Pepinemab/Avelumab Combo Shows Early Tolerability and Antitumor Activity in Advanced NSCLC

The combination of pepinemab (VX15/2503) and avelumab (Bavencio) was found to be well tolerated and demonstrated initial signals of antitumor activity in patients with advanced stage, non–small cell lung cancer (NSCLC), according to interim data from the phase 1b/2 CLASSICAL-Lung trial (NCT03268057).¹

Results were presented by Jonathan W. Goldman, MD, of the Ronald Reagan UCLA Medical Center, during the 2020 AACR Virtual Annual Meeting I. Data showed that 81% of 21 evaluable, immunotherapy-naïve patients experienced disease control with the combination. Clinical benefit of 1 year or more was achieved in 4 patients; benefit lasting 6 months or longer was reported in 6 patients. Five patients in this subgroup achieved a partial response (PR) with the combination.

Over half, or 59%, of evaluable patients who had previously progressed during or following immunotherapy achieved benefit by switching over to the combination regimen; notably, doing so led to a reversal of tumor growth. Three patients were primary refractory to immunotherapy prior to enrolling on the trial. Two patients who had progressed on pembrolizumab (Keytruda) experienced PRs with a 65% and 52% tumor reduction. A durable response of at least 1 year was experienced by 1 patient in this subgroup; 5 patients had a response lasting at least 6 months.

“We continue to be encouraged by data from the CLASSICAL-Lung trial and are pleased to see preliminary signals suggesting durable responses,” Maurice Zauderer, PhD, President and CEO of Vaccinex, the developer of pepinemab, stated in a recent press release.² “The combination of pepinemab and avelumab has potential to halt or reverse tumor progression, both in immunotherapy-naïve patients and those for whom prior single-agent immunotherapy treatments have failed. We look forward to continuing to advance pepinemab in additional cancer indications.”

The open-label, single arm, first-in-human study was designed to evaluate the safety, tolerability, and effectiveness of pepinemab in combination with avelumab in patients with advanced stage IIIB/IV NSCLC who have either progressed on first- or second-line systemic therapy who have declined treatment with those therapies.

In the phase 1b, dose-escalation portion of the trial, the primary objective was to examine the safety and tolerability of ascending doses of pepinemab twice weekly in combination with avelumab at 10 mg/kg twice weekly and to identify the recommended phase 2 dose. This portion of the trial included 12 immunotherapy-naïve patients. Three patients received a 5-mg/kg dose of pepinemab, 6 received 10-mg/kg dose, and 3 received a 20-mg/kg dose.

The phase 2, dose-expansion portion of the trial included a total of 50 patients: 32 who had progressed on immunotherapy and 18 who were immunotherapy naïve. The secondary objectives of the trial included evaluation of efficacy, immunogenicity, pharmacokinetics/pharmacodynamics, and an exploratory objective to determine candidate biomarkers of activity with the combination.

Additional results from an exploratory analysis of pre- and on-treatment biopsies showed an increase in CD8-positive T-cell density in the majority of tumors after treatment with pepinemab/avelumab; the presence of CD8-positive T cells within the tumor was found to correlate with tumor response. In 10 of 11 biopsies collected from patients with a PR or stable disease (SD) showed either absence or reduction of the tumor. No tumor was identified in biopsies from 4 of 5 patients with a PR and 3 of 6 patients with SD.

A PD-L1 analysis was also performed using the PD-L1 Dako 73-10 assay, and data pertaining to PD-L1 status were available for 51 of 62 study participants. Twenty-nine patients who had achieved PR and SD were evaluated and 28% were found to either have PD-L1 negativity or low expression (0%-80%). Ten patients were PD-L1 negative. The majority of patients who achieved PR and SD with the combination were reported to have either negative or low PD-L1 expression.

Regarding safety, pepinemab plus avelumab proved to be well-tolerated at all dose levels, with no concerning safety signals reported.The most common adverse effects (AEs) were fatigue, pyrexia, and chills and they were all grades 1/2. One dose-limiting toxicity, grade 3 pulmonary embolism, was reported in the escalation cohort, in a patient who received 10 mg/kg of pepinemab plus 10 mg/kg of avelumab; the event was reported to resolve. Two immune-related AEs were also reported in patients in the expansion cohort; these events included myositis and pneumonitis. As of the cutoff date of January 14, 2020, no deaths have been reported.

“In summary, pepinemab, an anti-[semaphorin] 4D antibody, attempts to shift the balance in the tumor immune microenvironment to overcome immune exclusion in myeloid suppression. This was demonstrated and supported by the proof-of-concept, on-trial biopsies,” Goldman said during his virtual presentation. “Immunotherapy-naive patients [and those who have progressed on immunotherapy] appear to benefit from pepinemab and avelumab treatment, including those with low PD-L1 expression and those who progressed on recent immune checkpoint inhibitors.”

References:

1. Goldman JW, Fisher TL, Evans E, et al. Interim results from CLASSICAL-Lung, phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC. Presented at: the 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. Abstract CT191. bit.ly/2ZrerDO.

2. Updated interim results from CLASSICAL-Lung, phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab (BAVENCIO) in non-small cell lung cancer presented at the american association for cancer research (AACR) virtual annual meeting. News release. Vaccinex, Inc. Published April 27, 2020. Accessed July 13, 2020. bit.ly/3g4fv6e.