Magrolimab/Nivolumab Combos Drive Responses in Unresectable Advanced/Recurrent CRC

First-line treatment with magrolimab (ONO-7913) in combination with nivolumab (Opdivo) and FOLFOX (leucovorin, fluorouracil, and oxaliplatin), with bevacizumab (Avastin) or cetuximab (Erbitux), produced responses in patients with unresectable advanced or recurrent colorectal cancer (CRC), according to data from a phase 1 trial (NCT06540261).

Findings presented at the 2025 ESMO Gastrointestinal Cancers Congress showed that no dose-limiting toxicities were reported at the 30-mg/kg dose level of magrolimab. Treatment-emergent adverse effects (TEAEs) did not lead to the discontinuation of all protocol treatment in any patients, and TEAEs did not lead to any deaths. No blood transfusions were required for magrolimab- or nivolumab-related anemia.

At a median follow-up of 17.5 months, patients with RAS-mutant CRC treated with magrolimab, nivolumab, FOLFOX, and bevacizumab in cohort 1 (n = 32) experienced an overall response rate (ORR) of 62.5% (95% CI, 43.7%-78.9%), where best overall responses comprised a complete response (CR) rate of 3.1% (95% CI, 0.1%-16.2%), a partial response (PR) rate of 59.4% (95% CI, 40.6%-76.3%), a stable disease (SD) rate of 37.5% (95% CI, 21.1%-56.3%), and a progressive disease (PD) rate of 0% (95% CI, 0%-10.9%). The disease control rate (DCR) was 100% (95% CI, 89.1%-100%).

In cohort 2 at a median follow-up of 14.7 months, patients with RAS wild-type CRC and left-sided tumors treated with magrolimab, nivolumab, FOLFOX, and cetuximab (n = 32) achieved an ORR of 78.1% (95% CI, 60.0%-90.7%), including CR, PR, SD, and PD rates of 3.1% (95% CI, 0.1-16.2), 75.0% (95% CI, 56.6%-88.5%), 15.6% (95% CI, 5.3%-32.8%), and 3.1% (95% CI, 0.1%-16.2%), respectively. One patient (3.1%) in this cohort was not evaluable for response. The DCR in cohort 2 was 93.8% (95% CI, 79.2%-99.2%).

Magrolimab Background and Phase 1 Trial Design

Magrolimab is a CD47 monoclonal antibody designed to target the CD47-SIRPα and enhance the macrophage phagocytosis of cancer cells.

To evaluate the use of the agent in 2 different combinations, investigators enrolled patients at least 20 years of age with unresectable advanced or recurrent CRC who received no prior systemic therapy in the advanced or recurrent setting. Patients needed to have at least 1 measurable lesion per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and a life expectancy of at least 3 months. Patients with BRAF-mutated CRC or mismatch repair–deficient/microsatellite instability–high disease were excluded.

In cohort 1, patients with RAS-mutant CRC received magrolimab at a priming dose of 1 mg/kg on day 1 of cycle 1, then as a maintenance dose of 30 mg/kg (dose level 1) or 20 mg/kg (dose level 2) given on days 8, 15, and 22 of cycle 1, then days 1 and 15 of subsequent cycles. The recommended dose of magrolimab was then further tested in dose expansion. Patients also received nivolumab at 480 mg once every 4 weeks, FOLFOX, and bevacizumab.

In cohort 2, those with RAS wild-type CRC received the same regimen, with the exception of cetuximab, given instead of bevacizumab.

Safety and tolerability were the trial’s primary end point. Secondary end points comprised ORR, duration of response (DOR), progression-free survival (PFS), and pharmacokinetics.

The median age at baseline was 64.5 years (range, 37-82) in cohort 1 and 58.0 years (range, 22-77) in cohort 2. Most patients were male (cohort 1, 50%; cohort 2, 62.5%), had an ECOG performance status of 0 (93.8%; 93.8%), had primary unresectable disease (93.8%; 93.8%), and had left-sided tumors (71.9%; 100%)

Number of metastatic sites included 1 (cohort 1, 25.0%; cohort 2, 40.6%), 2 (43.8%; 25.0%), 3 (18.8%; 18.8%), and 4 or more (9.4%; 12.5%). Common metastatic sites included liver (68.8%; 68.8%) and lung (59.4%; 34.4%).

Additional Efficacy and Safety Data

Further findings from cohort 1 showed that the median PFS was 11.1 months (95% CI, 7.5-14.9), and the median DOR was 14.5 months (95% CI, 9.2-28.0). The median overall survival (OS) was not applicable (NA; 95% CI, 24.9-NA).

In cohort 2, the median PFS was 14.8 months (95% CI, 9.3-16.6), the median DOR was 14.6 months (95% CI, 7.3-NA), and the median OS was NA (95% CI, 25.8-NA).

Any-grade TEAEs occurred in all patients in both cohorts. The rates of grade 3 or higher TEAEs were 75.0% in both groups. In cohort 1, 28.1% of patients experienced grade 3/4 TEAEs related to magrolimab or nivolumab. This rate was 21.9% in cohort 2.

In cohort 1, TEAEs led to interruption of any study drug in 87.5% of patients and withdrawal of any study drug in 65.6% of patients. These respective rates were 87.5% and 56.3% in cohort 2. Serious TEAEs occurred in 15.6% of patients in both groups, which led to interruption of any study drug in 40.6% of patients in both arms. Serious TEAEs led to the withdrawal of any study drug in 9.4% of patients in cohort 1 and 15.6% of patients in cohort 2.

The most common TEAEs related to magrolimab or nivolumab reported in at least 10% of patients included pyrexia (cohort 1, 46.9%; cohort 2, 37.5%), anemia (43.8%; 21.9%), headache (21.9%; 15.6%), malaise (15.6%; 9.4%), diarrhea (12.5%; 9.4%), increased lipase levels (12.5%; 21.9%), nausea (12.5%; 12.5%), increased fibrin D-dimer levels (12.5%; 6.3%), pruritus (12.5%; 6.3%), increased amylase levels (9.4%; 25.0%), decreased neutrophil count (6.3%; 12.5%), red blood cell agglutination (6.3%; 28.1%), and rash (6.3%; 12.5%).

Reference

Yamaguchi K, Takashima A, Boku S, et al. Phase I study of magrolimab (ONO-7913) and nivolumab (ONO-4538, NIV) in combination with FOLFOX and bevacizumab (Bev) or cetuximab (Cet) as first-line treatment in patients with unresectable advanced or recurrent colorectal cancer (CRC). Presented at: 2025 ESMO Gastrointestinal Cancers Symposium; July 2-5, 2025; Barcelona, Spain. Abstract 10P.