Checkpoint Inhibitor Combination Well-tolerated, Effective in Ovarian Cancer Patients, Phase 1b Trial Shows

Checkpoint Inhibitor Combination Well-tolerated, Effective in Ovarian Cancer Patients, Phase 1b Trial Shows

A combination of two checkpoint inhibitor therapies, magrolimab (Hu5F9-G4) and Bavencio (avelumab), has an acceptable safety profile, is well-tolerated, and stabilizes disease in more than half of heavily-treated ovarian cancer patients, results from a Phase 1b trial show.

The findings of the trial (NCT03558139) were presented in a poster at the 2020 Clinical Immuno-Oncology Symposium, organized by the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer

The poster was titled “A phase Ib study of the anti-CD47 antibody magrolimab with the PD-L1 inhibitor avelumab (A) in solid tumor (ST) and ovarian cancer (OC) patients.

Macrophages are a type of front-line immune cell that attacks infectious agents and cancer cells. They identify their targets because they lack a protein on the cell surface called CD47.

Normal, healthy cells produce CD47 to tell the macrophages not to attack them. However, nearly all types of cancer cells, including those from ovarian cancer, produce CD47 to hide from macrophage attack, helping the disease to progress.

Forty Seven‘s magrolimab (Hu5F9-G4) is an antibody — called a checkpoint inhibitor — that blocks CD47 on cancer cells, allowing them to be identified and attacked by macrophages.

Magrolimab has shown antitumor activity in combination with other checkpoint-inhibiting antibodies that block the programmed cell death ligand (PD-L1) — a protein that suppresses immune T-cells from attacking cancers in a similar way as CD47. 

One such PD-L1 inhibitor, Bavencio, developed by Merck KGaA (known as EMD Serono in the U.S. and Canada) and Pfizer, is approved for advanced forms of a skin cancer called Merkel cell carcinoma, bladder cancer, and kidney cancer.

The combination therapy of magrolimab and Bavencio is being tested in a two-part Phase 1b trial, conducted by Forty Seven in collaboration with Merck.

The first part included 13 patients with advanced solid tumors who received one of two magrolimab doses — 30 mg/kg or 45 mg/kg — plus a fixed dose of Bavencio. The goal was to evaluate the safety and tolerability of the combination and establish the optimal dose for magrolimab treatment — defined as 45 mg/kg once weekly.

Anemia, a common side effect of CD47-targeting therapies, was mitigated by giving all participants a starting 1 mg/kg dose of magrolimab

The second part was designed to confirm the treatment’s safety and assess the anti-tumor activity of the established dose in 21 ovarian cancer patients who had progressed within six months of platinum-based chemotherapy and had never received checkpoint inhibitors.

The patients ranged in age from 47 to 88 and had received a median of five prior therapies. 

No dose-limiting toxicities were reported in the dose-escalation part, and no severe treatment-related adverse events (TRAEs) were reported in either part of the trial. The most common TRAEs were headaches (62% of patients), fatigue (47%), infusion-related reactions (44%), fever (38%), chills (35%), and nausea (35%).

Treatment discontinuation due to TRAEs occurred in 15% of patients, which was higher than that observed in other magrolimab trials, the researchers reported. 

Anti-tumor activity was observed in two patients. One was an ovarian cancer patient enrolled in the second part who achieved stable disease, and remained on treatment for more than nine months. The second was a patient in the solid tumors group who had a confirmed partial response lasting four months before progression and remained on therapy for more than 13 months. 

In 18 ovarian cancer patients from both groups, 56% had stable disease and 44% progressed. 

An analysis of 13 ovarian cancer biopsies found that two were PD-L1 positive. Of these, the one patient who had PD-L1 specifically on tumor cells was the only patient to show tumor shrinkage. 

Overall, magrolimab plus avelumab is a novel, well-tolerated combination treatment regimen, the scientists said, adding that “additional studies in ovarian cancer should focus on patients who are positive for PD-L1 tumor expression.”