This week a first patient was dosed in DESTINY-CRC02 (NCT04744831), a global phase II clinical trial evaluating the efficacy and safety of trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca) in patients with HER2 overexpressing locally advanced, unresectable or metastatic colorectal cancer with progression following treatment with standard of care chemotherapy.

Trastuzumab deruxtecan* is a HER2-directed antibody-drug conjugate (ADC). Designed using Daiichi Sankyo’s proprietary DXd ADC technology, trastuzumab deruxtecan is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform.

Trastuzumab deruxtecan consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

In May 2020, trastuzumab deruxtecan received Breakthrough Therapy Designation (BTD) in the U.S. for the treatment of patients with metastatic non-small cell lung cancer whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.

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Third most common cancer
Colorectal cancer is the third most common cancer and second most common cause of cancer death globally.[1] Approximately 20% of patients have metastatic disease at diagnosis, meaning the disease has spread to distant organs, and about 50-60% of patients initially diagnosed with early-stage colorectal cancer will eventually develop metastases. [2] There are currently no medicines approved to specifically treat HER2overexpressing colorectal cancer, which affects approximately 2 to 5% of patients.[3]

Many patients with advanced or metastatic disease eventually progress on the current standard of care treatments.[4]

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung, and colorectal cancers. Overexpression and amplification of HER2 occur in approximately 2 to 5% of patients with colorectal cancer.[3] Research indicates that HER2 amplification may be associated with resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy and shorter survival.[5][6]

“Patients with metastatic colorectal cancer often have limited treatment options following progression on the standard of care therapy, making it important to understand new ways to treat these patients. Identifying patients with HER2 overexpression is an important area of research to further explore,” said Gilles Gallant, BPharm, Ph.D., FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo.

“Based on the encouraging data from the DESTINY-CRC01 (NCT03329690) phase II trial, we have initiated this second phase 2 study to further evaluate the potential of targeting HER2 with ENHERTU at the 5.4 mg/kg and 6.4 mg/kg doses in patients with HER2 overexpressing advanced colorectal cancer,” Gallant added.

The DESTINY-CRC02 trial is a global, phase II trial evaluating the efficacy and safety of two doses (5.4 mg/kg or 6.4 mg/kg) of trastuzumab deruxtecan in patients with HER2 overexpressing BRAF wild-type, RAS wild-type or mutant locally advanced, unresectable or metastatic colorectal cancer with progression following treatment with standard of care chemotherapy.

Treatment
Previously, treatments options, if clinically indicated and not contraindicated, should include chemotherapy (fluoropyrimidine, oxaliplatin, and irinotecan); targeted therapy (anti-epidermal growth factor receptor (EGFR) treatment, (i.e. RAS wild-type); or, anti-vascular endothelial growth factor (VEGF) treatment); and/or immunotherapy (anti-programmed death-ligand 1 (PD-[L]-1) therapy, if the tumor is microsatellite instability (MSI)-high/deficient mismatch repair (dMMR), or tumor mutational burden (TMB)-high.

Clinical study and endpoint
The study will be conducted in two stages. In stage 1, 80 patients will be randomized 1:1 to receive either 5.4mg/kg or 6.4 mg/kg of trastuzumab deruxtecan administered every three weeks. After enrollment is completed in stage 1, 40 patients will be enrolled to the 5.4 mg/kg arm at stage 2.

The primary endpoint is confirmed objective response rate (ORR) as assessed by blinded independent central review. Secondary endpoints include duration of response, disease control rate, clinical benefit ratio, investigator-assessed ORR, progression-free survival, overall survival, pharmacokinetics, patient-reported outcomes, and safety.

Note
* Known as Fam-trastuzumab deruxtecan-nxki in the U.S

Clinical trials
DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Gastric Cancer [DESTINY-Gastric01] – NCT03329690
Trastuzumab Deruxtecan in Participants With HER2-overexpressing Advanced or Metastatic Colorectal Cancer (DESTINY-CRC02) – NCT04744831

Highlights of Prescription information
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Capecitabine (Fluoropyrimidine; Xeloda®; Roche) [Prescribing Information]
Oxaliplatin  (Eloxatin®; Sanofi Genzyme) [Prescribing Information]
Irinotecan liposome (Onivyde®; Ipsen)[Prescription Information]

References
[1] World Health Organization. Cancer Factsheet. Online. Last accessed on Accessed April 6, 2021.
[2] Jeong JH, Kim J, Hong YS, Kim D, Kim JE, Kim SY, Kim KP, Yoon YK, Kim D, Chun SM, Park Y, Jang SJ, Kim TW. HER2 Amplification and Cetuximab Efficacy in Patients With Metastatic Colorectal Cancer Harboring Wild-type RAS and BRAF. Clin Colorectal Cancer. 2017 Sep;16(3):e147-e152. doi: 10.1016/j.clcc.2017.01.005. Epub 2017 Jan 25. PMID: 28223103.
[3] Siena S, Sartore-Bianchi A, Marsoni S, Hurwitz HI, McCall SJ, Penault-Llorca F, Srock S, Bardelli A, Trusolino L. Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol. 2018 May 1;29(5):1108-1119. doi: 10.1093/annonc/mdy100. PMID: 29659677; PMCID: PMC5961091.
[4] Holch J, Stintzing S, Heinemann V. Treatment of Metastatic Colorectal Cancer: Standard of Care and Future Perspectives. Visc Med. 2016 Jun;32(3):178-83. doi: 10.1159/000446052. Epub 2016 Jun 7. PMID: 27493945; PMCID: PMC4945779.
[5] Martin V, Landi L, Molinari F, Fountzilas G, Geva R, Riva A, Saletti P, De Dosso S, Spitale A, Tejpar S, Kalogeras KT, Mazzucchelli L, Frattini M, Cappuzzo F. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients. Br J Cancer. 2013 Feb 19;108(3):668-75. doi: 10.1038/bjc.2013.4. Epub 2013 Jan 24. PMID: 23348520; PMCID: PMC3593567.
[6] Wang XY, Zheng ZX, Sun Y, Bai YH, Shi YF, Zhou LX, Yao YF, Wu AW, Cao DF. Significance of HER2 protein expression and HER2 gene amplification in colorectal adenocarcinomas. World J Gastrointest Oncol. 2019 Apr 15;11(4):335-347. doi: 10.4251/wjgo.v11.i4.335. PMID: 31040898; PMCID: PMC6475672.

Featured Image: Healthcare. Women in Laboratory. Photo Courtesy: © 2021 Diane Serik on Unsplash | Used with Permission.

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