Pepinemab and Avelumab Combination Shows Positive Signs at Interim Analysis for NSCLC

Michael Shafique, MD

Michael Shafique, MD

Pepinemab (VX15/2503) plus avelumab (Bavencio) has shown initial signals of antitumor activity and is well tolerated in patients with advanced non—small cell lung cancer (NSCLC), according to an interim analysis of the CLASSICAL-Lung phase Ib/II clinical trial (NCT03268057) presented at the 2020 American Society of Clinical Oncology-Society for Immunotherapy of Cancer Clinical Immuno-Oncology Symposium in Orlando, Florida.¹

Pepinemab, a first-in-class humanized monoclonal antibody, is an agent that targets and block the signaling activity of semaphorin 4D (SEMA4D), that may result in overcoming resistance mechanisms of immune exclusion and myeloid suppression. When an anti-SEMA4D drug is combined with immunotherapy, it has enhanced T-cell infiltration and activity, and has been shown to result in durable tumor regression in preclinical animal models.^1,2

SEMA4D binds to plexin receptors located on myeloid cells in the tumor microenvironment. When the SEMA4D protein is blocked, it eliminates the SEMA4D barrier. Once the barrier is breached, inflammatory dendritic cells and pro-inflammatory antigen-presenting cells migrate and infiltrate into the tumor.

“For cancer immunotherapy, SEMA4D antibodies do seem to be synergistic with various checkpoint inhibitors,” said Michael Shafique, MD, a medical oncologist at Moffitt Cancer Center in Tampa, Florida, who presented the findings at the meeting.

There were 29 evaluable patients whose tumors progressed during or following immunotherapy (IOF). At the time of the analysis, 2 had confirmed partial responses (PRs) and 15 patients experienced stable disease (SD), leading to a disease control rate of 59%.

In the group of 21 evaluable patients who were immunotherapy-naïve (ION), 5 experienced PR, 3 were observed to have ≥1 year of clinical benefit, and the disease control rate¾PR plus SD¾was 81%.

At data cut off, 79% of patients with PR and SD had negative or low PD-L1.

An analysis of pre- and on-treatment biopsies showed increased CD8+ T-cell density correlating with response, with 10 of 11 tumor biopsies in patients with PR or SD demonstrating this.

For the phase Ib section of the study design, 12 ION patients were treated with escalated doses of pepinemab and 10 mg/kg avelumab every 2 weeks; 3 received 5 mg/kg of pepinemab, 6 received 10 mg/kg, and 3 received 20 mg/kg. In the phase II study design, 32 IOF patients and 18 ION patients were treated by a dose-expansion of 10 mg/kg of pepinemab and 10 mg/kg of avelumab every 2 weeks.

The primary end points of the CLASSICAL-Lung trial are safety, tolerability, and identification of the recommended phase II dose for dose expansion. Secondary end points consist of efficacy, immunogenicity, and pharmacokinetics and pharmacodynamics. There is also an exploratory objective of identifying candidate biomarkers of activity.

The median age of the 62 patients enrolled in the study was 66 years (range, 30-85), with 55% of patients being ≥65 years old. Men made up 60% of the study subjects and 92% of all patients were white. Patients had an ECOG performance status of 0 (24%) or 1 (76%), and all but 1 (98%) had stage IV disease at screening. There were 63% of patients with adenocarcinoma histology, and the rest had squamous cell NSCLC.

Patients’ PD-L1 status by Dako 73-10 pharmDx assay varied in the study. Forty-three percent had 1% to 49% PD-L1 expression and 37% of patients had no PD-L1 expression. Of those with high expression, 18% expressed 50% to 79% PD-L1 and 2% expressed ≥80%. Eleven patients did not have available PD-L1 status.

No major safety signals were identified with the combination, and it was well tolerated among patients at all dose levels in the study thus far. There has been 1 dose-limiting toxicity, which was a grade 3 pulmonary embolism, in a patient in the escalation cohort receiving 10 mg/kg of pepinemab and 10 mg/kg of avelumab. The adverse event (AE) was resolved and did not recur in that patient, nor any others.

For all of the participants on the study, the most common treatment related AEs were grade 1 or 2 fatigue, pyrexia, or chills. The expansion cohort had 2 immune-related AEs of immune-related myositis and immune-mediated pneumonitis. Investigators did not report any deaths related to the combination by January 14, 2020, and there are no concerns about overall immunogenicity with the combination.

References

1. Shafique MR, Fisher TL, Evans EE, et al. Interim results from a phase Ib/II study of pepinemab in combination with avelumab in advanced NSCLC patients following progression on prior systematic and/or antiPDx therapies. 2020;38(suppl 5):75. doi: 10.1200/JCO.2020.38.5_suppl.75.
2. Evans EE, Fisher TL, Bussler H, et al. Abstract 1545: Altered myeloid and lymphoid composition of tumor microenvironment following anti-SEMA4D and immune checkpoint combination therapies.Cancer Res. 2019;79(suppl 13):1545. doi: 10.1158/1538-7445.AM2019-1545.