BI 836880/Ezabenlimab Combo Had Limited Antitumor Activity, But Manageable Safety in Advanced MSS CRC

The VEGF/Ang2–targeting bispecific nanobody BI 836880, in combination with ezabenlimab (BI 754091), produced antitumor activity found to be comparable to that of available third-line therapy options in patients with advanced microsatellite stable (MSS) colorectal cancer (CRC), according to data from a subset of patients within module C of a phase 2 trial (NCT03697304).¹

Results, which were presented during the 2022 Gastrointestinal Cancers Symposium, showed an objective response rate (ORR) of 7% among 30 patients, which was comprised of partial responses (PRs). Both PRs were observed in patients who had no prior treatment with bevacizumab (Avastin). At the time of data cutoff, 50% of patients had stable disease, and 37% experienced disease progression.

“BI 836880 plus ezabenlimab had a manageable safety profile in patients with advanced MSS CRC,” Susanna Ulahannan, MD, MMEd, study author, assistant professor in the Section of Hematology/Oncology, and associate director of the Oklahoma TSET Phase I Program, Stephenson Cancer Center, The University of Oklahoma, said in a poster presentation on the data. “However, antitumor activity was limited in these patients, the majority of whom had received prior bevacizumab.”

Preclinical data have suggested that anti–PD-1 antibodies may have synergistic effects with other immunomodulatory or targeted agents. The combination of VEGF and Ang2 has been shown to have an immunosuppressive effect in the tumor microenvironment, creating the rationale to combine anti-VEGF/Ang2 with anti­­­­­–PD-1 therapy.² The combination of BI 836880 and ezabenlimab demonstrated preliminary antitumor activity in an ongoing phase 1b trial (NCT03468426).³

The open-label phase 2 trial investigated ezabenlimab in combination with other agents, and module C specifically examined BI 836880 plus ezabenlimab. The data presented during the meeting were from a cohort of patients with MSS CRC within module C. Other solid tumor cohorts in the trial included: gastric/gastroesophageal adenocarcinoma, solid tumors (except nonsquamous non–small cell lung cancer or melanoma) with secondary resistance to anti–PD-L1 treatment, solid tumors with primary resistance to anti–PD-L1 treatment, and mismatch repair–proficient/MSS endometrial carcinoma.

The MSS CRC cohort enrolled patients who were at least 18 years of age who had locally advanced, unresectable or metastatic MSS CRC. To be eligible for enrollment, patients needed to have at least 1 measurable lesion per RECIST v1.1 criteria, have received at least 1 line of prior systemic therapy in the metastatic setting, have a life expectancy of at least 12 week, and an ECOG performance status of 0 or 1. Patients could not have previously received anti–PD-1 therapy, but previous antiangiogenic therapy was permitted.

Patients in this cohort were administered intravenous ezabenlimab at 240 mg and BI 836880 at 720 mg every 3 weeks for 1 year or until disease progression, withdrawn consent, or unacceptable toxicity.

The primary end point of the study was investigator-assessed ORR per RECIST v1.1 criteria, and key secondary end points included duration of response, disease control, and progression-free survival.

Patients enrolled to the MSS CRC cohort had a median age of 61.5 years, and 57% were male. All 30 patients underwent prior chemotherapy, and the median number of prior lines of chemotherapy received was 4 (range, 1-10). Additionally, 77% received prior treatment with bevacizumab, and 43% received prior radiotherapy.

Of the 30 patients treated, 4 remained on treatment at the time of data cutoff, which was November 1, 2021. The median duration of treatment was 115.5 days (range, 28-354).

Additional data showed that among the 2 patients who achieved PRs to treatment, the duration of their responses was 85 and 122 days, respectively. One of these patients is still receiving treatment with the combination. Among the 15 patients who achieved stable disease, the median duration was 126 days (range, 42-299).

Among those who did not receive prior bevacizumab (n = 7), 2 patients achieved PRs, 1 had stable disease, 3 had progressive disease, and 1 was not evaluable. No patients with prior bevacizumab exposure (n = 23) experienced a PR with the combination, although 14 patients had stable disease, 8 experienced disease progression, and 1 was not evaluable.

Only 1 patient received the combination as a second-line therapy, and that patient was not evaluable at data cutoff. In the subset of patients who received the doublet as third-line therapy (n = 8), 1 experienced a PR, 2 patients achieved stable disease, 4 had progressive disease, and 1 was not evaluable. Among those who received the combination as fourth-line or later therapy (n = 21), 1 had a PR, 13 had stable disease, and 7 experienced disease progression.

In terms of safety, 97% of patients experienced at least 1 adverse effect (AE) with the doublet. Grade 3 toxicities were experienced by 57% of patients, and 7% experienced a grade 4 AE. Notably, no grade 5 toxicities were reported. Eighty percent of patients experienced a treatment-related AE, and 20% experienced an immune-related AE. Serious AEs were observed in 43% of patients who received the combination.

The most common AEs of any grade included nausea (40%), peripheral edema (33%), fatigue (30%), hypertension (27%), vomiting (27%), and hypothyroidism (20%). Notably, 3 patients experienced AEs that resulted in treatment discontinuation; 1 patient had grade 4 thrombocytopenia, another had grade 3 bile duct stone, and the third had grade 2 peripheral edema. Three patients had infusion-related reactions that were either grade 1 (n = 1) or grade 2 (n = 2).

References

1. Ulahannan SV, Percent IJ, Arrowsmith E, et al. Ezabenlimab (BI 754091), an anti-PD-1 antibody, in combination with BI 836880, a VEGF/Ang2-blocking nanobody, in patients (pts) with advanced colorectal cancer (CRC). J Clin Oncol. 2022;40(suppl 4):98. doi:10.1200/JCO.2022.40.4_suppl.098
2. Fukumura D, Kloepper J, Amoozgar Z, et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15(5):325-340. doi:10.1038/nrclinonc.2018.29
3. Girard N, Wermke, Barlesi F, et al. Phase 1b study of BI 836880, a VEGF/Ang2-blocking nanobody, in combination with BI 754091, an anti–PD-1 antibody: initial results in patients (pts) with advanced non–small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9566-9566. doi:10.1200/JCO.2020.38.15_suppl.9566