FAP-2286 — A Targeted Radionuclide Therapy With Broad Potential in the Treatment of Solid Tumors

Clovis Oncology’s lead targeted radionuclide therapy candidate, FAP-2286, has the potential for broad clinical utility by targeting an array of solid tumors – a potential “pan-cancer” approach.

Fibroblast Activation Protein — A Ubiquitous Target

A common misconception is that tumors are uniform masses comprised of cancerous cells. In fact, tumors are highly complex tissues made up of many different components, including cancer cells, infiltrating immune cells, fibroblasts, interstitial components, as well as supporting vascular tissue that provides blood flow to the tumor. This complex arrangement of non-cancerous cells, signaling molecules and supporting extracellular matrix associated with the mass of cancerous cells is known as the tumor microenvironment. Some of the most important cancer therapeutic targets are elements of the tumor microenvironment, and not cancer cells themselves.

Cancer associated fibroblasts (CAF) are cells that occur abundantly within solid tumors.  In healthy tissues, fibroblast cells contribute to the extracellular matrix, collagen and structural framework for healthy tissues, and play a critical role in wound healing. However, when associated with cancer cells, they become CAFs and take on a more deleterious role, secreting tumor growth factors and suppressing the body’s immune response to the tumor.

Cancer associated fibroblasts (CAF) are one of the most abundant cell types present in many solid tumors.

Cancer associated fibroblasts (CAF) are one of the most abundant cell types present in many solid tumors.

Fibroblast activation protein (FAP) is a cell surface protein that is found in a wide range of cancers, including breast, lung, colorectal and pancreatic cancers. FAP is highly expressed on the surface of CAFs. FAP is also expressed on the cell surface of some tumor cells.

In the fibroblast cells of healthy tissues, FAP expression is very limited, which reduces the potential for FAP-2286 to target normal, healthy tissues. When healthy fibroblasts convert to CAFs, FAP becomes highly expressed on the cell surface. The high levels of FAP expression observed on CAFs and tumor cells across multiple solid tumor types make FAP a compelling target to explore in clinical development.

Fibroblast activation protein is highly expressed on cancer-associated fibroblasts and tumor cells within the tumor.

Fibroblast activation protein is highly expressed on cancer-associated fibroblasts and tumor cells within the tumor.

FAP-2286 — A Pan-cancer targeted radionuclide therapy candidate

FAP-2286, Clovis Oncology’s lead targeted radionuclide therapy candidate, links the isotope lutetium-177 with a peptide designed to have a high binding affinity for FAP. Preclinical studies have shown that when administered, FAP-2286 is intended to potently and selectively bind to FAP on the surface of CAFs and tumor cells and deliver the radiation-emitting radionuclide in a highly targeted and controlled manner. Once bound, FAP-2286 induces DNA damage and cell death of FAP-positive CAFs and neighboring tumor cells and in some tumor types, FAP-2286 accumulates directly in the tumor, inducing cell death.

FAP-2286 is designed to bind to FAP on the surface of CAFs and tumor cells and deliver radiation in a highly targeted and controlled manner.

Beyond FAP-2286’s potential as a monotherapy, it may also offer the potential to enhance existing cancer treatments. For example, FAP-2286 may restore anti-tumor immune responses in the body through suppression of CAF populations. In combination with the checkpoint inhibitor PD-(L)1, FAP-2286’s mechanism of action might overcome resistant cancers, and potentially allow cancer to be treated once again with immunotherapy.

Potential as an Imaging Agent

To further increase its potential clinical utility, FAP-2286 is being developed as a theranostic, which may potentially be used as a therapeutic or imaging agent. The companion imaging agent can be used to confirm the presence of a target and whether a patient may be appropriate for therapy.

Clovis is exploring FAP-2286 linked to lutetium-177 as a therapeutic agent, and linked to gallium-68 as an imaging agent.

For FAP-2286 the companion imaging agent is achieved by replacing the lutetium-177 radionuclide with gallium-68. An imaging agent can also be a standalone imaging product used to diagnose and stage cancer.

Using theranostics, clinicians have the ability to treat what they see and see what they treat.

Using theranostics, clinicians have the ability to treat what they see and see what they treat.

LuMIERE — FAP-2286 Phase 1/2 Clinical Trial

LuMIERE, Clovis Oncology’s first radiopharmaceutical clinical study, is a Phase 1/2 trial of FAP-2286 as a treatment and imaging agent in a variety of solid tumors. The Phase 1 portion of the LuMIERE clinical study will assess safety and identify the recommended Phase 2 dose of lutetium-177 labeled FAP-2286 (177Lu-FAP-2286) and is currently ongoing. Once the recommended Phase 2 dose is determined, Phase 2 expansion cohorts are planned in multiple tumor types. Gallium-68 labeled FAP-2286 (68Ga-FAP-2286) will be utilized as an FAP-targeted imaging agent to identify patients eligible for treatment in the study. Data from Phase 1 as well as data from an ongoing investigator-initiated trial (IIT) at University of California San Francisco (NCT04621435, Phase 1 single-arm imaging study with dosimetry and 68Ga-FAP-2286 imaging cohorts using 68Ga-FAP-2286 in patients with solid tumors) will be used to inform additional tumor type selection for the LuMIERE Phase 2 expansion cohorts.

LuMIERE is a Phase 1/2 clinical trial of FAP-2286 as a targeted radionuclide therapy and imaging agent in a variety of solid tumors.

LuMIERE is a Phase 1/2 clinical trial of FAP-2286 as a targeted radionuclide therapy and imaging agent in a variety of solid tumors.

References

[1] Information on File. Clovis Oncology. Year of information 2021.

[8] Rettig WJ, Garin-Chesa P, Healey JH, Su SL, Ozer HL, Schwab M, Albino AP, Old LJ. Regulation and heteromeric structure of the ­fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. Cancer Res. 1993 Jul 15;53(14):3327-35. PMID: 8391923.

[9] Garin-Chesa, P.. Old. L. J.. and Rettig. W. i. Cell surface glycoprotein of reactive stromal ­fibroblasts as a potential antibody-target in human epithelial cancers. Proc. Nati. Acad. Sci. USA, 87: 7235-7239, 1990.

[10] Information on File. Clovis Oncology. Year of information 2019.

[11]. Zboralski, D, et al. Preclinical Evaluation of FAP-2286, a Peptide-targeted Radionuclide Therapy to Fibroblast Activation Protein. Poster or Paper presented at: ESMO Virtual Conference 2020; 19-21 September 2020; Virtual Conference.

[12] Brennen, W Nathaniel et al. Rationale behind targeting fi­broblast activation protein-expressing carcinoma-associated fi­broblasts as a novel chemotherapeutic strategy. Molecular cancer therapeutics vol. 11,2 (2012): 257-66. doi:10.1158/1535-7163.MCT-11-0340.

[13] Yang L. V. (2017). Tumor Microenvironment and Metabolism. International journal of molecular sciences, 18(12), 2729. https://doi.org/10.3390/ijms18122729.

[14] Liu, T., Han, C., Wang, S. et al. Cancer-associated ­fibroblasts: an emerging target of anti-cancer immunotherapy. J Hematol Oncol 12, 86 (2019). https://doi.org/10.1186/s13045-019-0770-1.

[15] Puré, E., Blomberg, R. Pro-tumorigenic roles of ­fibroblast activation protein in cancer: back to the basics. Oncogene 37, 4343–4357 (2018). https://doi.org/10.1038/s41388-018-0275-3.

[16] National Cancer Institute. (2020). Cancer Imaging Basics. Available at: https://imaging.cancer.gov/imaging_basics/cancer_imaging.htm (Accessed: May 7, 2021).

[17] Jeelani, S et al. “Theranostics: A treasured tailor for tomorrow.” Journal of pharmacy & bioallied sciences vol. 6,Suppl 1 (2014): S6-8. doi:10.4103/0975-7406.137249.

[19] Information on File. Clovis Oncology. Year of information 2020.

[20]. Information on File. Clovis Oncology. Year of information 2021.

[21] Information on File. Clovis Oncology. Year of information 2019.

[22] Feig C, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated ­fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA. 2013 Dec. 10;110(50):20212-7. doi: 10.1073/pnas.1320318110. Epub 2013 Nov 25. PMID: 24277834; PMCID: PMC3864274.

[23] Takahashi S. (2011). Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull, 34(12):1785-8. doi: 10.1248/bpb.34.1785. PMID: 22130231.

[27] National Cancer Institute. (2020). Targeted Cancer Therapies. Available at: https://www.cancer.gov/about-cancer/treatment/types/radiation-therapy/side-effects (Accessed: May 14, 2021).

[28] Granot Z. (2019). Neutrophils as a Therapeutic Target in Cancer. Front Immunol. 10:1710. doi: 10.3389/fimmu.2019.01710. PMID: 31379884; PMCID: PMC6659000.

[30] Baghban, R., Roshangar, L., Jahanban-Esfahlan, R. et al. (2020). Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal, 18:59. https://doi.org/10.1186/s12964-020-0530-4.

[31] National Cancer Institute. (2021). Definition of Radionuclide. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/radionuclide (Accessed: May 21, 2021).

[32] Science Direct. (2021). Lutetium 177 Overview. Available at: https://www.sciencedirect.com/topics/medicine-and-dentistry/lutetium-177 (Accessed May 21, 2021).

[33] Banerjee, S. R., & Pomper, M. G. (2013). Clinical applications of Gallium-68. Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine, 76, 2–13. https://doi.org/10.1016/j.apradiso.2013.01.039.

[34] Mona, C.E., et al. Validation of FAPi PET biodistribution by immunohistochemistry in patients with solid cancers A prospective exploratory study. Poster or Paper presented at: 2021 ASCO Annual Meeting; 4-8 June 2021; Virtual Conference.