By Gregory Friberg, Vice President and Therapeutic Area Head (Global Development), Amgen
Despite the great strides that have been made in understanding the biology of cancer and developing targeted therapies in recent decades, many patients with difficult-to-treat cancer still lack therapeutic options that improve their health outcomes and quality of life. The significant unmet needs of these patients and their families underscore just how important researching innovative modalities and targets continues to be.
By harnessing the power of the body’s immune system, leveraging deep knowledge of the human and cancer genomes, and by exploring emerging biomarkers, Amgen Oncology strives to drive innovation in cancer treatment. We are proud to have relentlessly focused our research on difficult targets such as KRAS G12C, one of cancer’s biggest challenges, which has eluded the best efforts of the scientific community for nearly 40 years; and on the rapidly advancing field of immuno-oncology (IO), which has only been effective for certain patients and tumor types.1,2
Surmounting the KRAS hurdle
KRAS is a member of the RAS family of genes, which are the most frequently mutated oncogenes that drive or initiate cancer and maintain its growth and development.3
KRAS mutations are especially prevalent in solid tumors, where they occur in ~90% of pancreatic tumors and account for the vast majority of RAS mutations in lung and colorectal cancers (CRC).3 One of the most frequent KRAS mutations is KRAS G12C,4 which is found in 13% of patients with non-small cell lung cancer (NSCLC), as well as many CRC and other solid tumor types.5,6,7,8,9,10
Despite decades of research, KRAS has not been successfully targeted. Reasons for this include the protein’s relatively smooth surface, which lacks pockets for binding by conventional drug molecules, as well as the difficulty in targeting mutant KRAS without interfering with the function of normal KRAS.3,11 The lack of progress against mutant KRAS has left patients whose cancers harbor the mutation to rely on limited therapeutic options.
Amgen’s innovative approach to targeting KRAS G12C focuses on features of the mutant protein that normal KRAS lacks.5,12,13 We are investigating a first-in-class investigational small molecule that aims to irreversibly inactivate KRAS G12C and its ability to drive the growth and survival of cancer cells, and are also exploring KRAS G12C as a potential target for a variety of tumor types, including NSCLC. Our ultimate goal is to address significant unmet need where there are limited therapeutic options and no targeted therapies for patients.
Bolstering immune responses with bispecific molecules
For some patients with cancers of the blood, bone marrow, and lymph nodes, as well as those with solid tumors, current IO therapies may not always be effective. New and different options are needed to deliver the benefits of IO to these patients.
One technology with the potential to advance the IO field and bring innovation to patients is Amgen’s Bispecific T-cell Engager (BiTE®) platform, which is being explored across a broad set of solid and hematological malignancies. BiTE technology is designed to engage the natural power of a patient’s own T cells and overcome cancer cells’ evasion of the immune system and directly target cancer cells. A BiTE molecule is bispecific, engineered from two antibodies that target specific cells. One is for a selected tumor antigen (e.g. DLL3, BCMA), the other for CD3 found on T cells.14 Once together, the BiTE molecule is designed to engage the T cell to activate an immune response against the cancer cell.
Our BiTE platform has been studied in thousands of patients with hematologic and solid malignances.15,16 Amgen scientists have designed this versatile technology with the goal of treating cancers by targeting any tumor-associated antigen. We are investigating almost a dozen BiTE molecules — including a DLL3-targeted BiTE molecule in small cell lung cancer patients, a BCMA-targeted BiTE molecule in multiple myeloma patients, and a PSMA-targeted BiTE molecule in prostate cancer patients.17
At Amgen Oncology, we are excited about the potential of the BiTE platform, and the evolution towards off-the-shelf immunology-oncology approaches which do not require the ex vivo manipulation of a patient’s T cells, with the goal of being readily available to patients regardless of their treatment setting.
For over 40 years, Amgen has been pursuing breakthroughs that can benefit cancer patients with hard-to-treat cancers and their families. We currently have the most diverse pipeline of cutting-edge therapies in our company’s history, and we will keep looking ahead toward the next frontier of innovation — with patients always at the forefront of our minds.
To learn more about KRAS G12C, the BiTE platform, and Amgen’s pursuit of innovative targets and modalities for difficult-to-treat tumor types, visit AmgenOncology.com.
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4 Liu P, et al. Acta Pharmaceutica Sinica B. 2019;9(5):871-879.
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6 Amgen Data on File, 2020 Analysis of AACR Genie v8.
7 Neumann J, et al. Pathol Red Pract. 2009;205:858-862.
8 Jones RP, et al. Br J Cancer. 2017;16:923-929.
9 Wiesweg M, et al. Oncogene. 2019;38:2953-2966.
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12 Lanman BA, et al. Cancer Res. 2019;79(suppl 13):abstract 4455.
13 Saiki AY, et al. Cancer Res. 2019;79(suppl 13):abstract 4484.
14 Baeuerle PA, Kufer P, Bargou R. Curr Opin Mol Ther. 2009;11(1):22-30.
15 Amgen Data on File, 2019.
16 Gökbuget N, Dombret H, Zugmaier G, et al. Oral presentation at: European Hematology Association Congress; June, 2019; Amsterdam, Netherlands.
17 Amgen pipeline. https://www.amgenpipeline.com/-/media/themes/amgen/amgenpipeline-com/amgenpipeline-com/pdf/amgen-pipeline-chart.pdf. Accessed March 25, 2021.