Chemotherapy and immune checkpoint inhibitors (ICIs) are approved for treatment of non-small-cell lung cancer (NSCLC). However, there still remains a high medical need in NSCLC, eg. in patients non-responsive to ICIs or progressed after treatment with ICIs. Mesothelin (MSLN) is expressed in ~60% of lung adenocarcinomas. Here, we describe the mesothelin targeting antibody drug conjugate anetumab ravtansine (ARav) with the maytansinoid payload (DM4) as a novel treatment option for NSCLC.

In the NSCLC cell line-derived xenograft model NCI-H322, ARav dosed at 2.5 mg/kg or 10 mg/kg, Q3Dx3, i.v., showed significant antitumor activity and was superior to cisplatin (dosed 3 mg/kg, Q3Dx12, ip). In addition, ARav monotherapy also showed antitumor activity in MSLN-positive NSCLC patient-derived xenograft (PDX) tumor models ST1243 and ST1684 at 15 mg/kg, Q2W.

Maytansinoids and maytansinoid-based ADCs have been described to induce immunogenic cell death and immune response in vitro and in vivo, respectively. To explore the effects of ARav alone or in combination with anti PD-L1 Ab on tumor growth and the immune system, the MC38 C57BL/6 mouse colon cancer cell line was stably transfected with human mesothelin (MC38-hMSLN).

MC38-hMSLN cells were transplanted s.c. in immunocompetent C57BL/6 mice to evaluate the anti-tumor activity of ARav. MC38-hMSLN had a high hMSLN expression level as shown by IHC. A dose of 10 mg/kg of ARav (Q3Dx3, i.v.) was highly efficacious with 11/12 animals showing complete regression of the tumor. Tumor free survivors (TFS) re-challenged 80 days after treatment all rejected MC38-hMSLN (11/11 animals), indicating the development of an immune memory response. The specificity of the immune response was further confirmed in an independently conducted experiment, where previously ARav treated MC38-hMSLN TFS mice were re-challenged with B16-F10 melanoma cells, which grew.

Next, a lower dose of ARav (3 mg/kg, Q3Dx3, i.v.) was combined with an anti PD-L1 antibody in the MC38-hMSLN tumor bearing mice. The combination led to increased frequency of TFS compared to each monotherapy (12/12 TFS in the combination versus 7/12 for the anti PD-L1 and 2/12 for ARav). Further studies are currently ongoing to optimize the combination dosing and schedule as well as to characterize the immune cells involved in the response.

In summary, the data supports the development of ARav in NSCLC and further exploration of ARav in combination with immune checkpoint inhibitors in MSLN-positive cancer indications.

Anetumab ravtansine clinical activity is currently assessed at phase I studies in ovarian cancer in combination with pegylated liposomal doxorubicin (Phase 1b, NCT02751918), in multiple indications including NSCLC (Phase Ib, NCT03102320), and in combination with the anti PD-L1 antibody atezolizumab in NSCLC (Phase I /II, NCT03455556).

Citation Format: Anette Sommer, Pascale Lejeune, Sabine Hoff, Annette O. Walter, Sandra Berndt, Lars Roese, Andreas Schlicker, Michael J. Wick, Cem Elbi, Dominik Mumberg, Christoph Schatz. Anetumab ravtansine has monotherapy efficacy in mesothelin positive patient-derived NSCLC tumor models and in a syngeneic tumor model in immunocompetent mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4816.