Introduction: Targeted therapies in HER2+ MBC significantly improve outcomes but efficacy is limited by therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Our group reported objective responses with 17-AAG plus trastuzumab in HER2+ MBC. Ganetespib, a synthetic, second generation HSP90 inhibitor has increased potency and tolerability compared with earlier agents. We reported anti-tumor activity in metastatic HER2+ and triple negative breast cancer with single agent ganetespib. Preclinically, HSP90 inhibition has synergistic anti-tumor activity with taxanes and trastuzumab. This study will define the MTD and RP2D of ganetespib plus paclitaxel and trastuzumab in HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab-resistant HER2+ MBC receive weekly trastuzumab and paclitaxel (80mg/m2) with ganetespib on day 1, 8, 15 of a 28 day cycle. HR+ positive patients are required to have at least one prior line of endocrine therapy. DLT of ganetespib monotherapy is diarrhea and therefore patients receive prophylactic anti-motility agents. Based on prior experience with ganetespib plus docetaxel in NSCLC, only 3 dose levels of ganetespib were explored: 100mg/m2, 150mg/m2 and a 3rd cohort of 125mg/m2, if needed. Secondary endpoints include evaluation of effects of ganetespib on the pharmacokinetics (PK) of paclitaxel and preliminary efficacy assessment. Results: The dosing cohorts (100 mg/m2 (n=3) and 150 mg/m2 (n=6)) have been completed without any DLTs. Median age was 46 years (range 29-65), median prior lines of chemotherapy and anti-HER2 therapy were 3 (range 2-6) and 3 (range 2-4) respectively, including prior pertuzumab in 9/9 and T-DM1 in 8/9 patients. There were no grade 3/4 adverse events (AEs) related to ganetespib. Most common AEs related to ganetespib were diarrhea, fatigue, anemia and rash. Paclitaxel PK data available from 6/9 patients are not appreciably different from those reported in literature. Overall response rate was 25% (2/8 had PR in 150 mg/m2 cohort; 1 patient was not evaluable), SD in 63% (5/8), and clinical benefit rate (CR+PR+SD>24 weeks) was 50% (4/8). 3 patients remain on study. Conclusion: The RP2D of ganetespib is 150mg/m2 in combination with paclitaxel and trastuzumab. The combination was safe and well tolerated. Updated PFS and PK data will be presented. Despite prior taxanes, pertuzumab and T-DM1, clinical activity of this triplet regimen in this heavily pre-treated cohort is very promising and together with our prior experience with 17-AAG plus trastuzumab and single agent ganetespib warrants further study in HER2+ MBC. A phase 2 trial is being planned in trastuzumab-refractory HER2+ MBC who have progressed on prior pertuzumab and T-DM1. Additionally, the protocol is amended to assess the safety of ganetespib in combination with paclitaxel, trastuzumab and pertuzumab in the first-line setting. Citation Format: Jhaveri K, Teplinsky E, Chandarlapaty S, Solit D, Cadoo K, Speyer J, D'Andrea G, Adams S, Patil S, Haque S, Friedman K, Neville D, Esteva F, Hudis C, Modi S. A phase I trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-21.

Background Among women with an elevated risk of hereditary breast and ovarian cancer who previously tested negative for pathogenic mutations in BRCA1 and BRCA2, a subset remain at increased risk of having hereditary breast, ovarian or other cancers, and should be offered multi-gene panel testing. We tested three groups of women who were enrolled in the UCSF Cancer Genetics and Prevention Program: (i) 97 women with a personal history of bilateral breast cancer, (ii) 104 women with a personal history of breast cancer and a first-degree or second-degree relative with ovarian cancer, and (iii) 99 women with a personal history of ovarian, fallopian tube, or primary peritoneal cancer. All women previously tested negative for pathogenic BRCA1 and BRCA2 mutations by either limited or comprehensive testing. Methods We performed comprehensive next-generation sequencing using a panel of 19 genes developed by Color Genomics (a CLIA-certified laboratory) covering ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53. Results Across the groups tested, 9% had pathogenic mutations in one or more of the genes analyzed (8% in genes other than BRCA1 and BRCA2). Among these women, Ashkenazi Jewish and Hispanic women had elevated mutation rates compared to those of other ethnicities. In addition, we identified two women with pathogenic mutations in two cancer susceptibility genes, which has significant implications for family testing. These results demonstrate the importance of genetic testing of genes other than BRCA1 and BRCA2. Conclusions Among women with an elevated risk of hereditary breast and ovarian cancer who have previously tested negative for BRCA1 and BRCA2 mutations, we propose that women with characteristics of any of the three groups above be considered for subsequent multi-gene panel testing. Additionally, ethnicity and the possibility of multiple mutations may be indications for additional testing in these women and in family members of carriers. Citation Format: Crawford BB, Adams SB, Sittler T, Van den Akker J, Chan SB, Leitner O, Ryan LN, Gil E, Van 't Veer LJ. Multi-gene panel testing for hereditary cancer predisposition in unsolved high risk breast and ovarian cancer patients [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 P3-08-02.

Background: TNBC is defined by a lack of ER and PR expression and the absence of HER2 overexpression. As such, the only approved systemic treatment option approved for mTNBC is chemotherapy, which is associated with median survival of <1 year. The programmed death receptor 1 (PD-1) pathway is frequently altered in cancer and used by tumors to evade an immune response. Pembrolizumab, an anti–PD-1 monoclonal antibody that prevents PD-1 from binding to its ligands, PD-L1 and PD-L2, has shown durable antitumor activity and a manageable toxicity profile in many advanced cancers, including mTNBC. In the phase 1b KEYNOTE-012 study, pembrolizumab 10 mg/kg given every 2 weeks (Q2W) provided an ORR of 18.5% and a 6-month PFS rate of 24.4% (RECIST v1.1, central review) in a cohort of 32 heavily pretreated patients with PD-L1–positive mTNBC. Trial Design: KEYNOTE-086 is a 2-part, multicohort, nonrandomized, phase 2 trial of pembrolizumab monotherapy for women and men with mTNBC (ClinicalTrials.gov, NCT02447003). Key eligibility for all cohorts include age ≥18 years, centrally determined mTNBC, ECOG PS 0 or 1, measurable disease per RECIST v1.1 by central review, and provision of a tumor sample for assessment of ER, PR, HER2, and PD-L1 status at a central laboratory. PD-L1 expression will be assessed by immunohistochemistry using the 22C3 antibody (Merck), with positivity defined as PD-L1 expression in the stroma or in ≥1% of tumor cells. Part 1 includes 2 cohorts that will enroll simultaneously. In cohort A, up to 160 pts with any PD-L1 status who have received ≥1 systemic treatment for metastatic breast cancer, were treated with an anthracycline and a taxane in the (neo)adjuvant and/or metastatic setting, and had documented disease progression on their most recent therapy will be enrolled. In cohort B, up to 40 pts with PD-L1–positive tumors who have received no prior systemic therapy for metastatic breast cancer will be enrolled. Part 2 is an expansion cohort of cohort A that will enroll up to 45 pts with tumors strongly positive for PD-L1 expression; part 2 will be initiated only if ≥1 response is observed in the cohort A PD-L1-strong-positive population. The definition of strongly positive PD-L1 expression will be determined in part 1. In all cohorts, pts will receive pembrolizumab 200 mg Q3W for 24 mo or until disease progression, intolerable toxicity, or patient or investigator decision. Clinically stable pts may continue pembrolizumab beyond initial RECIST-defined progression. Response will be assessed per RECIST v1.1 by central review every 9 wk for the first 12 mo and every 12 wk thereafter. AEs will be monitored throughout treatment and for 30 days thereafter (90 days for serious AEs and events of clinical interest). Primary end point is ORR. Secondary end points include duration of response (DOR), disease control rate, PFS, and OS. Efficacy and safety will be evaluated in all patients who receive ≥1 pembrolizumab dose. The Kaplan-Meier method will be used to estimate DOR, PFS, and OS. Current Status: Enrollment in KEYNOTE-086 will begin in June 2015 and continue until up to 245 patients are accrued. For additional information on KEYNOTE-086, contact MerckClinTrialSupport@merck.com. Citation Format: Adams S, Card D, Zhao J, Karantza V, Aktan G. A phase 2 study of pembrolizumab (MK-3475) monotherapy for metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-20.

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