Targeted Radionuclide Therapy – Advancing Precision Oncology

At Clovis Oncology, we are committed to advancing the fight against cancer and realizing the promise of precision medicine for cancer. We aim to develop precision therapies to better serve patients and ensure the right drug gets to the right patient. To that end, Clovis is developing a pipeline of novel targeted radionuclide therapies for cancer treatment and imaging. Our lead candidate, FAP-2286 is a peptide-targeted radionuclide therapy that binds to fibroblast activation protein and has the potential to treat multiple tumor types in a “pan-cancer” approach.

For more information and to view FAP-2286 scientific presentations click here

How Clovis Aims to Shape the Next Generation of Oncology Treatments

Targeted Radionuclide Therapy — An Emerging Class of Cancer Therapeutic and Imaging Agents

The goal of targeted radionuclide therapy is to enable potent yet controlled delivery of radiation treatment directly to the tumor environment while minimizing radiation exposure to normal tissue. In addition, targeted radionuclides can also be used as imaging agents to select patients for therapeutic applications; this is known as “theranostics.”

Radiation Therapy Precisely Delivered

Radiation therapy can be highly effective in treating cancer, or alleviating symptoms in patients with untreatable advanced stage cancers. Approximately half of all cancer patients will receive radiation therapy at some point in their treatment, which uses externally or internally delivered x-rays, protons or other high energy particles to target and destroy cancer cells. While improved technological approaches have reduced healthy tissue deterioration, traditional radiotherapy still causes side effects that can be difficult for some patients to tolerate. In addition, traditional radiotherapy is unable to target more than one site of disease, limiting its utility for patients with metastatic cancer. However, traditional radiotherapy remains one of oncology’s most powerful treatment tools.

This novel approach to tumor treatment — targeted radionuclide therapy — is reengineering the use of radiation treatments in precision oncology and delivering a new class of cancer therapies. The goal of targeted radionuclide therapy development is to combine alpha-, beta- or gamma-particle emitting isotopes — or radionuclides — with peptides, antibodies, or small molecules, to develop therapies with high specificity for certain types of tumors. Delivered to the patient intravenously, targeted radionuclide therapies are designed to travel directly to the tumor to deliver therapeutic radiation with high precision. This precision is intended to focus delivery of the radiation to the tumor tissue while minimizing radiation exposure to normal tissue.

Targeted radionuclide therapies have the potential to deliver therapeutic doses of radiation with high specificity for certain types of tumors.

Targeted radionuclide therapies have the potential to deliver therapeutic doses of radiation with high specificity for certain types of tumors.

Theranostics: Seeing What we Treat — Treating What we See

Radionuclides can be delivered to tumors using precision targeting agents to both treat cancer and image a patient for cancer. Agents that can use one radionuclide to image tumors while using a different radionuclide to deliver cancer-killing radiation directly to tumors are known as “theranostics”. By replacing cancer-killing beta- and alpha-particle emitting radionuclides with other radionuclides, such as the positron-emitter gallium-68, a single highly effective targeting molecule of a targeted radionuclide therapy can be transformed into an imaging agent. Theranostic radionuclide imaging agents target the same cells and tissues as the accompanying therapeutic agents. This allows oncologists to image treatable cancer tissues more completely, select patients for therapeutic applications, see precisely where therapeutic agents will be delivered, and monitor the ability of the therapeutic agent to shrink tumors over time. Theranostics provide oncologists with novel and highly effective tools to create precision treatment strategies for their cancer patients.

Replacing a therapeutic radionuclide with an imaging-specific radionuclide allows the clinician to see where the therapeutic agent will be delivered.

Replacing a therapeutic radionuclide with an imaging-specific radionuclide allows the clinician to see where the therapeutic agent will be delivered.

References

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

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[4] National Cancer Institute. (2019). Radiation Therapy to Treat Cancer. Available at: https://www.cancer.gov/about-cancer/treatment/types/radiation-therapy (Accessed: 22 March 2021).

[5] National Cancer Institute. (2018). Radiation Therapy Side Effects. Available at: https://www.cancer.gov/about-cancer/treatment/types/radiation-therapy/side-effects (Accessed: 22 March 2021).

[6] Sgouros, G., Bodei, L., McDevitt, M.R. et al. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov 19, 589–608 (2020). https://-doi.org/10.1038/s41573-020-0073-9.

[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.

[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.

[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.

[18] Turner JH. Recent advances in theranostics and challenges for the future. Br J Radiol. 2018 Nov;91(1091):20170893. doi: 10.1259/bjr.20170893. Epub 2018 Mar 29. PMID: 29565650; PMCID: PMC6475948.

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

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

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[26] Philip Sutera, David A. Clump, Ronny Kalash, David D’Ambrosio, Alina Mihai, Hong Wang, Daniel P. Petro, Steven A. Burton, Dwight E. Heron. (2019). Initial Results of a Multicenter Phase 2 Trial of Stereotactic Ablative Radiation Therapy for Oligometastatic Cancer. International Journal of Radiation Oncology*Biology*Physics, 103 (1): 116 DOI: 10.1016/j.ijrobp.2018.08.027.

[29] Cancer Quest. (2021). Radiation Therapy. Available at: https://www.cancerquest.org/patients/treatments/radiation-therapy#toc-advantages-iIwIA-Qd (Accessed: May 17, 2021).

[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.

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 highly expressed on the surface of CAFs, which are found in the majority of cancer types, at varying levels, potentially making it a suitable target across a wide range of tumors. 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. High FAP expression has been shown in multiple tumor types including pancreatic ductal adenocarcinoma, salivary gland, mesothelioma, colon, bladder, sarcoma, squamous NSCLC, and head and neck cancers as well as in cancers of unknown primary. High FAP expression was detected in both primary and metastatic tumor samples and was independent of tumor stage or grade.

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.

[35] Kwan T et al. Pan-Cancer Analysis of Fibroblast Activation Protein Alpha (FAP) Expression to Guide Tumor Selection for the Peptide-Targeted Radionuclide Therapy FAP-2286. Virtual Presentation 2021 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2021.

Clovis Oncology — Shaping the Future of Targeted Radionuclide Therapies

Clovis is committed to being a leader in the development of targeted radionuclide therapies and realizing their potential for patients.

Seeking to Lead in targeted radionuclide therapy development

Targeted radionuclide therapies are an emerging class of therapies with potential to be applied across many solid tumor types, and Clovis is pursuing a broad and accelerated clinical development program to support this potential new pillar in oncology drug development. FAP-2286, the lead candidate in Clovis Oncology’s targeted radionuclide therapy development pipeline, binds to fibroblast activation protein, or FAP, with the potential to offer a “pan-cancer” approach to treating tumors. Clovis also has global rights to three additional targeted radionuclide therapy candidates currently in discovery. Clovis, together with licensing partner 3B Pharmaceuticals, is highly committed to this emerging field in oncology drug development and we are building the expertise and infrastructure to support the global development and distribution of FAP-2286, and future development of compounds for targeted radionuclide therapies.

Clovis is committed to building the expertise and infrastructure to support a broad development pipeline.

Clovis is committed to building the expertise and infrastructure to support a broad development pipeline.

Clovis Oncology is on a Mission to Advance the Fight Against Cancer

At Clovis Oncology, we are committed to realizing the promise of precision medicine for cancer. We seek to develop targeted therapies to better serve patients and ensure the right drug gets to the right patient. Our mission will be achieved by excelling at the science, development and commercialization of drugs that will further advance the treatment of cancer.

Founded in 2009, Clovis Oncology (NASDAQ: CLVS) is a commercial stage biotechnology company focused on acquiring, developing and commercializing cancer treatments in the United States, Europe and other international markets.

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.

[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.

[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.

Glossary of terms

C
Cancer Associated Fibroblast (CAF)
Fibroblast cells associated with the tumor microenvironment that are metabolically distinct from healthy fibroblast cells. CAFs secrete tumor growth factors and suppress the body’s immune response to the tumor.
F
Fibroblast Activation Protein (FAP)
A cell-surface protein that is highly expressed in cancer associated fibroblasts and cancer cells.
G
Gallium-68
A radioactive isotope of Gallium, which is a gamma particle emitting radionuclide. Gallium-68 is a commonly used radionuclide in diagnostic imaging tools in healthcare.
L
Lutetium-177
A radioactive isotope of Lutetium, which is a beta particle emitting radionuclide.
R
Radionuclide
Short for radioactive nuclide, a radionuclide is an unstable atom that emits radioactive particles in the form of alpha, beta, or gamma particles.
T
Theranostics
The combination of using one radionuclide to image tumors and a second radionuclide to treat tumors.
Tumor Microenvironment (TME)
The tumor microenvironment is the environment surrounding the mass of cancerous tumor cells, including blood vessels, immune cells, cancer associated fibroblasts, signaling molecules and the extracellular matrix. The tumor is supported by its surrounding microenvironment.

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