SABCS '15 --promising drug vs her2+ BRAIN METS PROCEEDING TO PHASE 2 TRIAL

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SABCS15: Promising phase 1 results lead to phase 2 for ONT-380 in HER2+ breast cancer

BY GARTH SUNDEM IN FEATURED, LATEST NEWS, RESEARCH · DECEMBER 9, 2015 · NO COMMENTS


Virginia Borges, MD, MMSc, and colleagues show promising early results of ONT-380 against HER2+ breast cancer.

Results of an ongoing phase 1b clinical trial presented today at the 2015 San Antonio Breast Cancer Symposium show promise of the experimental anti-cancer agent ONT-380 against metastatic HER2+ breast cancer, especially against brain metastases commonly associated with progression of the disease. Of 33 evaluable patients with metastatic HER2+ breast cancer (with and without brain metastases), 19 (58 percent) showed clinical benefit, with 16 achieving at least “stable disease” (i.e. no tumor progression while on trial), of which 11 patients experienced “partial response” (i.e. tumor shrinkage of more than 30 percent). Of 8 patients with brain metastases, 5 achieved at least stable disease, with 2 partial responses and one complete response in which existing brain metastases were undetectable after treatment.

“When you look at the clinical benefit for women previously treated, we’ve had patients with controlled brain lesions for over six months or a year, which is pretty unheard of,” says Virginia Borges, MD, MMSc, director of the Breast Cancer Research Program and Young Women’s Breast Cancer Translational Program at the University of Colorado Cancer Center and one of the study’s co-principal investigators.

“And they’re able to get this benefit by taking a pill that has essentially no side effects for most women,” she says.

Results of this ongoing phase I clinical trial (NCT01983501) support the initiation of a phase II clinical trial (NCT02614794), which Borges hopes will start accruing patients by the end of January 2016.

In about 25 percent of the 1-in-8 women who will develop breast cancer during their lifetimes, the HER2 gene creates an abnormal amount of HER2 protein, which acts as a “receptor” for human epidermal growth factor. The presence of more HER2 receptors allows a cell to trap more growth-promoting hormones, which tells the cell to grow in an out-of-control, cancerous way.

ONT-380, invented by Array Biopharma in Boulder, CO and now being developed by Oncothyreon in Seattle, WA, is a small molecule inhibitor of the HER2 growth factor receptor. The drug works by targeting the HER2 “tyrosine kinase” – a link in the chain of communication that allows HER2 receptors to signal the growth of the cell. The fact that it is a small molecule means the drug is able to pass through the blood-brain barrier to act against brain metastases of the disease. HER2+ breast cancer is more likely to affect younger women and also more likely than other breast cancers to metastasize specifically to the brain.

“I don’t want to downplay this drug’s potential to provide overall control of HER2+ breast cancer, but it’s a real game-changer for its specific ability to control brain metastases. What distinguishes ONT-380 from other players in the field is that you get both,” Borges says.

Side-effects were generally mild and included nausea, fatigue, diarrhea, vomiting, thrombocytopenia, AST/ALT elevation, headache, decreased appetite, epistaxis, constipation, and hypokalemia.

“If ONT-380 continues its current trajectory, we hope it could present a real option for controlling brain metastases in HER2+ breast cancer,” Borges says.

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Supported by NRG Oncology grants U10CA180868 & U10CA180822 from the National Cancer Institute (NCI).

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[P4-14-20] A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+ metastatic breast cancer (MBC)

Ferrario C, Hamilton E, Aucoin N, Falkson CI, Khan Q, Krop IE, Welch S, Bedard PL, Conlin A, Chaves J, Vo A, Walker L, Borges V. Segal Cancer Centre -Jewish General Hospital, Montreal, QC, Canada; Sarah Cannon Research Institute, Nashville, TN; Hopital de la Cite-de-la Sante, Laval, QC, Canada; University of Alabama Comprehensive Cancer Center, Birmingham, AL; University of Kansas Medical Center, Westwood, KS; Dana-Farber Cancer Institute, Boston, MA; London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada; Princess Margaret Cancer Center – University Health Network, Toronto, ON, Canada; Providence Oncology and Hematology Care Clinic, Eastside, Portland, OR; Northwest Medical Specialties PLLC, Tacoma, WA; Oncothyreon Inc, Seattle, WA; University of Colorado Cancer Center, Aurora, CO; Tennessee Oncology PLLC, Nashville, TN

Background: ONT 380 is a potent HER2 selective tyrosine kinase inhibitor with minimal EGFR-like side effects. Preclinical studies demonstrate synergism with trastuzumab (T) and chemotherapy, as well as activity in models of HER2+ CNS disease. Based on the potential for increased clinical activity of dual HER2 blockade in the context of a targeted cytotoxic agent, we evaluated the safety, tolerability, and anti-tumor activity of ONT-380 in combination with T-DM1 in patients (pts) with MBC with and without CNS metastases (mets).
Methods: 3+3 dose escalation with MTD expansion cohorts in pts with/without CNS mets evaluating ONT-380 (300 or 350 mg PO BID) combined with T-DM1 3.6 mg/kg IV q 21 days. Prior treatment with T and taxane was required; prior lapatinib and asymptomatic brain mets (treated or untreated) were allowed. Assessments included safety, PK, and systemic (RECIST 1.1) and CNS (modified RECIST) tumor response, with brain MRI at baseline and q 6 wks in pts with CNS mets at baseline. DLT was defined as the occurrence of protocol-specified events during the 1st treatment cycle.
Results: As of 01 June 2015, 51 pts have been enrolled and have received between 1 and 22 cycles, with safety data available for 43 pts (n=36 at 300 mg BID; n=7 at 350 mg BID). Pts had a median of 2 prior treatments for MBC, including T (n=43); pertuzumab (n=15) and lapatinib (n=7). The MTD for ONT-380 was 300 mg BID with 5/36 pts (14%) with DLT (Gr 3 AST/ALT [n=4]; Gr 2 vomiting/Gr1 diarrhea [n=1]) vs. 3/7 pts (43%) with DLT at 350 mg BID (Gr 3 vomiting [n=1]; Gr 3 hypersensitivity [n=1]; Gr 3 fatigue [n=1]). Overall, the majority of AEs have been Gr 1 or 2. The most common AEs, regardless of relationship, were nausea, fatigue, diarrhea, vomiting, thrombocytopenia, AST/ALT elevation, headache, decreased appetite, epistaxis, constipation, and hypokalemia. Gr 3 AST/ALT elevation has occurred in 7/43 pts (16%), with no events meeting Hy's law, and has been reversible with dose interruption and reduction except in 2 pts found to have progressive liver mets. No Gr 3 diarrhea has occurred at any dose. ONT-380 PK was dose proportional, and no drug-drug interaction was observed with T-DM1. In 33 of 43 pts with data available from at least one follow-up scan to evaluate response, best systemic response regardless of dose was 11 PR, 16 SD, and 6 PD, with clinical benefit rate (CBR= CR, PR, or SD >6 mos) of 19/33 (58%). The most common reason for treatment discontinuation was PD, with 3 pts coming off study for AEs (n=1 each of Gr 3 hypersensitivity, Gr 2 vomiting, Gr 3 AST/ALT). Eight pts to date have been evaluable for CNS response (untreated or progressive CNS mets with ≥1 follow-up MRI), with best CNS response of 1 CNS CR, 2 CNS PR, and 5 CNS SD, with a CNS CBR of 5/8 (63%). All pts with CNS response are still active.
Conclusion: Treatment with ONT-380 300 mg BID and T-DM1 3.6 mg/kg has been tolerable. Early evidence of anti-tumor activity has been seen, including clinical benefit in patients with CNS mets. Updated results will be presented.

Friday, December 11, 2015 7:30 AM

Poster Session 4: Treatment: HER2-Targeted Therapy (7:30 AM-9:00 AM)