LAUSR

The JAVELIN Solid Tumor clinical trials group recently reported the results of a multi-center open-label phase 1b study (NCT01772004) evaluating avelumab in patients with progressive or platinum-resistant metastatic or recurrent non-small cell lung cancer (NSCLC) [1]. Avelumab, a fully human IgG1 monoclonal antibody (mAb) that binds PD-L1, is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma refractory to platinum-based chemotherapy. Avelumab has shown an acceptable safety profile and encouraging clinical activity across a spectrum of metastatic solid tumors [2]. Among the five currently FDA-approved anti-PD-1/ PD-L1 agents, avelumab is unique due to its unmodified fragment crystallizable (Fc) domain which may potentiate antibody-dependent cell-mediated cytotoxicity (ADCC) via interaction with CD16 (FcɣRIIIa) on natural killer (NK) cells [3]. The importance of ADCC to the efficacy of anti-PD-1/PD-L1 mAbs has not been evaluated clinically. Preclinical work has shown that ADCC may augment anti-tumor immunity, particularly among anti-PD-L1 mAbs. Further, avelumab has been demonstrated to induce ADCC across a wide variety of human tumor cell lines and enhance antigen-specific T-cell responses in vitro [3]. However, there is theoretical concern that ADCC could also lead to lysis of PD-L1-expressing immune cells. Indeed, IgG4 isotype mAbs (nivolumab, pembrolizumab) were selected due to low affinity for FcɣR, and IgG1 isotype mAbs (atezolizumab, durvalumab) have undergone Fc modification to specifically mitigate ADCC. To address this concern, Donahue and colleagues recently performed a comprehensive analysis of the peripheral immunome of patients treated with multiple cycles of avelumab (many enrolled on NCT01772004) observing minimal modulation of PD-L1+ immune subsets after treatment [4]. This study also demonstrated that avelumab mediated lysis of tumor cells but not peripheral blood mononuclear cells in vitro. With a median follow up of 8.8 months in the NSCLC dose-expansion cohort, the JAVELIN investigators enrolled 184 patients with stage IIIB or IV NSCLC with disease progression after prior platinumbased doublet therapy for metastatic disease across 58 academic centers [1]. Based on the safety analyses and pharmacokinetic (PK) and pharmacodynamic profiling of PD-L1 receptor occupancy from the phase Ia doseescalation trial, a dose schedule of infusional avelumab 10mg/kg every two weeks until progression or toxicity was selected for this study and other JAVELIN trials [2]. This study population was heterogeneous and heavily pre-treated and patient selection was agnostic of tumor histology or PD-L1 expression. Furthermore, unlike other studies of PD-1/PD-L1 inhibitors, this study allowed enrollment of sicker patients beyond the second line setting (33% of patients were in ≥3rd line of therapy) and with other driver mutations (EGFR or KRAS mutation, ALK translocation). Multiple studies across multiple treatment modalities including immunotherapy have shown lower response rates with more advanced disease / later lines of therapy. Objective response rate (ORR) was 12% (n = 22), and 1-year progression-free and overall survival rates were 18% and 36%, respectively. Ongoing follow-up has confirmed an additional 4 responses, raising the ORR to Editorial