Vidula, Neelima

Abstract Background: Two PARP inhibitors are approved for germline BRCA1/2 mutant metastatic breast cancer (MBC), based on clinical trials demonstrating an improvement in patient outcomes and quality of life. However, germline BRCA1/2 mutations are identified in 5-10% of breast cancer, limiting their potential applicability. Our prior work demonstrated that somatic BRCA1/2 mutations can be detected in cell-free DNA (cfDNA) in a proportion of patients with MBC who are not germline BRCA1/2 carriers, and that a PARP inhibitor caused growth inhibition in a circulating tumor cell line generated from a patient with MBC and a pathogenic somatic BRCA1 mutation (Vidula, Dubash, CCR, 2020). Thus, we hypothesize that a PARP inhibitor may have efficacy in somatic BRCA1/2 mutant MBC identified by cfDNA. Trial Design: This phase II investigator initiated open label clinical trial is enrolling 30 patients who have pathogenic somatic BRCA1/2 mutations found in cfDNA. Patients must not be known germline BRCA1/2 carriers. Patients receive treatment with the PARP inhibitor, talazoparib, until disease progression. Serial imaging (CT chest, abdomen, pelvis, and bone scan) occurs every 3 months, and cfDNA is collected monthly to evaluate changes in the genomic environment. Patients will also have blood collected at baseline for the Cancer Risk B assay (CR-B), a novel flow variant assay to assess double strand break repair mutations in circulating blood cells (Syeda, Genetics, 2017). Eligibility criteria: Patients with MBC (TNBC with ≥ 1 prior chemotherapy or HR+/HER2- with ≥ 1 prior hormone therapy or ineligible for hormone therapy) with a somatic BRCA1/2 mutation identified in cfDNA (established pathogenic variant) are being enrolled. Patients should not be known germline BRCA1/2 carriers (genetic testing is not required but can be obtained per physician discretion) and may not have previously received a PARP inhibitor. There is no limit on the number of prior therapies, and a prior platinum chemotherapy is allowed in the absence of disease progression on the platinum. Patients must have adequate performance status and organ function. Specific Aims: The primary endpoint is progression-free survival (PFS) using RECIST 1.1. Secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory objectives include evaluating serial changes in BRCA1/2 mutant allelic frequency in cfDNA, evaluating the impact of BRCA1/2 reversion mutations, comparing pre- and post-treatment cfDNA results to identify markers of resistance, evaluating the CR-B assay positivity rate, and ultimately correlating these analyses with treatment response. Statistical Methods: A two-stage design with 80% power to demonstrate that talazoparib is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha) is being used. Accrual: This study (NCT03990896) is currently open at Massachusetts General Hospital, where 4 patients are completing screening for enrollment. This study will be activated soon at the University of California San Francisco, MD Anderson, Mayo Clinic Rochester and Jacksonville, Northwestern, and Emory (7 academic centers). Funding: Support for this study is provided by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Erica Blouch, Erin Basile, Nathan Royce Ruffle-Deignan, Nora Horick, Senthil Damodaran, Alvaro Moreno Aspitia, Manali Bhave, Ami Shah, Minetta C. Liu, Joseph Sparano, Harry Ostrer, Hope Rugo, Leif W. Ellisen, Aditya Bardia. Phase II study of a PARP inhibitor in metastatic breast cancer with somaticBRCA1/2mutations identified by cell-free DNA: Genotyping based clinical trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-24-03.

Abstract Background: A significant number of patients with breast cancer may develop chest wall recurrence, which can be difficult to treat, and is associated with a poor prognosis. Given the inflammatory nature of chest wall disease, and the association of chest wall disease with lymphovascular invasion, we hypothesized that immunotherapy may be beneficial in this setting. Furthermore, combining immunotherapy and chemotherapy may have a synergistic effect; indeed, the combination of the anti-programmed cell death 1 (PD-1) antibody, pembrolizumab, with chemotherapy has been approved for metastatic triple negative breast cancer (TNBC). Consequently, in this study, we are evaluating the combination of pembrolizumab/carboplatin vs. carboplatin alone for chest wall recurrence. Trial design: This is a phase II study of patients with chest wall disease from breast cancer. Patients are randomized in a 2:1 manner to pembrolizumab/carboplatin x 6 cycles (Arm A) with the option to continue pembrolizumab +/- carboplatin after 6 cycles (Arm Ax) vs. carboplatin alone (Arm B) with the option to cross-over to pembrolizumab +/- carboplatin on progression (Arm Bx). Carboplatin is dosed at AUC 5 IV every 3 weeks, and pembrolizumab at 200 mg IV every 3 weeks. Trastuzumab may be continued with study treatment in patients with HER2 positive disease. Imaging scans (CT chest, abdomen, and pelvis, and bone scan) occur at baseline and every 3 cycles. Chest wall biopsies and peripheral blood is collected at baseline and after completing 2 cycles of treatment for correlative studies. Eligibility criteria: Patients must have chest wall disease from breast cancer. Distant metastases are allowed. TNBC, hormone receptor positive/HER2 negative disease (after 2 prior hormone therapies), and HER2 positive disease (progressed on standard HER2 directed treatment) are eligible. Any number of prior lines of chemotherapy are acceptable, including a prior platinum chemotherapy in the absence of disease progression on the platinum. Specific Aims: Primary aim is to determine disease control rate in the chest wall and other distant sites at 18 weeks of treatment with RECIST 1.1. Secondary aims including determining toxicity, progression-free survival, response based on irRECIST, and response based on tumor PD-L1 expression. Exploratory aims include studying changes in: 1) immune composition of tumor and peripheral blood, 2) peripheral blood cell-free DNA and circulating tumor cells, 3) soluble PD-L1 expression, and 4) association of MYC with PD-1 and immune markers, based on preclinical data demonstrating that MYC upregulates these markers. Statistical Methods: 84 patients (Arm A: 56, Arm B: 28) are being enrolled at 7 sites in the Translational Breast Cancer Research Consortium. The study is powered to identify a 20% difference in disease control rates between Arms A and B (HR 0.52, α= 0.10, ß=0.20). A futility analysis will occur for Arm B after 18 patients are enrolled to allow for early closure if lack of efficacy. Accrual: Present accrual is 57 patients (Arm A: 39, Arm B: 18). (NCT03095352). This trial is partly funded by grants from Merck and University of California San Francisco. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Rita Nanda, Kathy Miller, Leisha Emens, Vandana Abramson, Ben Park, Minetta C. Liu, Andrei Goga, Hope Rugo. Randomized phase II trial of pembrolizumab/carboplatin vs. carboplatin alone for breast cancer with chest wall recurrence: TBCRC044 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-08.

TPS1111 Background: Chest wall recurrence is a subtype of breast cancer that is challenging to treat, and associated with a short duration of response to treatment and an increased risk of development of distant metastases. Given the inflammatory nature of this disease and the association of chest wall disease with lymphovascular invasion, which is correlated with higher programmed cell death 1 (PD-1) expression, we hypothesized that immunotherapy may be beneficial as treatment. Combinations of immunotherapy and chemotherapy have a synergistic effect and demonstrated efficacy in the treatment of metastatic triple negative breast cancer (TNBC). This study is evaluating the efficacy of pembrolizumab, an anti-PD-1 antibody, in combination with carboplatin, in patients with chest wall infiltration from breast cancer. This drug combination has shown efficacy in advanced lung cancer. Methods: This is a multicenter, 2:1 randomized phase II study of pembrolizumab/carboplatin (Arm A, 56 patients) vs. carboplatin (Arm B, 28 patients) in 84 patients with chest wall disease from breast cancer, with or without distant metastases. Patients may have TNBC, hormone receptor positive/HER2 negative (following receipt of 2 prior hormone therapies), or HER2 positive breast cancer (with option to continue trastuzumab on study). Pembrolizumab is administered as 200 mg IV every 3 weeks, and carboplatin as AUC 5 IV every 3 weeks. Patients on Arm A may continue pembrolizumab +/- carboplatin (Arm Ax) after completion of 6 cycles of treatment, while patients in Arm B can cross-over to pembrolizumab (+/- carboplatin) on progression (Arm Bx). Patients must have adequate organ function, performance status ≤ 2, and may have received any number of lines of prior chemotherapy. Patients undergo serial chest wall photography and imaging (CT chest, abdomen, and pelvis, and bone scan) at baseline and every 6 weeks, as well as blood collection for correlative studies and chest wall biopsies at baseline and after 2 cycles of treatment. The primary endpoint is disease control rate (RECIST 1.1) at 18 weeks of treatment, and the study is powered to determine a 20% difference in disease control rates between arms (HR 0.52, a = 0.10, ß = 0.20). An interim analysis will occur for Arm B after 18 patients are enrolled, with a stopping rule for futility. Secondary endpoints include progression-free survival, toxicity (NCI CTCAE), and response based on irRECIST and tumor programmed death ligand 1 (PD-L1) expression. Exploratory objectives include evaluating changes in soluble PD-L1, tumor and peripheral blood immune composition, circulating tumor cells and cell-free DNA, and MYC oncogene expression. This study (NCT03095352) is open at 7 sites in the Translational Breast Cancer Research Consortium (TBCRC). 52 patients are enrolled. Grant funding is provided by Merck and UCSF. Clinical trial information: NCT03095352 .

TPS1110 Background: PARP inhibitors are approved for the treatment of HER2 negative metastatic breast cancer (MBC) with germline BRCA1/2 mutations, based on phase III studies demonstrating an improvement in progression-free survival (PFS) compared to chemotherapy in this population and better patient reported outcomes (Robson, NEJM, 2017; Litton, NEJM, 2018). However, germline BRCA1/2 mutations account for only 5-10% of breast cancer, limiting the current clinical applicability of PARP inhibitors. Somatic BRCA1/2 mutations are detectable in circulating cell-free DNA (cfDNA) in ̃13.5% of patients with MBC; in pre-clinical models, pathogenic somatic BRCA1/2 mutations have been shown to respond to PARP inhibition (Vidula, CCR, 2020). The purpose of this study is to evaluate the efficacy of talazoparib, a PARP inhibitor, in patients with MBC who have somatic BRCA1/2 mutations detectable in cfDNA, in the absence of a germline BRCA1/2 mutation, which we hypothesize will be effective in this setting. This study may help expand the population of patients with MBC who benefit from PARP inhibitors. Methods: This is an investigator initiated multicenter, single arm, phase II clinical trial studying the efficacy of talazoparib in 30 patients with MBC who have pathogenic somatic BRCA1/2 mutations detected in cfDNA. Patients with MBC who are found to have pathogenic somatic BRCA1/2 mutations detected in cfDNA in the absence of a germline BRCA1/2 mutation are eligible. Patients may have triple negative (with ≥ 1 prior chemotherapy), or hormone receptor positive/HER2 negative breast cancer (with ≥ 1 prior hormone therapy). Patients may have received any number of prior lines of chemotherapy, including a prior platinum (in the absence of progression). They must have adequate organ function and ECOG performance status ≤2, and should not have previously received a PARP inhibitor. Patients are treated with talazoparib 1 mg daily until disease progression or intolerability, with serial imaging using CT chest/abdomen/pelvis and bone scan performed at baseline and every 12 weeks, and cfDNA collection every 4 weeks. Primary endpoint is PFS by RECIST 1.1. Patients are being enrolled in a two-stage design with 80% power to demonstrate that the treatment is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety (NCI CTCAE v 5.0). Exploratory analyses include studying serial changes in cfDNA BRCA1/2 mutant allelic frequency and comparing pre-and post-treatment cfDNA for the emergence of BRCA1/2 reversion and resistance mutations. This study is activated and open at Massachusetts General Hospital, where 2 patients are completing screening. It is also opening soon at 6 other academic centers (NCT03990896). Grant support includes a Pfizer ASPIRE award and 2020 Conquer Cancer Foundation of ASCO – Breast Cancer Research Foundation – Career Development Award. Clinical trial information: NCT03990896 .

Abstract Background: Chest wall recurrence may occur in up to 30% of patients with breast cancer, and is associated with a high morbidity and mortality. We hypothesized that immunotherapy may be beneficial in this setting because of the inflammatory nature of this disease, and the association of chest wall disease with lymphovascular invasion. Combination immunotherapy and chemotherapy may have a synergistic effect. In this study, we combined pembrolizumab, an anti-programmed cell death 1 (PD-1) antibody with carboplatin, in patients with chest wall disease. This combination has previously been shown to be effective in advanced lung cancer. Trial design: This is a 2:1 randomized phase II study of pembrolizumab and carboplatin (Arm A) versus carboplatin alone (Arm B) in patients with chest wall involvement from breast cancer. Pembrolizumab is dosed at 200 mg IV every 3 weeks, and carboplatin is dosed at AUC 5 IV every 3 weeks. Patients on Arm A have the option to continue on pembrolizumab alone after 6 cycles of combination treatment (Arm Ax). Patients on Arm B have the option to cross-over to pembrolizumab (+/- carboplatin) after 6 cycles of carboplatin alone (Arm Bx). Patients with HER2 positive disease may continue trastuzumab in addition to the study treatment. Patients undergo chest wall biopsies and peripheral blood collection for correlative studies at enrollment and after 2 cycles of treatment, and also imaging with CT chest, abdomen, and pelvis, and bone scan every 3 cycles. Eligibility criteria: Patients must have chest wall involvement from breast cancer, with or without distant metastases. Patients may have triple-negative breast cancer, hormone receptor positive, HER2- disease (after two prior lines of hormone therapy), or refractory HER2 positive disease. Patients may have received any number of lines of prior chemotherapy. A prior platinum is allowed as long as there was not disease progression on this agent. Specific Aims: 1. (Primary aim) Disease control rate in the chest wall and other distant sites at 18 weeks of treatment using RECIST 1.1 criteria, 2. progression-free survival, 3. toxicity, 4. response based on tumor PD-L1 expression, and 5. response based on irRECIST. Exploratory aims include evaluating: 1. Soluble PD-L1 expression, 2. changes in tumor and peripheral blood immune composition, 3. peripheral blood circulating tumor cells, 4. peripheral blood cell-free DNA, and 5. the association of MYC with PD-1 and TIM-3 on tumor cells, based on preclinical data to suggest that MYC may upregulate these inflammatory markers. Statistical Methods: 84 patients (56 in Arm A and 28 in Arm B) are being enrolled at 7 sites in the Translational Breast Cancer Research Consortium. The study is powered to determine a 20% difference in disease control rates between arms (HR 0.52, α= 0.10, ß=0.20). A futility analysis was originally planned to occur for Arm B after 18 patients are enrolled, but a subsequent amendment has enabled an earlier assessment after 14 patients were enrolled. Accrual: Present accrual is 40 patients. (NCT03095352). This trial is funded in part by Merck and a Development Program Grant from the University of California San Francisco. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Rita Nanda, Kathy Miller, Paula Pohlmann, Vandana Abramson, Leisha A. Emens, Ben H. Park, Minetta C. Liu, Andrei Goga, Hope S. Rugo. Translational breast cancer research consortium 044 trial: Randomized phase 2 study of pembrolizumab and carboplatin versus carboplatin alone for chest wall recurrence of breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-09.

TPS1114 Background: Immunotherapy combined with chemotherapy is being studied in metastatic breast cancer, and may have durable outcomes. Chest wall recurrence represents a difficult to treat subtype of breast cancer with a poor prognosis, with lymphovascular invasion in the primary tumor a significant risk factor. Given the inflammatory nature of this disease and the association of programmed cell death 1 (PD-1) expression with lymphovascular invasion, we hypothesized that the combination of pembrolizumab, an anti-PD-1 antibody, with carboplatin may be effective as treatment for breast cancer chest wall recurrences. Methods: This randomized phase II study is enrolling 84 patients with breast cancer involving the chest wall, who may also have distant metastases. Patients receive treatment with pembrolizumab 200 mg and carboplatin AUC 5 every 3 weeks for 6 cycles (Arm A, n = 56) followed by maintenance pembrolizumab +/- carboplatin (Arm Ax), or carboplatin AUC 5 every 3 weeks for 6 cycles (Arm B, n = 28) with an option to cross-over to pembrolizumab +/- carboplatin on progression (Arm Bx). Patients with all disease subtypes, triple-negative, hormone receptor positive/HER2- after 2 prior lines of hormone therapy, and HER2+ disease (with the option to continue trastuzumab) are eligible, with no limit on the number of prior therapies. Prior platinum chemotherapy is allowed in the absence of overt disease progression. Patients undergo clinical assessment with every cycle of treatment including chest wall photography, scans (CT chest, abdomen, and pelvis) every 2 cycles, and have peripheral blood and chest wall biopsies collected at baseline and the start of cycle 3 for correlative studies. The primary endpoint is the disease control rate in the chest wall and distant sites at 18 weeks of treatment based on RECIST 1.1. The study is powered to determine a 20% difference in disease control between arms (hazard ratio 0.52, α = 0.10, β = 0.20). Additional endpoints include response by tumor programmed death ligand 1 (PD-L1) status and irRECIST, progression-free survival, and toxicity. Chest wall tumor samples will be analyzed for changes in tumor immune composition, and PD-L1 and MYC oncogene expression, based on preclinical data to suggest that PD-L1 may be upregulated by MYC. Peripheral blood samples will be evaluated for changes in PD-L1 expression, cell-free DNA, and circulating tumor cells with treatment. The study is enrolling patients at 7 sites within the Translational Breast Cancer Research Consortium (TBCRC), with current enrollment of 38/84 patients. Clinical trial information: NCT03095352 .

Abstract Background: Chest wall recurrence can occur as a complication of breast cancer. This type of breast cancer is difficult to treat with short-lived responses to therapy, and associated with the development of distant metastases. Better therapies are needed in this setting. Immune checkpoint inhibition is being explored in breast cancer, with an immunotherapy agent currently approved for triple-negative breast cancer (TNBC). We hypothesize that pembrolizumab, an anti-programmed cell death 1 (PD-1) antibody, may be effective in treating chest wall recurrence of breast cancer given the inflammatory nature of this disease and high expression of PD-1 seen in tumors with lymphovascular invasion that may predispose patients to chest wall recurrence. Platinum chemotherapy may augment anti-tumor immunity, with the combination of pembrolizumab and carboplatin shown to be effective in advanced lung cancer. This study is evaluating the efficacy of pembrolizumab and carboplatin for breast cancer patients with chest wall disease. Methods: In this phase II study, 84 patients are being randomized 2:1 to treatment with pembrolizumab in combination with carboplatin (Arm A) versus carboplatin alone (Arm B) with an option to cross over to pembrolizumab alone (Arm Bx) on progression. Pembrolizumab is dosed at 200 mg IV every 3 weeks, and carboplatin is dosed at AUC 5 IV every 3 weeks. Patients may have TNBC, hormone receptor positive (HR)+/HER2- breast cancer that has progressed on 2 prior lines of hormone therapy, or refractory HER2+ breast cancer (may continue herceptin). Patients may have distant metastases, but must have surgically unresectable disease. Prior chest wall radiation is allowed. The primary endpoint is to determine the disease control rate (chest wall and distant sites) at 18 weeks of treatment. Patients undergo chest wall assessments with photography of skin lesions with every cycle of treatment, and imaging (CT chest, abdomen, and pelvis, and bone scan) every 2 cycles to evaluate for progression. The study is powered to determine a 20% difference in disease control rates between arms A and B (hazard ratio of 0.52, α= 0.10, β= 0.20). Secondary endpoints include response stratified by tumor programmed death ligand 1 (PD-L1) expression, progression free survival, response by irRECIST, and toxicity. The study incorporates many translational studies using chest wall biopsy tissue collected at baseline and after 2 cycles of treatment, as well as correlative blood tests, including assessing changes in tumor and blood PD-L1 expression, circulating cell-free DNA, circulating tumor cells, soluble PD-L1 expression, and changes in the expression of MYC, an oncogene that may upregulate the expression of PD-1. Patients are currently being enrolled at 7 sites in the TBCRC. As of July 2019, 30 patients are enrolled. This study is supported by Merck and the TBCRC. (NCT03095352). Citation Format: Neelima Vidula, Rita Nanda, Kathy Miller, Vandana Abramson, Paula Pohlmann, Adam Brufsky, Ben Park, Minetta Liu, Andrei Goga, Hope S. Rugo. Pembrolizumab in combination with carboplatin versus carboplatin alone in breast cancer patients with chest wall disease: Translational Breast Cancer Research Consortium (TBCRC) 44 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-05.

Abstract Background: Thirty percent of patients with breast cancer may experience chest wall recurrence, which is associated with a higher risk of developing distant metastases and a poor prognosis. Cancer cells may evade immune rejection through the programmed cell death 1 (PD-1) pathway. Pembrolizumab, an anti-PD-1 antibody, binds PD-1 and inhibits its interaction with the programmed death ligand 1 (PD-L1) to facilitate tumor immune rejection. We hypothesize that pembrolizumab may be an effective therapy in chest wall recurrence, given the inflammatory nature, and the high expression of PD-1 in tumors with lymphovascular invasion. Platinum agents may enhance anti-tumor immunity in a synergistic manner, and the combination of pembrolizumab and carboplatin has demonstrated efficacy in advanced lung cancer. In this study, the combination of pembrolizumab and carboplatin is being evaluated in breast cancer patients with chest wall disease. Methods: This is a randomized phase II study of breast cancer patients with advanced, unresectable breast cancer involving the chest wall, being conducted through the Translational Breast Cancer Research Consortium (TBCRC). Patients may have hormone resistant disease (at least 2 prior lines of hormone therapy), triple negative breast cancer, or refractory HER2+ disease for enrollment. They may have other sites of distant metastases, have received any number of prior lines of therapy, have had prior surgery, but prior chest wall radiation is not necessary. Eighty-four patients at 7 TBCRC sites will be randomized 2:1 to treatment with pembrolizumab 200 mg IV and carboplatin AUC 5 IV every 3 weeks followed by pembrolizumab 200 mg IV alone every 3 weeks (Arm A, n=56) or carboplatin AUC 5 IV every 3 weeks (Arm B, n=28), with an option for patients in Arm B to cross-over to single agent pembrolizumab 200 mg IV every 3 weeks (arm Bx) on progression. Patients will undergo imaging with CT chest, abdomen, and pelvis at baseline and every 2 cycles of treatment for response evaluation. The primary endpoint is the disease control rate in the chest wall and distant sites at 18 weeks of treatment, and this study is powered to determine a 20% difference in disease control rates between arms A and B (hazard ratio of 0.52, α= 0.10, β= 0.20). After 18 patients are enrolled into Arm B, an interim analysis for futility will be conducted to enable early closure of that arm for lack of efficacy. Secondary endpoints in the study are toxicity, progression free survival, and response based on PD-L1 expression and irRECIST. Exploratory endpoints, which will be studied using peripheral blood testing and chest wall tumor biopsies at baseline and after 2 cycles of treatment, include determining associations of response with changes in tumor and peripheral blood immune composition, soluble PD-L1 expression, circulating tumor cells, cell free DNA, and tumor PD-L1 and MYC genomic expression. Ultimately this study promises to improve our understanding of checkpoint inhibition and chemotherapy for chest wall disease, and the underlying mechanism of action. This study is open for enrollment and 2 patients are currently enrolled. (NCT03095352). Citation Format: Vidula N, Goga A, Hwang J, Liu MC, Park BH, Nanda R, Pohlmann PR, Storniolo AM, Brufsky A, Abramson V, Rugo HS. A randomized phase II study of pembrolizumab in combination with carboplatin versus carboplatin alone in breast cancer patients with chest wall disease, with immunologic and genomic correlative studies [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-04-04.

Abstract Background: Patients with breast cancer (BC) and chest wall disease have limited treatment options. We hypothesize that checkpoint inhibition may be an effective treatment approach due to the inflammatory nature of chest wall infiltration, and the association of PD-1 expression with lymphocytic infiltration. Platinum chemotherapy may facilitate anti-tumor immunity in a synergistic manner, and clinical studies of the PD-1 inhibitor pembrolizumab with platinum combinations have been effective in the treatment of advanced lung cancer. In this study, we will evaluate the combination of carboplatin and pembrolizumab in BC patients with chest wall disease. Methods: This is a randomized phase II multicenter study in the TBCRC including patients with advanced, unresectable BC with hormone resistant or triple negative chest wall disease. Patients may have had prior surgery, prior chest wall radiation is not required, and other sites of distant metastases are allowed. Eighty-four patients at TBCRC sites will be randomized 2:1 to receive pembrolizumab and carboplatin (n=56, Arm A) or carboplatin alone (n=28, Arm B) until disease progression. Patients randomized to Arm B may cross-over following progression to pembrolizumab alone (Arm Bx). Patients in Arm A will be treated with pembrolizumab 200 mg IV and carboplatin AUC 5 IV every 3 weeks for at least 6 cycles followed by maintenance pembrolizumab 200 mg IV every 3 weeks if stable or responding disease. Patients in Arm B will be treated with carboplatin AUC 5 IV every 3 weeks until progression, then may cross-over to pembrolizumab 200 mg IV every 3 weeks alone (Arm Bx). An interim analysis for futility will be performed after 18 patients are enrolled into Arm B to allow early closure of that arm for lack of efficacy. The primary endpoint is disease control rate at 18 weeks of treatment; the study is powered to detect a 20% difference in disease control rates between arms (hazard ratio 0.52, α= 0.10, β= 0.20). Secondary endpoints include progression free survival, toxicity, and response based on PD-L1 expression and irRECIST. Exploratory endpoints include association of response with a number of biomarkers including tumor PD-L1 gene expression, tumor and peripheral blood immune composition and cytokine expression, peripheral T-cell PD-1 expression, circulating tumor DNA, circulating tumor cells, and tumor MYC genomic expression using tumor biopsy and peripheral blood testing before and after treatment. This study should be open to accrual by August of 2017. (NCT03095352) Citation Format: Vidula N, Goga A, Krummel M, Hwang J, Liu M, Park BH, Nanda R, Pohlmann P, Storniolo AM, Van Poznak C, Brufsky A, Abramson V, Wolff A, Rugo HS. TBCRC 044: A randomized phase II study of pembrolizumab in combination with carboplatin versus carboplatin alone in breast cancer patients with chest wall disease [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-02-03.