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CLASSICAL-Lung phase 1b/2 clinical trial in non-small cell lung cancer: Pepinemab, a SEMA4D inhibitor, associated with Avelumab, an immune checkpoint inhibitor


Results from CLASSICAL-Lung clinical trial were published in Clinical Cancer Research, a publication of the American Association for Cancer Research ( AACR ).
CLASSICAL-Lung is a phase 1b/2 trial evaluating Pepinemab, a novel monoclonal antibody that blocks the activity of SEMA4D, in combination with the immune checkpoint inhibitor Avelumab ( Bavencio ) for the treatment of non-small cell lung cancer ( NSCLC ).

Data have shown that Pepinemab is clinically active when combined with Avelumab and was well tolerated, with no identified safety concerns.
The combination is appeared to halt or reverse tumor progression ( partial response or stable disease ) in a subset of both immunotherapy naïve patients, including patients with often difficult to treat PD-L1–negative or PD-L1–low tumors, and some patients with primary or acquired resistance to prior single-agent anti-PD-1 / PD-L1 therapy.

Among 21 evaluable immunotherapy naïve patients, most of whom had negative or low tumoral expression of the PD-L1 biomarker, five patients experienced partial responses, four patients evidenced clinical benefit at or greater than one year, and the disease control rate ( DCR ) was 81%.
The objective response rate ( ORR ) with the combination therapy was higher than previously reported for single agent Avelumab in the PD-L1 negative / low population.

Among 29 evaluable patients who previously experienced disease progression during or following anti-PD-1 / PD-L1 immunotherapy, the subsequent combination treatment resulted in a disease control rate of 59%, including two partial responses and seven patients with durable clinical benefit of at least 23 weeks.

Exploratory biomarker analysis from biopsies demonstrated improved penetration of killer CD8+ T cells into the tumor.

The results of the CLASSICAL-Lung study is supporting hypothesis that adding Pepinemab to a checkpoint inhibitor for the treatment of NSCLC can shift the tumor microenvironment toward anti-tumor immunity and away from immunosuppression. This appears to enhance the efficacy of checkpoint inhibition, even in some patients who did not respond to prior anti-PD-1 / PD-L1 therapies.

The design of the CLASSICAL-Lung trial consisted of a 12-subject dose escalation phase to determine the recommended phase 2 dose of Pepinemab in combination with Avelumab, followed by a 50-subject dose expansion phase.
The study has included a total of 21 evaluable patients who were immunotherapy naïve and 32 patients who were refractory or resistant to prior treatment with immune checkpoint inhibitors ( predominantly anti–PD-1 ).
The primary objective was to assess safety and tolerability. Secondary objectives included evaluation of efficacy, immunogenicity, and PK/PD.
An exploratory objective was to identify candidate biomarkers of activity. ( Xagena )

Source: Vaccinex, 2021

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