Abstract P4-21-01: Efficacy results of a phase 1b study of ONT-380, an oral HER2-specific inhibitor, in combination with capecitabine (C) and trastuzumab (T) in HER2+ metastatic breast cancer (MBC), including patients (pts) with brain metastases (mets)
Authors: Hamilton E , Borges V , Conlin A , Walker L , Moulder S 
Published: March 2017

Abstract
Background: ONT-380, a potent, highly selective, orally available small molecule inhibitor of HER2, has been associated with clinical benefit and minimal EGFR-type toxicities in single agent and combination studies of pts with HER2+ MBC, including pts with brain mets. In this Phase 1b study, ONT-380 was evaluated in combination with C and/or T in pts with HER2+ MBC who had been treated with T, a taxane, and ado-trastuzumab emtansine (T-DM1). During doublet dose escalation, ONT-380 300 mg PO BID was well tolerated and responses were seen in combination with either C or T alone; no maximum tolerated dose (MTD) was reached. ONT-380 300 mg PO BID was then studied in combination with both C and T as triplet therapy in order to provide dual blockade of HER2 in combination with cytotoxic chemotherapy. Safety and efficacy results of the triplet cohort are reported here.
Methods: ONT-380 300 mg PO BID was administered with C (1000 mg/m2 PO BID 14 days of a 21-day cycle), and T (8 mg/kg IV loading; then 6 mg/kg IV once every 21 days). Prior treatment with T, a taxane, and T-DM1 were required; prior pertuzumab, lapatinib, or neratinib were permitted; prior capecitabine exposure was prohibited. Pts with asymptomatic brain mets (treated or untreated) were also eligible. Assessments included safety and tumor response by RECIST 1.1 and Modified CNS RECIST 1.1.
Results: Enrollment was complete as of December 2015. Interim safety and efficacy results as of May 27, 2016 are reported here, with mature data to be presented at the meeting. 27 pts were treated with ONT-380 + C + T: median age 50 y, 56% ER/PR+, 44% ER/PR, 47% PS 0, 53% PS 1. Pts received a median of 3 prior HER2 agents: 100% prior T and TDM-1, 74% prior pertuzumab, 37% prior lapatinib. 11 pts had brain mets at baseline, including 7 patients with untreated or progressive brain mets. Most toxicities were Gr 1. The most common adverse events (&gt;40%) were diarrhea, nausea, palmar-plantar erythrodysaesthesia (PPE), vomiting, and fatigue. Gr 3 events included PPE (11%), diarrhea (11%), fatigue (11%), and reversible increase in AST/ALT (7%). Dose reductions of ONT-380 were required in 6 pts, with 4 of these patients having continued disease control &gt;6 months at the reduced dose. In 24 pts with measurable disease at baseline, ORR was 58%, with best responses of 1 CR, 13 PR, 6 SD, and 4 PD, and clinical benefit rate (SD ≥ 6 mos, PR, CR) in all 27 pts was 67%. Median PFS as of this data cut was 6.3 m (95% CI: 4.1-n/a). Median time on treatment for all 27 pts was 6.2 mo (range 1.4-21.4 mo), with 12 pts still active.
Conclusion: ONT-380 in combination with C and T exhibits an acceptable well tolerated safety profile and shows evidence of responses and long-term disease control in pts who have received contemporary standard of care treatment for HER2+ MBC with both pertuzumab and T-DM1, including pts with brain mets. Based on these encouraging data, a randomized placebo-controlled Phase 2 study (HER2CLIMB) is now enrolling to further evaluate the activity of ONT-380 in this population, including pts with brain mets.Background: ONT-380, a potent, highly selective, orally available small molecule inhibitor of HER2, has been associated with clinical benefit and minimal EGFR-type toxicities in single agent and combination studies of pts with HER2+ MBC, including pts with brain mets. In this Phase 1b study, ONT-380 was evaluated in combination with C and/or T in pts with HER2+ MBC who had been treated with T, a taxane, and ado-trastuzumab emtansine (T-DM1). During doublet dose escalation, ONT-380 300 mg PO BID was well tolerated and responses were seen in combination with either C or T alone; no maximum tolerated dose (MTD) was reached. ONT-380 300 mg PO BID was then studied in combination with both C and T as triplet therapy in order to provide dual blockade of HER2 in combination with cytotoxic chemotherapy. Safety and efficacy results of the triplet cohort are reported here.
Methods: ONT-380 300 mg PO BID was administered with C (1000 mg/m2 PO BID 14 days of a 21-day cycle), and T (8 mg/kg IV loading; then 6 mg/kg IV once every 21 days). Prior treatment with T, a taxane, and T-DM1 were required; prior pertuzumab, lapatinib, or neratinib were permitted; prior capecitabine exposure was prohibited. Pts with asymptomatic brain mets (treated or untreated) were also eligible. Assessments included safety and tumor response by RECIST 1.1 and Modified CNS RECIST 1.1.
Results: Enrollment was complete as of December 2015. Interim safety and efficacy results as of May 27, 2016 are reported here, with mature data to be presented at the meeting. 27 pts were treated with ONT-380 + C + T: median age 50 y, 56% ER/PR+, 44% ER/PR, 47% PS 0, 53% PS 1. Pts received a median of 3 prior HER2 agents: 100% prior T and TDM-1, 74% prior pertuzumab, 37% prior lapatinib. 11 pts had brain mets at baseline, including 7 patients with untreated or progressive brain mets. Most toxicities were Gr 1. The most common adverse events (&gt;40%) were diarrhea, nausea, palmar-plantar erythrodysaesthesia (PPE), vomiting, and fatigue. Gr 3 events included PPE (11%), diarrhea (11%), fatigue (11%), and reversible increase in AST/ALT (7%). Dose reductions of ONT-380 were required in 6 pts, with 4 of these patients having continued disease control &gt;6 months at the reduced dose. In 24 pts with measurable disease at baseline, ORR was 58%, with best responses of 1 CR, 13 PR, 6 SD, and 4 PD, and clinical benefit rate (SD ≥ 6 mos, PR, CR) in all 27 pts was 67%. Median PFS as of this data cut was 6.3 m (95% CI: 4.1-n/a). Median time on treatment for all 27 pts was 6.2 mo (range 1.4-21.4 mo), with 12 pts still active.
Conclusion: ONT-380 in combination with C and T exhibits an acceptable well tolerated safety profile and shows evidence of responses and long-term disease control in pts who have received contemporary standard of care treatment for HER2+ MBC with both pertuzumab and T-DM1, including pts with brain mets. Based on these encouraging data, a randomized placebo-controlled Phase 2 study (HER2CLIMB) is now enrolling to further evaluate the activity of ONT-380 in this population, including pts with brain mets.
Citation Format: Hamilton E, Borges V, Conlin A, Walker L, Moulder S. Efficacy results of a phase 1b study of ONT-380, an oral HER2-specific inhibitor, in combination with capecitabine (C) and trastuzumab (T) in HER2+ metastatic breast cancer (MBC), including patients (pts) with brain metastases (mets) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-01.