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Bifunctional Immunotherapy M7824 – New Data Presented at ESMO 2018 Congress
Katrina Mountfort
Senior Medical Writer, Touch Medical Media, Goring-on-Thames, UK

In recent years, immunotherapies have transformed the treatment landscape for cancer. Monoclonal antibodies targeting immune checkpoints, such as programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1), have become the mainstays of immunotherapy. However, for most solid tumour types, with the exception of melanoma, only 10–20% of patients typically respond to PD-1/PD-L1-targeted therapies.1 In order to maximise the potential of these powerful agents, we need to improve the overall response rate by combining immune checkpoint inhibitors with other therapeutic modalities.

The tumour microenvironment (TME) is an increasingly important therapeutic target in oncology. In addition to expressing immune checkpoints, the TME contains other immunosuppressant molecules, among them transforming growth factor-beta (TGFβ). This cytokine plays a regulatory role in a number of anti-tumour effects, including preventing proliferation, activating T cells and promoting differentiation and apoptosis of tumour cells. However, as tumours develop, these protective effects are often diminished due to the loss of TGFβ receptor expression.2 High TGFβ serum level and loss of TGFβ receptor expression on tumours have been associated with poor prognosis,3 making TGFβ a potentially useful therapeutic target.4 However, to date, TGFβ-targeted therapies have shown limited clinical activity.4

Since PD-L1 and TGFβ have different mechanisms of action in the TME, it has been proposed that simultaneous targeting of both pathways might increase therapeutic efficacy. M7824 counteracts the TGFβ-mediated differentiation of regulatory T cells and immune tolerance, and may therefore provide a useful strategy in tumours that are resistant to immune checkpoint inhibitors.5 M7824 is a first-in-class bifunctional fusion protein that comprises the extracellular domain of human TGFβ receptor II linked to the C-terminus of the human αPD-L1 heavy chain, and is designed to sequester TGF-β in the TME as well as its anti-PD-L1 action.6 In preclinical studies, M7824 demonstrated extended survival and a positive impact on long-term protective immunity compared with monotherapies, as well as enhancing the activity of CD8-positive T cell and natural killer cells.6 The clinical development of M7824 is underway in a number of difficult-to-treat tumour types, and the latest data were presented at the European Society for Medical Oncology (ESMO) 2018 Congress in Munich, Germany. The presentations included a phase I expansion cohort (n=32; ClinicalTrials.gov Identifier: NCT02517398) investigating M7824 in advanced squamous cell carcinoma of the head and neck, for which few treatment options exist. The overall response rate (ORR) was 21.9%, but in human papillomavirus (HPV)-positive patients was 50.0%. Grade 3 treatment-related adverse events (TRAEs) were reported in 10 patients (31.3%).7 This is consistent with previous findings from this study, presented at the ASCO meeting earlier this year, which showed that M7824 had an overall response rate (ORR) of 45.5% in patients with known HPV-positive disease.8

In an expert interview at the ESMO 2018 congress, Dr Byoung Chul Cho talked to touchONCOLOGY about the recent phase I trial investigating M7824 in advanced solid tumours (ClinicalTrials.gov Identifier: NCT02517398), and the results in patients with squamous cell carcinoma of the head and neck. Despite the phase I status and small sample size, M7824 showed encouraging results that warrant further research in this indication. Dr Cho also discusses the potential of M7824 in other cancer types associated with the HPV virus. Please see the full interview below, or click here for full details.

Updated data from a phase I study (n=80; ClinicalTrials.gov Identifer: NCT02517398) of M7824 in non-small cell lung cancer also showed promising clinical activity, with an ORR of 40.7%. In patients with high PD-L1 expressing tumours (≥80%), the ORR was 71.4%. Grade 3 TRAEs were reported in 23 patients (28.8%) and grade 4 TRAEs occurred in two patients (2.5%): hypokalaemia and decreased blood magnesium, and increased amylase and lipase levels.9

Another phase I study (ClinicalTrials.gov Identifier: NCT02517398) is investigating the safety and tolerability of M7824 in Asian patients with metastatic or locally advanced solid tumours. New data from an expansion cohort (n=30) in patients with biliary tract cancer who had progressed after platinum-based first-line treatment, demonstrated an ORR of 20%, regardless of PD-L1 levels. The duration of response ranged from 8.3 months to more than 13.9 months. Grade 3 or higher TRAEs occurred in 10 patients (33.3%), and included three deaths due to adverse events: one due to septic shock (bacteraemia, aetiology unknown) and two due to interstitial lung disease (ILD). Both patients with ILD were Japanese; a higher incidence of drug-induced ILD has been reported among Japanese patients compared with non-Japanese populations.10

In an expert interview filmed at ESMO 2018, Dr Do-Youn Oh highlights the importance of these results for biliary tract cancer, and where she thinks future research could lead. Please click here for further information.

In addition, two posters showed promising preliminary efficacy for M7824 in ongoing phase I studies in heavily pre-treated patients with oesophageal squamous cell carcinoma (ClinicalTrials.gov Identifier: NCT02699515)11 and advanced oesophageal adenocarcinoma (ClinicalTrials.gov Identifier: NCT02517398),12 for whom limited therapeutic options exist. Another poster presented updated data in patients with pre-treated, recurrent or refractory gastric cancer (ClinicalTrials.gov Identifier: NCT02699515).13

Since M7824 is well tolerated by the majority of patients and its safety profile is similar to PD-1/PD-L1 inhibitors, it could provide a treatment option for patients who have tumours with a low response to PD-1 and PD-L1 inhibitors. M7824 will also be evaluated as a combination therapy with the targeted immunotherapies Prostvac and CV301 in a phase II clinical trial (ClinicalTrials.gov Identifier: NCT03315871) in patients with recurrent prostate cancer.

Luciano Rossetti, Executive Vice President, Head of Global Research & Development for the Biopharma business of Merck, said: 'We are excited to share encouraging updated and new data for M7824, including four additional difficult-to-treat cancers. The results we’ve seen to date will enable us to target those tumours and settings with the highest potential to impact people living with cancer, as we move into the next stage of our development program with this bifunctional immunotherapy.'14

References
1. Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8:328rv4. 2. Lebrun JJ. The dual role of TGFβ in human cancer: from tumor suppression to cancer metastasis. ISRN Mol Biol. 2012;2012:381428.
3. Hawinkels LJ, Verspaget HW, van Duijn W, et al. Tissue level, activation and cellular localisation of TGF-beta1 and association with survival in gastric cancer patients. Br J Cancer. 2007;97:398–404.
4. Akhurst RJ. Targeting TGF-beta signaling for therapeutic gain. Cold Spring Harb Perspect Biol. 2017;9:pii:a022301.
5. Ravi R, Noonan KA, Pham V. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun. 2018;9:741.
6. Knudson KM, Hicks KC, Luo X, et al. M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. Oncoimmunology. 2018;7:e1426519.
7. Cho BC, Daste A, Ravaud A, et al .M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients (pts) with advanced SCCHN: results from a phase 1 cohort. Ann Oncol. 2018;29 (suppl_8): viii372–399.
8. Strauss J, Gatti-Mays ME, Redman J, et al. Safety and activity of M7824, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with HPV associated cancers. J Clin Oncol. 2018;36: no. 15_suppl 3007.
9. Paz-Ares L, Kim TM, Vincente D, et al. Updated results of M7824 (MSB0011359C), a bifunctional fusion protein targeting TGF-β and PD-L1, in second-line (2L) NSCLC. Ann Oncol. 2018;29 (suppl_8):viii493–547. 10. Yoo C, Oh D-Y, Choi HC, et al. M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with pretreated biliary tract cancer: Preliminary results from a phase I trial. Ann Oncol. 2018;29(suppl_8):viii493–547.
11. Lin C-C, Muro K, Hou M-M, et al. Phase I study results from an esophageal squamous cell carcinoma (ESCC) cohort treated with M7824 (MSB0011359C), a bifunctional fusion protein targeting transforming growth factor β (TGF-β) and PD-L1. Ann Oncol. 2018;29(suppl_8):viii493–547.
12. Tan B, Khattak A, Felip E, et al. M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with post-platinum esophageal adenocarcinoma (EAC): Preliminary results from a phase I cohort. Ann Oncol. 2018;29(suppl_8):viii493–547.
13. Bang Y-J, Doi T, Kondo S, et al. Updated results from a phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with pretreated recurrent or refractory gastric cancer. Ann Oncol. 2018;29(suppl_8):viii493547.
14. Merch Press Release: Merck Presents Updated Results for Bifunctional Immunotherapy M7824 at ESMO 2018 Congress, 2018. Available at: www.merckgroup.com/en/news/m7824-at-esmo-22-10-2018.html (accessed 30 October 2018).