Encouraging Results for [Fam-] Trastuzumab Deruxtecan in HER2 Expressing Advanced Colorectal Cancer

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Updated Phase I safety and efficacy data for [fam-] trastuzumab deruxtecan (DS-8201), an investigational HER2 targeting antibody-drug conjugate or ADC, were presented at the 2018 annual congress of the European Society for Medical Oncology – ESMO 2018, in Munich, Germany for a subgroup of patients with heavily pretreated HER2 expressing colorectal cancer.

Colorectal cancer is the third most common cancer worldwide. In 2012, there were approximately 1.36 million new cases diagnosed and 690,000 deaths worldwide.[1] Approximately 25% of patients have metastatic disease at diagnosis, meaning the disease has spread to distant organs, and about 50% of patients with colorectal cancer will eventually develop metastases.[2] Prognosis for these patients remains poor.[3]

An increase in the number of approved targeted therapies for advanced colorectal cancer over the past decade has helped improve outcomes for some patients, however efficacy and tolerability of second and third-line treatments remain limited.[4][5][6][7][8]

Approximately 3% of colorectal cancers overexpress the HER2 protein, which is a well-established therapeutic target in breast and gastric cancer.[4] In addition, research indicates that HER2 amplification may be associated with resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy and shorter survival.[9][10]

Currently, no approved HER2 targeting therapies exist for patients with colorectal cancer.

Novel treatment option
[Fam-] trastuzumab deruxtecan, also known as DS-8201 (and known as [fam-] trastuzumab deruxtecan in the United States and trastuzumab deruxtecan in other regions of world) is the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise.

Antibody-drug Conjugates or ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy, known as “payload,” to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Designed using Daiichi Sankyo’s proprietary ADC technology, [fam-] trastuzumab deruxtecan is comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. This investigational agent is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

Clinical development
A broad and comprehensive clinical development program with [fam-] trastuzumab deruxtecan is underway in North America, Europe and Asia.

The investigational agent is in Phase III development versus ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche; DESTINY-Breast03 | NCT03529110) and versus investigator’s choice post T-DM1 (DESTINY-Breast02 | NCT03523585) for HER2 positive metastatic breast cancer. The agent is also investigated in a pivotal phase II clinical development for HER2 positive metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01 | NCT03248492), a pivotal Phase II development for HER2 positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01 | NCT03329690), a Phase II development for HER2 expressing advanced colorectal cancer, a Phase II development for metastatic non-squamous HER2 overexpressing or HER2 mutated Non-Small Cell Lung Cancer (NSCLC), and a Phase I development in combination with nivolumab for HER2 expressing metastatic breast and bladder cancer.

[Fam-] trastuzumab deruxtecan has been granted Breakthrough Therapy designation for the treatment of patients with HER2 positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab (Herceptin®; Genentech/Roche) and pertuzumab (Perjeta®; Genentech/Roche) and have disease progression after T-DM1, and Fast Track designation for the treatment of HER2 positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2 targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA).

In Japan the drug has received SAKIGAKE Designation for the treatment of HER2 positive advanced gastric or gastroesophageal junction adenocarcinoma, a rare type of cancer of the esophagus, by the Japan Ministry of Health, Labour and Welfare (MHLW).

Metastatic solid tumors
An open-label, two-part phase 1 study is currently evaluating [fam-] trastuzumab deruxtecan in patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerant to standard treatment, or for whom no standard treatment is available.

The primary objective of the dose escalation phase of this study was to assess the safety and tolerability of [fam-] trastuzumab deruxtecan and determine the maximum tolerated dose (MTD).

Data from this part of the study were published in the Lancet Oncology.[11]

In the dose expansion part of the phase I study, [fam-] trastuzumab deruxtecan is given in one of two doses (5.4 mg/kg and 6.4 mg/kg) to patients with HER2 positive advanced or metastatic breast cancer and gastric cancer, HER2 low expressing breast cancer and other HER2 expressing solid tumors including colorectal cancer.

Overall, 292 patients have been enrolled into this phase 1 study of [fam-] trastuzumab deruxtecan.

Subgroup analysis
An updated subgroup analysis in 19 evaluable patients with heavily pretreated HER2 expressing (defined as IHC ≥1+ or amplified) colorectal cancer receiving a recommended expansion dose of 6.4 mg/kg showed that [fam-] trastuzumab deruxtecan demonstrated a confirmed overall response rate of 15.8% (3 of 19 patients) and a disease control rate of 84.2% (16 of 19 patients).

Median duration of response has not been reached and median progression-free survival was 3.9 months (95% CI: 2.1, 8.3) for this subgroup of patients. These patients had tumors with varying degrees of HER2 expression based on central IHC assessment of archival tissue, including six patients with HER2 IHC of zero (0).

Tumor shrinkage primarily was observed in tumors with higher levels of HER2 IHC.

“We are encouraged by these preliminary results with [fam-] trastuzumab deruxtecan, particularly given the unmet medical need for patients with HER2 expressing colorectal cancer that has progressed on one or more prior therapies,” said Takayuki Yoshino, MD, PhD, Director of Gastroenterology and Gastrointestinal Oncology at National Cancer Center Hospital East, Kashiwa, Japan, a study investigator.

“These initial findings support further evaluation of [fam-] trastuzumab deruxtecan in this specific type of colorectal cancer,” Yoshino added.

Better understanding
“There are no therapies specifically approved for patients with HER2 expressing colorectal cancer, and continued study of [fam-] trastuzumab deruxtecan will provide a better understanding of the potential role of a HER2 targeting antibody-drug conjugate in these patients,” said Gilles Gallant, BPharm, PhD, Vice President, DS-8201 Global Team Leader, Oncology Research and Development, Daiichi Sankyo.

“Patient enrollment is underway into our global Phase II study evaluating safety and efficacy of [fam-] trastuzumab deruxtecan in patients with HER2 expressing advanced colorectal cancer,” Gallant added.

Other data
Updated overall safety data as of August 10, 2018 across all subgroups of the ongoing phase I study with [fam-] trastuzumab deruxtecan in various HER2 expressing cancers were also reported at the annual meeting of the European Society for Medical Oncology.

Among 259 patients who received at least one dose of [fam-] trastuzumab deruxtecan 5.4 or 6.4 mg/kg in Part 1 or Part 2 of the study (regardless of tumor type), the most common adverse events (≥30%, any Grade) included nausea (74.1%), decreased appetite (56.8%) vomiting (43.6%), anemia (37.8%), alopecia (37.5%), fatigue (34.0%), diarrhea (33.6%) and constipation (32.8%). A total of 54.1% of patients experienced a ≥ Grade 3 adverse event and 22.8% had a serious adverse event, including 4.6% of patients who experienced an adverse event that led to death.

As previously presented, five cases of Grade 5 interstitial lung disease (ILD)/pneumonitis were reported by the investigators for the overall population of the phase I study, none of which was observed in patients with colorectal cancer. Any reported cases of ILD/pneumonitis in the [fam-] trastuzumab deruxtecan clinical development program are evaluated by an independent adjudication committee.

References
[1] Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer. 2015 Mar 1;136(5):E359-86. doi: 10.1002/ijc.29210. Epub 2014 Oct 9. [Pubmed]
[2] Van Cutsem E, Cervantes A, Nordlinger B, Arnold D. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014 Sep;25 Suppl 3:iii1-9. doi: 10.1093/annonc/mdu260. Epub 2014 Sep 4.[PubMed]
[3] American Cancer Society. Colorectal Cancer Survival Rates by Stage. 2017.
[4] The National Comprehensive Care Network (NCCN). NCCN Clinical Practice Guidelines in Oncology, Colon Cancer, Rectal Cancer Version 2. 2017.
[5] Martin V, Landi L, Molinari F, Fountzilas G, Geva R, Riva A, Saletti P, et al. 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.[PubMed]
[6] Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016 Aug;27(8):1386-422. doi: 10.1093/annonc/mdw235. Epub 2016 Jul 5.[PubMed]
[7] Adenis A, De la Fouchardiere C, Paule B, Burtin P, Tougeron D, Wallet J, Dourthe LM, et al. Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBECCA) nested within a compassionate use program. BMC Cancer. 2016 Jul 7;16:412. doi: 10.1186/s12885-016-2440-9.[PubMed]
[8] Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. doi: 10.1056/NEJMoa1414325.[PubMed]
[9] Takegawa N, Yonesaka K. HER2 as an Emerging Oncotarget for Colorectal Cancer Treatment After Failure of Anti-Epidermal Growth Factor Receptor Therapy. Clin Colorectal Cancer. 2017 Dec;16(4):247-251. doi: 10.1016/j.clcc.2017.03.001. Epub 2017 Mar 9.[PubMed]
[10] Jeong, et al. Clinical Colorectal Cancer. 2017;16(3):147-152.
[11] Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, Shimizu C, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol. 2017 Nov;18(11):1512-1522. doi: 10.1016/S1470-2045(17)30604-6. Epub 2017 Oct 13.[PubMed]


Last Editorial Review: October 21, 2018

Featured Image: Annual Congress of ESMO 2018. Courtesy: © 2018 European Society for Medical Oncology. Used with permission.

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