Abstract CT138: Molecular markers in a phase I dose expansion study of PF-06801591 in locally advanced or metastatic non-small-cell lung cancer and urothelial carcinoma

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Abstract Introduction: PF-06801591 is a humanized IgG4 monoclonal antibody that binds to the programmed cell death (PD-1) receptor and blocks its interaction with PD-1/2 ligands (PD-L1/2). In a phase 1 dose expansion study (NCT02573259), 106 patients with locally advanced or metastatic non-small cell lung cancer (NSCLC; n=68) or urothelial carcinoma (UC; n=38) were treated with PF-06891591 300 mg subcutaneously monthly. 12 patients with NSCLC (17.9%) and 7 with UC (18.4%) had a best overall response of partial response (PR). Response rates were higher in patients with high (≥1%) vs low (<1%) tumor cell membrane PD-L1 staining. In UC, progression-free survival (PFS) was longer in patients with high PD-L1 expression. In NSCLC, higher baseline tumor mutational burden (TMB) was associated with longer overall survival (OS). Here, further analyses were conducted to evaluate possible additional predictive biomarkers. Methods: Baseline biopsies were required from all enrolled patients. Archival samples were collected from 95 patients (58 NSCLC; 37 UC); and fresh de novo samples from 11 patients (10 NSCLC; 1 UC). PD-L1 (clone SP-263) and panCK/CD8 expression were evaluated in formalin-fixed, paraffin-embedded tumor biopsies by immunohistochemistry (IHC) and pathologist scoring and/or digital image analysis. Whole-exome sequencing and RNA sequencing were profiled on tumor tissue to generate TMB and gene expression measurements. Cox Proportional Hazards model or logistic regression were used to identify baseline TMB, genes, and pathways potentially associated with outcomes. Results: In NSCLC, high baseline CD8 protein expression in certain tumor compartments was associated with better objective response rate (ORR), PFS and OS. High TMB was associated with prior smoking status and better ORR. Furthermore, RNA sequencing showed that gene expression signatures of CD8+ T cells and cell cycle activity were associated with better clinical response, whereas neutrophil signatures were associated with poor response. In UC, certain high baseline CD8 levels by IHC were associated with better ORR, PFS and OS. Additionally, enrichment of several immune gene signatures was associated with improved ORR. Effector memory CD8+ T cells by RNA sequencing deconvolution were associated with PFS. In a Hallmark pathway analysis, pathways associated with immune activation comprised the majority of those significantly upregulated in responders vs non-responders. Conclusion: Despite a relatively small sample size and a range of biopsy collection dates prior to PF-06801591 treatment, several baseline tumor tissue biomarkers, beyond PD-L1 expression, were associated with clinical benefit in patients with NSCLC and UC. Higher TMB, immune signatures and CD8 cells at baseline may facilitate the immunomodulatory activity of anti-PD1 therapy resulting in an enhanced anti-tumor immune response. Citation Format: Byoung Chul Cho, Konstantin Penkov, Igor Bondarenko, Joanna Pikiel, Hee Kyung Ahn, Alison Forgie, Ira Jacobs, Vinicius Bonato, Xinmeng Jasmine Mu, Keith Ching, Jeffrey Chou, Melissa L. Johnson. Molecular markers in a phase I dose expansion study of PF-06801591 in locally advanced or metastatic non-small-cell lung cancer and urothelial carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT138.