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Phase II study of pembrolizumab and nab-paclitaxel in HER2-negative metastatic breast cancer: Hormone receptor-positive cohort [Meeting Abstract]

Novik, Y; Klar, N; Zamora, S; Kwa, M; Speyer, J; Oratz, R; Muggia, F; Meyers, M; Hochman, T; Goldberg, J; Adams, S
Background: PD-1/PD-L1 checkpoint blockade in combination with chemotherapy has improved outcomes in triple-negative breast cancer, but its role in hormone receptor-positive (HR+) metastatic breast cancer (MBC) is less clear. We report the results of the HR+ cohort of a HER2-negative MBC trial.
Method(s): Prospective phase 2 trial where 20 HR+/HER2- MBC patients (pts) received nab-paclitaxel (A) (100mg/m2 IV d1/8, q 3 wks) and pembrolizumab (P) (200mg IV d1, q 3 wks, starting with cycle 2). Eligibility: ER/PR >=1%, HER2 negative, maximum of 2 lines of cytotoxic therapy for MBC, pts could have received prior endocrine and/or targeted therapy. Primary endpoint: best overall response rate (BORR) by RECIST v1.1; secondary endpoints: safety, PFS, clinical benefit rate (CBR), duration of response (DOR), and overall survival (OS). Biomarker analyses are ongoing.
Result(s): In this 20-patient cohort, the median age was 56 (34-75), median lines of cytotoxic chemotherapy was 1 (0-2), 70% (14/20) were ER>10%, 80% (16/20) received prior hormone therapy, and 60% (12/20) received prior CDK 4/6 inhibitors. BORR was partial response (PR) in 5/20, stable disease (SD) in 7/20, and progressive disease (PD) in 7/20. CBR was 35% (7/20). Median PFS was 5.6 mos (95%CI 2.07-8.18), median OS 15.7 mos (95%CI 3.88-27.70) and median DOR was 3.9 mos (95%CI 2.07-not yet reached). Out of 5 pts who achieved PR, 4 (80%) received prior CDK 4/6 inhibitors. The most common related adverse events (AE) were anemia (50%), diarrhea, nausea and ALT abnormalities (40% each). 14 pts experienced grade 3 AEs, the most common being neutropenia, 1 pt had grade 4 AEs (pneumonitis, blood/lymphatics, hyponatremia), and no grade 5 AEs. [Formula presented]
Conclusion(s): P plus A was efficacious with PR in 5/20 and SD in 7/20 pts with a manageable toxicity profile. Importantly, responses were observed in patients previously treated with CDK 4/6 inhibitors. Further investigation of this regimen in HR+/HER2- MBC is warranted. Clinical trial identification: NCT02752685. Legal entity responsible for the study: NYU Langone Health.
Funding(s): Merck (drug-pembrolizumab and financial funding); Celgene (drug-nab-paclitaxel). Disclosure: F. Muggia: Advisory/Consultancy, Member of data safety monitoring committee of Pembrolizumab trials run by Merck: Merck. S. Adams: Advisory/Consultancy, Research grant/Funding (institution), consultant (uncompensated): Merck; Research grant/Funding (institution): Celgene. All other authors have declared no conflicts of interest.
ISSN: 0923-7534
CID: 4470992

Serial immunological parameters in a phase II trial of exemestane and low-dose oral cyclophosphamide in advanced hormone receptor-positive breast cancer

Kwa, Maryann; Li, Xiaochun; Novik, Yelena; Oratz, Ruth; Jhaveri, Komal; Wu, Jennifer; Gu, Ping; Meyers, Marleen; Muggia, Franco; Speyer, James; Iwano, Alyssa; Bonakdar, Maryam; Kozhaya, Lina; Tavukcuoglu, Ece; Budan, Bahar; Raad, Roy; Goldberg, Judith D; Unutmaz, Derya; Adams, Sylvia
BACKGROUND AND PURPOSE: Resistance to endocrine therapies in hormone receptor (HR)-positive breast cancer is a significant challenge. Prior studies have shown that low-dose oral cyclophosphamide can transiently deplete regulatory T cells (Tregs) and improve anti-tumor immunity. We investigated the combination of exemestane with cyclophosphamide in patients with advanced HR-positive breast cancer and assessed changes in circulating immune cell subsets. METHODS: This was a single-arm phase II trial of exemestane with cyclophosphamide in patients with metastatic HR-positive/HER2-negative breast cancer who had progressed on prior endocrine therapy ( NCT01963481). Primary endpoint was progression-free survival (PFS) at 3 months (RECIST 1.1). Secondary objectives included median PFS, objective response rate, duration of response, and safety. Circulating Tregs (FOXP3+Helios+) and other immune cell subsets were monitored during treatment and compared with healthy controls. RESULTS: Twenty-three patients were enrolled. Treatment was well tolerated, without grade 4/5 toxicities. Objective responses were seen in 6/23 patients (26.1%; 95% CI 10.2-48.4%) and were durable (median 11.6 months). Three-month PFS rate was 50.1% (95% CI 33.0-76.0%); median PFS was 4.23 months (95% CI 2.8-11.7). No treatment-related decrease in Tregs was observed. However, elevated baseline levels of Naive Tregs [greater than 2.5 (the median of the naive Tregs)] were associated with relative risk of disease progression or death [hazard ratio 11.46 (95% CI 2.32-56.5)]. In addition, the baseline levels of Naive Tregs (adj-p = 0.04), Memory Tregs (adj-p = 0.003), CD4 + Central Memory T cells (adj-p = 0.0004), PD-1 + CD4 + Central Memory T cells (adj-p = 0.008), and PD-1 + CD4 + Effector Memory T cells (adj-p = 0.009) were significantly greater in the patients than in the healthy controls; the baseline levels of %CD4 + Naive T cells (adj-p = 0.0004) were significantly lower in patients compared with healthy controls (n = 40). CONCLUSION: Treg depletion was not observed with low-dose cyclophosphamide when assessed by the specific marker FOXP3 + Helios +; however, baseline naive Tregs were associated with 3-month PFS. Exemestane/cyclophosphamide combination had favorable safety profile with evidence of clinical activity in heavily pretreated patients.
PMID: 29124456
ISSN: 1573-7217
CID: 2772912

Phase II trial of pembrolizumab in combination with nab-paclitaxel in patients with metastatic HER2-negative breast cancer [Meeting Abstract]

Kwa, Maryann J.; Iwano, Alyssa; Esteva, Francisco J.; Novik, Yelena; Speyer, James L.; Oratz, Ruth; Meyers, Marleen Iva; Axelrod, Deborah M.; Hogan, Rebecca; Mendoza, Sandra; Goldberg, Judith D.; Muggia, Franco; Adams, Sylvia
ISSN: 0732-183x
CID: 3726432

Results of a phase I-II study of adjuvant concurrent carboplatin and accelerated radiotherapy for triple negative breast cancer

Formenti, Silvia C; Golden, Encouse B; Goldberg, Judith D; Li, Xiaochun; Taff, Jessica; Fenton-Kerimian, Maria B; Chandrasekhar, Sharanya; Demaria, Sandra; Novik, Yelena
Purpose: To determine feasibility and explore the clinical efficacy of concurrent radiotherapy and carboplatin as adjuvant treatment of triple negative breast cancer (TNBC). Patients and Methods: Women with Stage I-II TNBC were treated after surgery in a phase I-II prospective trial [NCT01289353]. Weekly carboplatin (AUC = 2.0) was delivered for 6 weeks. Concurrent radiotherapy was delivered in the prone position during weeks 2-4, for a total dose of 40.5 Gy in 15 fractions to the breast, and 46.5 Gy in 17 fractions to the tumor bed. Adverse events (AE) were assessed weekly during treatment, once at 45-60 d, and every 6 mo thereafter, using the Common Terminology Criteria for AE (CTCAE) v3.0. Results: A total of 39 patients accrued and 36 received treatment. Eight patients (22%, exact 95% CI: 10%, 39%) developed grade 2 or greater acute radiation dermatitis. Overall, grade 2 AE were seen in nine and grade 3 in two patients. Twenty-three patients (64%) received additional adjuvant chemotherapy. With a median follow-up of 48 mo, 34/36 (94%) are alive and disease free. One patient died of pulmonary failure with possible but unproven breast cancer recurrence, and one patient died of pelvic malignancy. One patient recurred locally and is alive and disease free after surgical management. Brisk lymphocytic infiltrate was present pre-treatment in 39% of 18 patients with evaluable tumor. Conclusions: Adjuvant concurrent carboplatin and prone accelerated radiotherapy is a well-tolerated and promising treatment of early stage TNBC. The observed 3% compares favorably with the expected 30% recurrence rate within 1-4 y from treatment, warranting further studies.
PMID: 28405497
ISSN: 2162-4011
CID: 2527872

Phase II trial of exemestane with immunomodulatory oral cyclophosphamide in metastatic hormone receptor (HR)-positive breast cancer: Prolonged progression-free survival (PFS) in patients with distinct T regulatory cell (Treg) profile [Meeting Abstract]

Kwa, M; Novik, Y; Oratz, R; Jhaveri, K; Wu, J; Gu, P; Meyers, M; Muggia, F; Bonakdar, M; Abidoglu, C; Kozhaya, L; Li, X; Joseph, B; Iwano, A; Friedman, K; Goldberg, JD; Unutmaz, D; Adams, S
ISSN: 1538-7445
CID: 2411072

Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: a New York Cancer Consortium trial

Adelson, Kerin; Ramaswamy, Bhuvaneswari; Sparano, Joseph A; Christos, Paul J; Wright, John J; Raptis, George; Han, Gang; Villalona-Calero, Miguel; Ma, Cynthia X; Hershman, Dawn; Baar, Joseph; Klein, Paula; Cigler, Tessa; Budd, G Thomas; Novik, Yelena; Tan, Antoinette R; Tannenbaum, Susan; Goel, Anupama; Levine, Ellis; Shapiro, Charles L; Andreopoulou, Eleni; Naughton, Michael; Kalinsky, Kevin; Waxman, Sam; Germain, Doris
The proteasome inhibitor bortezomib enhances the effect of the selective estrogen receptor (ER) downregulator (SERD) fulvestrant by causing accumulation of cytoplasmic ER aggregates in preclinical models. The purpose of this trial was to determine whether bortezomib enhanced the effectiveness of fulvestrant. One hundred eighteen postmenopausal women with ER-positive metastatic breast cancer resistant to aromatase inhibitors (AIs) were randomized to fulvestrant alone (Arm A-500 mg intramuscular (i.m.) day -14, 1, 15 in cycle 1, and day 1 of additional cycles) or in combination with bortezomib (Arm B-1.6 mg/m2 intravenous (i.v.) on days 1, 8, 15 of each cycle). The study was powered to show an improvement in median progression-free survival (PFS) from 5.4 to 9.0 months and compare PFS rates at 6 and 12 months (alpha=0.10, beta=0.10). Patients with progression on fulvestrant could cross over to the combination (arm C). Although there was no difference in median PFS (2.7 months in both arms), the hazard ratio for PFS in Arm B versus Arm A (referent) was 0.73 (95% confidence interval (CI)=0.49, 1.09, P=0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 alpha level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (P=0.03, 1-sided chi2-test; 95% CI for difference (14.5%)=-0.06, 29.1%). Of 27 patients on arm A who crossed over to the combination (arm C), 5 (18%) were progression-free for at least 24 weeks. Bortezomib likely enhances the effectiveness of fulvestrant in AI-resistant, ER-positive metastatic breast cancer by reducing acquired resistance, supporting additional evaluation of proteasome inhibitors in combination with SERDs.
PMID: 28721390
ISSN: 2374-4677
CID: 2640042

A Phase I-II Study of Adjuvant Concurrent Carboplatin and Accelerated Radiation Therapy for Triple Negative Breast Cancer: Updated Results [Meeting Abstract]

Golden, EB; Chhabra, AM; Fenton-Kerimian, MB; Novik, Y; Oratz, R; Speyer, J; Formenti, SC
ISSN: 1879-355x
CID: 2097822

Pregnancy-Associated Breast Cancer (PABC) in a Contemporary Cohort of Women With Newly Diagnosed Breast Cancer [Meeting Abstract]

Schnabel, Freya; Chun, Jennifer; Yeh, Janet; Schwartz, Shira; Rokosh, Sarah; Sure, Akhila; Novik, Yelena; Guth, Amber; Axelrod, Deborah; Hiotis, Karen
ISSN: 1534-4681
CID: 1788732

Clinical Trial Evidence of the Antitumor Activity of Topical Imiquimod for Breast Cancer Skin Metastases [Letter]

Adams, Sylvia; Novik, Yelena; Oratz, Ruth; Axelrod, Deborah; Speyer, James; Tiersten, Amy; Goldberg, Judith D; Bhardwaj, Nina; Unutmaz, Derya; Demaria, Sandra; Formenti, Silvia
PMID: 25092780
ISSN: 0732-183x
CID: 1105352

Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer

Singh, Jasmeet; Novik, Yelena; Stein, Stacey; Volm, Matthew; Meyers, Marlene; Smith, Julia; Omene, Coral; Speyer, James; Schneider, Robert; Jhaveri, Komal; Formenti, Silvia; Kyriakou, Victoria; Joseph, Benson; Goldberg, Judith D; Li, Xiaochun; Adams, Sylvia; Tiersten, Amy
INTRODUCTION: Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. Combination of everolimus also known as RAD001 (oral mammalian target of rapamycin (mTOR) inhibitor) and carboplatin may have activity in metastatic triple-negative breast cancer (TNBC). METHODS: The primary objective of this study was to determine clinical benefit rate (CBR), that is (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting >/=6 months) and the toxicity of everolimus/carboplatin in women with metastatic TNBC. Prior carboplatin was allowed. Treatment consisted of intravenous carboplatin area under the curve (AUC) 6 (later decreased to AUC 5 and subsequently to AUC 4) every 3 weeks with daily 5 mg everolimus. RESULTS: We enrolled 25 patients in this study. Median age was 58 years. There were one CR, six PRs, seven SDs and eight PDs (progression of disease). CBR was 36% (95% confidence interval (CI) 21.1 to 57.4%). One SD was achieved in a patient progressing on single agent carboplatin. The median progression free survival (PFS) was 3 months (95% CI 1.6 to 4.6 months) and overall survival (OS) was 16.6 months (95% CI 7.3 months to not reached). There were seven patients (28%) with >/= grade 3 thrombocytopenia; three (12%) with grade 3 neutropenia (no bleeding/febrile neutropenia) and one (4%) with grade 3 anemia. Greater hematological toxicity was seen in the first seven patients treated with carboplatin AUC5/6. After the amendment for starting dose of carboplatin to AUC 4, the regimen was well tolerated with only one out of 18 patients with grade 3 neutropenia and two patients with grade 3 thrombocytopenia. There was only one case of mucositis. CONCLUSION: Everolimus-carboplatin was efficacious in metastatic TNBC. Dose limiting hematological toxicity was observed when AUC5/6 of carboplatin was combined with everolimus. However, carboplatin AUC 4 was well tolerated in combination with everolimus with continuing responses. TRIAL REGISTRATIONS: NCT01127763.
PMID: 24684785
ISSN: 1465-542x
CID: 1583872