Report from the 2025 ASCO Gastrointestinal Cancers Symposium

NEJM Group was on hand to cover the 2025 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, held January 23 to 25 in San Francisco. Here, NEJM Journal Watch Oncology and Hematology Associate Editor Dr. David Ilson reviews key trials. Abstracts are available in the meeting proceedings.

In patients with unresectable or metastatic colorectal cancer and microsatellite instability–high or mismatch repair–deficient (MSI-H/dMMR) status, treatment with nivolumab plus ipilimumab improves progression-free survival (PFS) compared with nivolumab alone, according to findings from the industry-supported, phase 3, open-label CheckMate 8HW study (abstract LBA143).

Roughly 700 immunotherapy-naive patients were randomized to receive nivolumab plus ipilimumab or nivolumab alone for a maximum of 2 years. Approximately half the participants were treated in the first-line setting.

Among patients with centrally confirmed MSI-H/dMMR status, PFS was significantly improved with nivolumab plus ipilimumab compared with nivolumab alone over a median follow-up of 47 months (hazard ratio, 0.62). In particular, the PFS rate at 12 months was 76% with nivolumab plus ipilimumab versus 63% with nivolumab alone; at 36 months, the rate was 68% versus 51%, respectively.

No new safety concerns emerged. Among all treated patients, grade 3–4 adverse events leading to treatment discontinuation occurred in 9% of those receiving nivolumab plus ipilimumab and 4% of those receiving nivolumab alone.

Summary by Amy Herman, Staff Editor

COMMENT — Dr. David Ilson

These updated results from CheckMate 8HW indicate superiority for dual targeted immunotherapy over single-agent therapy as first-line treatment in MSI-H metastatic colorectal cancer. The concern about early disease progression on single-agent therapy appears to be overcome by upfront use of combination therapy, and this regimen should be considered a standard-of-care first-line option.

Encorafenib plus cetuximab had strong results as a first-line treatment for BRAF V600E–mutant metastatic colorectal cancer in BREAKWATER, an open-label, phase 3, industry-sponsored trial (abstract 16).

Roughly 480 patients with untreated measurable disease and Eastern Cooperative Oncology Group performance status of 0–1 were randomized to receive either encorafenib–cetuximab plus chemotherapy (oxaliplatin, leucovorin, and 5-F) or standard-of-care treatment (chemotherapy with or without bevacizumab). Among the first 110 patients randomized, the encorafenib–cetuximab group had a significantly higher objective response rate, a coprimary endpoint, than the standard-of-care group (60.9% vs. 40.0%).

Data on overall survival, a key secondary endpoint, were immature but supported a sustained survival benefit with encorafenib–cetuximab. Safety outcomes were as expected, with serious adverse events in 37.7% of the encorafenib–cetuximab group and 34.6% of the standard-of-care group.

Summary by Christine Sadlowski, Staff Editor

COMMENT — Dr. David Ilson

Findings from BREAKWATER indicate that adding encorafenib and cetuximab to first-line treatment of BRAF V600E–mutant metastatic colorectal cancer results in significant enhancements in response and duration of response and a substantial trend toward improved overall survival. First-line encorafenib and cetuximab added to chemotherapy in these patients is the new standard of care.

For patients with unresectable or recurrent gastroenteropancreatic neuroendocrine tumors (GEP-NETs), everolimus plus lanreotide leads to longer progression-free survival (PFS) than everolimus monotherapy, according to the open-label, phase 3 STARTER-NET trial (abstract 652).

Nearly 200 adults with grade 1/2, unresectable or recurrent, nonfunctioning GEP-NETs with poor prognosis were randomized to receive oral everolimus (10 mg per day) plus injectable lanreotide (120 mg every 28 days) or everolimus alone, as a first-line treatment.

The study was terminated early after an interim analysis found that median PFS, the primary endpoint, was significantly longer with everolimus–lanreotide than with everolimus monotherapy (30 months vs. 12 months). There was no significant difference in overall survival — the key secondary endpoint.

Patients taking the combination therapy tended to have more hematologic and nonhematologic adverse events, but the authors note that overall the safety profile was “manageable.”

Summary by Kelly Young, Staff Editor

COMMENT — Dr. David Ilson

This study indicates that single-agent everolimus was inferior to the combination of everolimus plus lanreotide, and it should not be used as initial therapy in this disease setting. However, for patients even with nonfunctional tumors, as long as they demonstrate avidity on positron emission tomography (PET) dotatate imaging, the first line of therapy should be lanreotide or octreotide. Missing from this trial is a treatment arm with lanreotide alone, and the contribution of everolimus added to lanreotide cannot be established from this trial.

The addition of evorpacept, a CD47 myeloid checkpoint inhibitor, to standard therapy shows promise in patients with advanced HER2-overexpressing gastric/gastroesophageal cancer, according to new phase 2 findings from the industry-funded, open-label ASPEN-06 trial (abstract 332).

Nearly 130 patients with HER2-positive advanced or metastatic gastric/gastroesophageal cancer that had progressed on or after prior anti-HER2 therapy were randomized to receive evorpacept (30 mg/kg once every 2 weeks) plus standard trastuzumab, ramucirumab, and paclitaxel (TRP) or TRP alone.

The overall response rate (ORR) was 40.3% in the evorpacept–TRP group and 26.6% in the TRP-alone group. The ORR with evorpacept–TRP did not show significant improvement compared with a historical reference rate of 30% (based on treatment with ramucirumab and paclitaxel). However, in an exploratory analysis, the 13.7-percentage-point difference in ORR between evorpacept–TRP and TRP alone was considered clinically meaningful.

Evorpacept–TRP showed a higher ORR (54.8%) in a subgroup of 48 patients with HER2-positive disease in fresh tumor tissues after prior anti-HER2 treatment.

Summary by Christine Judge, Staff Editor

COMMENT — Dr. David Ilson

The results of evorpacept added to second- or third-line paclitaxel/ramucirumab in patients with HER2-positive cancer progressing on trastuzumab are intriguing and require further study in a phase 3 trial. The rationale to continue trastuzumab after progression was not clearly explained given extant data suggesting no benefit of this strategy.