Results from an ongoing multiple clinical studies with ONT-380, an orally active, reversible and selective small-molecule HER2 inhibitor for the treatment of breast cancer being developed by Seattle-based Oncothyreon, shows that the trial drug is well tolerated in Phase Ib trials.

These results of the trials were presented during the annual meeting of the American Society of Clinical Oncology (ASCO) being held May 29 – June 2, 2015 in Chicago Ill, USA.

Multiple presentations
The first presentation updated data from the Phase 1b trial of ONT-380 in combination with capecitabine (Xeloda?; Genentech/Roche))and trastuzumab (Herceptin?; Genentech/Roche) in third line treatment of HER2-positive metastatic breast cancer. This trial data supports Oncothyreon’s plans to initiate a blinded, randomized, placebo-controlled Phase II trial in this indication. The second presentation focused on the role of ONT-380 in the treatment of HER2-positive breast cancer central nervous system (CNS) metastases.

…the level of clinical activity seen in these trials, both systemically and in the CNS … in heavily pretreated patients is very encouraging…


The Phase Ib trial [1] of ONT-380 in combination with capecitabine and/or trastuzumab is a parallel dose escalation study in patients previously treated with trastuzumab and ado-trastuzumab emtansine or TDM-1 (Kadcyla?; Genentech/Roche) for metastatic breast cancer. Data were presented for 32 patients, including seven in the ONT-380 plus capecitabine cohort, 13 in the ONT-380 plus trastuzumabcohort and 12 in the ONT-380 plus capecitabineand trastuzumab cohort. Twenty-seven of the patients were evaluable for best overall response using RECIST 1.1 criteria.

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Considering the three cohorts together, a complete response (CR) was seen in two patients, a partial response (PR) in 12 patients, stable disease (SD) in nine patients and progressive disease (PD) in four patients.

CNS metastases
HER2-positive patients have benefited from treatment with adjuvant trastuzumab since this treatment option has dramatically lowered the risk of recurrence inHER2-positive breast cancer. However, the development of metastases in the central nervous system (CNS) is considered is one of the most devastating consequences of breast cancer progression and may be the first site of relapse. Available epidemiologic studies suggest that the incidence of brain metastases in women with metastatic breast cancer is between 10-16%. Being aware of this risk, requires that physicians monitor their patients for the potentially worrisome neurologic symptoms.[3]

The reason, according to some researchers, is that the CNS may be a sanctuary site for micrometastatic disease, either because trastuzumab does not penetrate the blood?brain barrier or because of the loss ofHER2overexpression in breast cancer cells migrating to the brain.

Ongoing trials
Patients included in the presentation on the role of ONT-380 in the treatment of CNS metastases were selected from the above trial and from an ongoing Phase Ib trial[4] of ONT-380 in combination with ado-trastuzumab emtansinein patients who have been previously treated with trastuzumab and a taxane for metastatic breast cancer.

Patients were included if their presenting CNS lesions were evaluable for response using RECIST 1.1 criteria and they had either untreated, asymptomatic lesions having never received radiotherapy or surgery to the CNS (n=8) or new or progressive lesions following prior CNS therapy (n=14).

Best CNS response was a CR in one patient, a PR in four patients and SD in nine patients. No patient had progressive disease as a CNS best response. One patient was not evaluable for response having undergone surgery for a symptomatic CNS lesion; pathologic examination of the resected specimen found no evidence of viable tumor. Two patients were not evaluated because of progressive disease outside of the CNS, while five patients in the series remain too early to evaluate.

Common adverse events
ONT-380 has been well tolerated in both Phase Ib trials. The most common adverse events included diarrhea, nausea, constipation, fatigue, dyspepsia, headache and vomiting. Most adverse events were grade 1 or 2 in severity. Laboratory abnormalities included asymptomatic elevated liver function tests, which were more common in patients also receiving Kadcyla. No grade 3 diarrhea was seen in either trial at the recommended dose of ONT-380; anti-diarrheal prophylaxis was not a study requirement.

“The level of clinical activity seen in these trials, both systemically and in the CNS, in heavily pretreated patients is very encouraging,” noted Stacy Moulder, M.D., Associate Professor, Breast Medical Oncology, University of Texas MD Anderson Cancer Center and one of the authors of both presentations. “Moreover, ONT-380 has been well-tolerated in these trials, an important consideration in patients who may need prolonged therapy,” she continued.

Future development
“Oncothyreon is currently planning a blinded, randomized placebo-controlled Phase II trial of ONT-380 in combination with Herceptin and Xeloda for the treatment of HER2-positive metastatic breast cancer in patients who have failed both pertuzumab (Perjeta?; Genentech/Roche) and ado-trastuzumab emtansine, which we expect to initiate late this year,” explained Diana Hausman, M.D., Chief Medical Officer of Oncothyreon. “The trial design includes endpoints focused on the prevention and treatment of CNS metastases. We have also now enrolled over 40 patients in our trial of ONT-380 in combination with ado-trastuzumab emtansineand continue to evaluate this combination for the treatment of patients with CNS metastases.”

Additional Information
[1] A Phase 1b Study of ONT-380 Combined With Capecitabine and/or Trastuzumab in Patients With HER2+ Metastatic Breast Cancer. Identifier NCT02025192. Last Accessed May 29, 2015
[2] Mayer M/ A patient perspective on brain metastases in breast cancer. Clin Cancer Res. 2007 Mar 15;13(6):1623-4. [Article]
[3] Tsukada Y, Fouad A, Pickren JW, Lane WW. Central nervous system metastasis from breast carcinoma. Autopsy study.Cancer. 1983 Dec 15;52(12):2349-54.
[4] A Phase 1b Study of ONT-380 Combined With Ado-trastuzumab Emtansine (T-DM1) in Patients With HER2+ Breast Cancer. Identifier NCT01983501

Last editorial review: May 30, 2015

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