Wolfram C. M. Dempke SaWo Oncology Ltd May 13, 2017 Avelumab: New Wine in Old Bottles? Wolfram C. M. Dempke SaWo Oncology Ltd May 13, 2017

Avelumab (Bavencio®) Avelumab (MSB0010718C, Bavencio®) is co-developed by MerckSerono (Darmstadt, Germany) and Pfizer (New York, USA). Avelumab, a monoclonal IgG1/lambda antibody targeting PD-L1, has shown clinical activity in a range of human tumours. Currently, it is approved by FDA for Merkel cell carcinoma (1st line) and bladder carcinomas (2nd line after platinum-containing chemotherapy).

Avelumab: Molecular Biology Avelumab targets PD-L1 (CD274) and subsequently blocks PD-1/PD-L1 interactions. However, avelumab differs from other other checkpoint-blocking antibodies due to its ability to mediate ADCC-mediated cytotoxicity. Avelumab contains a Fc region which can also bind cognate receptors (e.g., CD16 on NK cells) and can subsequently trigger ADCC-mediate tumour cell lysis. Grenga et al. 2016; Boyerinas et al. 2015

Avelumab: Molecular Biology Avelumab binding to CD16 on NK cells can be inhibited by anti-CD16 blocking antibodies and by concanamycin A. Importantly, avelumab treatment did not result in lysis of PD-L1-positive activated immune cells. In vitro studies demonstrated an inverse correlation between the enhancement of CD8+ TIL activation and reduction CD4+ T cell proliferation induced by avelumab. The reduction of CD4+ T cells (e.g., Tregs) and a corresponding huge increase of CD8+ TILs by avelumab appears to be a new and significant finding. Grenga et al. 2016; Boyerinas et al. 2015

Avelumab: Molecular Biology Due to its dual mode of action the increase of antigen- specific immune activation of avelumab was much more pronounced when compared with other PD-1/PD-L1 antibodies. The additional tumour lysis by avelumab also prevents cells from resorting to alternative checkpoints as shown by targeting PD-1 and the subsequent upregulation of TIM-3 or LAG-3. Avelumab is currently evaluated in more than 15 different tumour types. Jochems et al. 2017; Hamilton & Rath 2017; Dempke et al. 2017

Dempke et al. 2017

Avelumab: Development Tumour Phase Treatment Line Patients Results Expected Osteosarcoma II 2nd 40 January 2023 Glioblastoma 30 March 2020 T cell lymphoma 35 May 2021 Renal cell carcinoma III 1st 583 September 2020 Breast cancer adjuvant 335 June 2023 Ovarian carcinoma Pt-resistant 550 March 2018 951 December 2021 Gastric carcinoma 3rd 330 September 2022 Bladder carcinoma 668 July 2020 Head & Neck Tumours 640 May 2022 NSCLC 792 January 2018 1095 April 2024

Avelumab: Merkel Cell Carcinoma Merkel cell carcinoma (MCC) is a very rare, but highly aggressive tumour of the skin (estimated incidence: 1/1,000,000). Most cases are associated with Merkel cell polyoma virus infection. Surgical resection is the treatment of choice. Other treatment options encompass chemotherapy, radiotherapy, and immunotherapy. 5-year OS (metastatic): < 20%

Merkel Cell Carcinoma

Avelumab: Merkel Cell Carcinoma JAVELIN Merkel 200 Trial (N = 88, NCT02155647, phase II) with locally advanced or metastatic Merkel cell carcinomas. Avelumab dosing: 10 mg/kg (over 60 minutes) every 2 weeks. Toxicity: Fatigue (50%), musculoskeletal pain (32%), nausea (22%), decreased appetite (20%) ORR (overall): 33% (CR in 11%) with 45% of responses durable for 12 months or longer. FDA approval obtained in March 2017 (indication: 1st line advanced or metastatic)

Avelumab: Bladder Carcinoma JAVELIN Solid Tumor Trial (N = 129, NCT01772004, phase Ib) including locally advanced or metastatic bladder carcinomas (after platinum-based chemotherapy). Avelumab dosing: 10 mg/kg (over 60 minutes) every 2 weeks. Toxicity: Fatigue (41%), musculoskeletal pain (25%), decreased appetite (21%) ORR = 16.1% FDA approval obtained in May 2017 (indication: 2nd line following platinum-based chemotherapy).

Bladder Carcinoma: Checkpoint Inhibitors Bladder cancers (urothelial carcinomas in more than 90%) are affecting 430,000 people in the US resulting in 165,000 deaths annually (2012). The greatest risk factor for bladder cancer is tobacco smoking. Modern treatment concepts encompasses surgical, chemotherapeutic (platinum-based), radiologic, and immunotherapeutic modalities. Bellmunt et al. 2017

Bladder Cancer: PD-1/PD-L1 Inhibitors Agent Phase (Patients) Dose Treatment Line ORR Atezolizumab (Tecentriq®) II (N = 310) 1,200 mg d1, qd22 2nd 16%; 28% in those with PD-L1 ≥ 5% Nivolumab (Opdivo®) I/II (N = 78) 3 mg/kg d1, qd15 24% in those with PD-L1 ≥1% (26% in those with PD-1 ≤ 1%) Pembrolizumab (Keytruda®) III (N = 542) 200 mg 21% overall Durvalumab (Imfinzi®) (N = 61) 10 mg/kg 31% overall; 46% in those with PD-L1 expression; 0% without PD-L1 expression Avelumab (Bavencio®) Ib (N = 129) 16.1% overall; 50% in those with PD-L1 expression

Summary Avelumab is a novel anti-PD-L1 monoclonal antibody (human IgG1- lambda) containing a Fc region. Avelumab represents a new class of anti-PD-L1 molecules since it blocks PD-L1/PD-1 interactions and also mediates ADCC-lysis of tumour cells (but not lysis of PD-L1 positive activated immune cells). Avelumab can be safely administered to cancer patients (toxicity profile comparable to other monoclonal antibodies of this class). Avelumab is currently approved by FDA for Merkel cell carcinoma (first-line) and bladder cancer (second-line). Avelumab is currently undergoing an extensive phase II/III development programme (solid and haematological malignancies).