A first patient was doses in a phase II clinical trial designed to evaluate patritumab deruxtecan (previously known as U3-1402), a HER3 directed DXd antibody-drug conjugate (ADC). The investigational drug is being studied in patients with advanced or metastatic colorectal cancer who are resistant, refractory, or intolerant to at least two prior lines of systemic therapy.

Patritumab deruxtecan is one of three ADCs being developed by Daiichi Sankyo. The drug includes of a human anti-HER3 antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and help deliver chemotherapy to cancer cells that express HER3 on the surface of tumor cells.

Standard of care
Standard treatment options for patients with advanced or metastatic colorectal cancer include surgery when possible, chemotherapy with or without targeted therapy, and radiation therapy.[1][2] However, many patients with advanced colorectal cancer will progress through multiple lines of therapy, and prognosis remains poor after failure of these therapies.[2][3] It is estimated that up to 83% of patients with colorectal cancer overexpress the HER3 protein, which can be associated with an increased incidence of metastases, reduced survival, and resistance to standard cancer treatment.[4][5][6][7]

Colorectal cancer is the third most common cancer and the second-leading cause of cancer-related deaths worldwide.[8] In 2020, there will be an estimated 147,950 new cases of colorectal cancer diagnosed in the U.S. and an estimated 53,200 deaths.[9] Approximately 25% of patients have metastatic disease at diagnosis, meaning the cancer has spread to distant organs, and about 50% will eventually develop metastases.[9][10] Only 14% of patients with metastatic colorectal cancer are expected to survive five years after they are diagnosed.[3]

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Most patients with metastatic colorectal cancer receive surgery (when possible), chemotherapy with or without targeted therapy, and radiation therapy.[1][2] The introduction of EGFR targeting treatments and other targeted therapies has helped prolong overall survival in advanced colorectal cancer compared to chemotherapy.[8][11] However, many patients eventually become resistant to these targeted treatments, underscoring the need for new treatment approaches for metastatic colorectal cancer.[2][4][5]

Patritumab deruxtecan targets the human epidermal growth factor receptor-3, (HER3), which is also known as receptor tyrosine-protein kinase erbB-3. HER3 is a member of the EGFR family of tyrosine kinase receptors, which are associated with aberrant cell proliferation and survival.[12] The HER3 protein is overexpressed in as many as 83% of colorectal cancers, and it is associated with an increased incidence of metastases and reduced survival.[4][5][6][7] Currently, no HER3 directed therapies are approved for any cancer.

Poor prognosis
“The prognosis of patients with advanced or metastatic colorectal cancer remains poor, and there is a need to develop new treatment strategies, including targeting HER3,” said Gilles Gallant, BPharm, Ph.D., FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo.

“In this study, we are exploring whether the targeted delivery of cytotoxic chemotherapy with patritumab deruxtecan to cancer cells with varying levels of HER3 expression may be a potential treatment option for previously treated advanced or metastatic colorectal cancer,” Gallant noted.

Study design
Patients participating in the multi-center, open-label, two-cohort, two-part, phase II study have been diagnosed with advanced or metastatic colorectal cancer. Their cancer is also resistant, refractory, or intolerant to at least two prior approved systemic therapies. Prior treatments must include chemotherapy fluoropyrimidine, irinotecan, and a platinum agent), an anti-EGFR agent if clinically indicated, and an anti-VEGF agent, unless contraindicated. Furthermore, patients diagnosed with confirmed microsatellite instability-high (MSI-H) colorectal cancer must have received treatment with an immune checkpoint inhibitor unless contraindicated.

The first part of the study includes two cohorts of patients with varying levels of HER3 expression. One cohort will include patients with HER3 high expression (IHC 3+ or 2+), and the second cohort will include patients with HER3 low/HER3 negative expression (IHC 1+ or 0). Based on a preliminary review of the data, specifically treatment response in both cohorts, additional patients may be enrolled into a second part of the study, which will further assess treatment with patritumab deruxtecan in patients with either HER3 high expression or both HER3 high and low expression.

The primary objective of the study is to assess the antitumor activity of patritumab deruxtecan, and will evaluate the objective response rate (ORR), as assessed by Blinded Independent Central Review per RECIST v1.1, as the primary endpoint. Secondary objectives of the study include the assessment of antitumor activity (evaluated by assessing duration of response (DoR), investigator-assessed ORR, disease control rate (DCR), time to response (TTR), progression-free survival (PFS) and overall survival (OS)), safety and tolerability, level of HER3 protein expression in tumor tissue and its relationship with efficacy, pharmacokinetics, and immunogenicity. Secondary efficacy assessments (ORR, DOR, DCR, TTR, and PFS) will be assessed by BICR and investigator per RECIST v1.1.

The study is expected to enroll up to approximately 80 patients in the United States, Europe, and Japan.

Patritumab deruxtecan is currently being evaluated in a phase 1 study in previously treated patients with metastatic or unresectable non-small cell lung cancer (NSCLC) and a phase 1/2 study in patients with HER3 expressing metastatic breast cancer.

Clinical trials
Phase I/II Study of U3-1402 in Subjects With Human Epidermal Growth Factor Receptor 3 (HER3) Positive Metastatic Breast Cancer – NCT02980341
U3-1402 in Metastatic or Unresectable Non-Small Cell Lung Cancer – NCT03260491
A Study to Evaluate U3-1402 in Subjects With Advanced or Metastatic Colorectal Cancer – NCT04479436

References
[1] Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386-1422. doi:10.1093/annonc/mdw235 [Pubmed]
[2] NCCN Clinical Practice Guidelines in Oncology (Colon Cancer). Version 4. 2020.
[3] National Cancer Institute. SEER, Cancer Statistics (1975-2016). Available online. Last accessed September 14, 2020
[4] Lyu H, Han A, Polsdofer E, Liu S, Liu B. Understanding the biology of HER3 receptor as a therapeutic target in human cancer. Acta Pharm Sin B. 2018;8(4):503-510. doi:10.1016/j.apsb.2018.05.010 [Pubmed]
[5] Baiocchi G, Lopes A, Coudry RA, et al. ErbB family immunohistochemical expression in colorectal cancer patients with higher risk of recurrence after radical surgery. Int J Colorectal Dis. 2009;24(9):1059-1068. doi:10.1007/s00384-009-0702-6
[6] Rajkumar T, Gooden CS, Lemoine NR, Gullick WJ, Goden CS. Expression of the c-erbB-3 protein in gastrointestinal tract tumours determined by monoclonal antibody RTJ1 [published correction appears in J Pathol 1993 Oct;171(2):154]. J Pathol. 1993;170(3):271-278. doi:10.1002/path.1711700309
[7] Maurer CA, Friess H, Kretschmann B, et al. Increased expression of erbB3 in colorectal cancer is associated with concomitant increase in the level of erbB2. Hum Pathol. 1998;29(8):771-777. doi:10.1016/s0046-8177(98)90444-0
[8] Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145-164. doi:10.3322/caac.21601
[9] American Cancer Society. Cancer Facts & Figures 2020. Atlanta: American Cancer Society, 2020.
[10] Jeong JH, Kim J, Hong YS, et al. HER2 Amplification and Cetuximab Efficacy in Patients With Metastatic Colorectal Cancer Harboring Wild-type RAS and BRAF. Clin Colorectal Cancer. 2017;16(3):e147-e152. doi:10.1016/j.clcc.2017.01.005
[11] Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020;5(1):22. Published 2020 Mar 20. doi:10.1038/s41392-020-0116-z
[12] Mishra R, et al. Oncol Rev. 2018;12(1):355. doi: 10.4081/oncol.2018.355. eCollection 2018 Jan 30.