and advisory roles from Bristol Myers Squibb, Takeda Pharmaceuticals, Ono Pharmaceutical, Novartis, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Merck, Astellas Pharma, Guardant Health Japan, Janssen, AstraZeneca, Zymeworks Biopharmaceuticals, ALX Oncology, Bayer, GlaxoSmithKline K.K., Healios K.K., Moderna, and Arcus Biosciences; honoraria from Bristol Myers Squibb, Ono Pharmaceutical, Janssen, Eli Lilly, Astellas Pharma, and AstraZeneca; and institutional research funding from Astellas Pharma, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai, Merck, Amgen, Eisai, PRA Health Sciences, Syneos Health, AstraZeneca, PPD-SNBL K.K, and Toray Industries. The CAP-ACE study was funded by Jiangsu Hengrui Pharmaceuticals Co, Ltd. Dr. Qvortrup reported financial relationships with Merck KGaA, Mirati Therapeutics, MSD Oncology, Pfizer, Pierre Fabre, Roche, and Servier. Dr. Teng and Dr. Williams reported no conflicts of interest.
REFERENCES
1. Shitara K, Wainberg Z, Tabernero J, et al: Final analysis of the randomized phase 2 part of the ASPEN-06 study: A phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2-overexpressing gastric/gastroesophageal cancer. 2025 ASCO Gastrointestinal Cancers Symposium. Abstract 332. Presented January 24, 2025.
2. Zhu H, Teng GJ, Fan W, et al: Transarterial chemoembolization (TACE) combined with camrelizumab and apatinib versus TACE alone in the treatment of unresectable hepatocellular carcinoma eligible for embolization: A multicenter, open-label, randomized, phase 2 study (CAP-ACE). 2025 ASCO Gastrointestinal Cancers Symposium. Abstract LBA522. Presented January 24, 2025.
3. Qvortrup C, Justesen T, Tarpgaard L, et al: Single-cycle neoadjuvant pembrolizumab in patients with stage I-III MMR-deficient colon cancer: Final analysis of the RESET-C study. 2025 ASCO Gastrointestinal Cancers Symposium. Abstract 19. Presented January 25, 2025.
4. Williams H, Fokas E, Diefenhardt M, et al: WW vs TME in patients with rectal cancer with a complete or near-complete response to TNT: Pooled analysis of CAO/ARO/AIO-12 and OPRA trials. 2025 ASCO Gastrointestinal Cancers Symposium. Abstract 21. Presented January 25, 2025.
