1. 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

2. Avelumab (Bavencio®)
Avelumab (MSB C, 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).

3. 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

4. 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

5. 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

6. Dempke et al. 2017

7. 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

8. 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%

9. Merkel Cell Carcinoma

10. Avelumab: Merkel Cell Carcinoma
JAVELIN Merkel 200 Trial (N = 88, NCT , 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 (indication: 1st line advanced or metastatic)

11. Avelumab: Bladder Carcinoma
JAVELIN Solid Tumor Trial (N = 129, NCT , 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).

12. 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

13. 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

14. 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).