Platinum-containing Regimens Research Articles

Platinum-containing regimens for metastatic breast cancer.

Studies have reported high tumour response rates for platinum-containing regimens in the treatment of women with metastatic breast cancer.To identify and review the evidence from randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with metastatic breast cancer.The specialised register maintained by the editorial base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied to create the register, and the procedure used to code references, are described in the Cochrane Breast Cancer Group module on The Cochrane Library.Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with metastatic breast cancer.Studies were assessed for eligibility and quality, and data (from published trials) were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes, where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data (not available) were extracted where present.Thirteen eligible trials were identified, of which 12 had published time-to-event data. The quality of randomisation was generally not described.Data, based on an estimated 987 deaths in 1377 women, was unable to show a statistically significant difference in favour of platinum-containing regimens. The hazard ratio (HR) for overall survival was 1.00 (95% confidence interval (CI) 0.88 to 1.15, p=0.96), with minor heterogeneity. Results were similar when the analysis was limited to trials in women receiving first line chemotherapy. There was no statistically significant difference in favour of platinum-containing regimens for time to progression (overall HR of 1.06 (95% CI 0.95 to 1.19, p=0.31) although there was marked evidence of heterogeneity (p< 0.0001). There was a statistically significant difference in overall response in favour of platinum-containing regimens (OR 1.47; 95% CI 1.23 to 1.76, p=0.0001). However, there was strong statistical evidence of heterogeneity (p < 0.00010) probably reflecting the varying efficacy of the comparator regimens used in the trials. Heterogeneity may also reflect the differences, and difficulties, in assessing response. Women receiving platinum-containing regimens experienced statistically significant greater toxicity levels for leukopenia, hair loss, nausea and vomiting and anaemia compared with those receiving non-platinum regimens.In view of the significant excess toxicity, lack of progression or survival benefit and the availability of less toxic active agents it is difficult to justify the use of platinum-containing regimens, particularly as first line treatment for women with metastatic breast cancer in routine clinical practice. Ongoing trials are examining the possibility of synergy between platins and trastuzamab, a monoclonal antibody treatment. No randomised trials containing oxalplatin were identified for the present review.

Two phase I/II open label clinical trials evaluating the safety and efficacy of autologous T cells expressing enhanced TCRs specific for NY-ESO-1 or MAGE-A10 in subjects with stage IIIb or stage IV non-small cell lung cancer (NCT02588612/NCT02592577).

TPS3096 Background: Non-small cell lung cancer (NSCLC) accounts for 84% of lung cancer. Survival has recently been impacted by molecularly targeted therapies and checkpoint inhibitors (CPI), and the promising CPI results implicate a role for the immune system in NSCLC. 10-40% of NSCLC express NY-ESO-1 or MAGE-A10 cancer/testis antigens. These studies will evaluate the safety and antitumor activity of genetically engineered affinity enhanced TCRs (NY-ESO-1c259T or MAGE-A10c796T) directed towards a NYESO-1 or MAGE-A10 derived peptides complexed with HLA-A*02. In addition, correlative studies to evaluate persistence, phenotype, functionality of engineered T cells, mechanisms of resistance and antigen spreading will be performed. Methods: Patients (pt) are screened (NCT02636855) to identify those who have the relevant HLA-A*02 alleles and NY-ESO-1 or MAGE-A10 tumor expression. For entry into either treatment protocol, pt must have Stage IIIb or IV NSCLC, have failed at least one platinum-containing regimen (may have received CPIs), have measurable disease, ECOG 0-1, adequate organ function, and be without brain metastases, history of severe autoimmune disease or current uncontrolled illness. Following apheresis, T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the NY-ESO-1c259T or MAGE-A10c795 TCR, and infused into the pt following lymphodepleting chemotherapy with fludarabine and cyclophosphamide. The NY-ESO-1c259T study is a 10 pt study utilizing a dose of 1-6 x 109 transduced T cells. The MAGE-A10c796T first-in-human study is a modified 3+3 design in up to 28 pt with escalating doses of 0.1, 1.0 and 1-6 x 109 transduced T cells, with staggered treatments to allow for safety review; dose escalation will be guided by the DLT observed and by safety review committee guidance. Response to treatment will be assessed by RECIST v1.1 at weeks 4, 8, 16, 24, every 3 months (for 2 yr) and every 6 months until disease progression. Clinical trial information: NCT02588612/NCT02592577.

Salvage chemotherapy for gestational trophoblastic neoplasia: Utility or futility?

ObjectiveTo determine the efficacy of chemotherapy after failed initial treatment in patients with high risk gestational trophoblastic neoplasia (GTN). MethodsWe performed a retrospective IRB-approved chart review of all patients with GTN seen at a single institution from 1985 to 2015, including all patients who failed initial treatment. We summarized clinical characteristics with descriptive statistics and estimated progression-free survival (PFS) and overall survival (OS) with the Kaplan-Meier method. ResultsOf 68 identified patients, 38 required >2 chemotherapy regimens. Patients were treated for GTN (n=53), including choriocarcinoma, persistent GTN, and invasive mole; for placental site trophoblastic tumor (PSTT) (n=5); and for intermediate trophoblastic tumor (ITT) (n=10). Patients with GTN had a median of 2 salvage regimens, median PFS of 4.0months, and median OS was not reached at median follow-up of 71.2months. Active regimens included EMACO, MAC, BEP, platinum- and etoposide-based combination therapies, and ICE; 8 of 53 patients died of disease (DOD). Patients with PSTT had a median of 3 salvage regimens, median PFS of 2.8months, and median OS of 38.8months. Active regimens included ICE and EMA-EP; 4 of 5 patients DOD. Patients with ITT had a median of 3 salvage regimens, median PFS of 4.1months, and median OS of 38.2months. Active regimens included liposomal doxorubicin, platinum-containing regimens, EMA-CO, and EMA-EP; 7 of 10 patients DOD. ConclusionsSeveral salvage chemotherapy regimens demonstrate activity in high risk GTN. Multiple regimens may be required and cure is not universal.

Renal Toxicity in Patients Treated with Anti-Pd-1 Targeted Agents for Solid Tumors

Aim Immune checkpoint inhibitors of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) have recently entered in the therapeutic armamentarium of several types of cancer. Besides the survival benefit, the true revolution of these agents is the distinctive toxicity profile. We aim to assess the incidence and relative risk (RR) of renal toxicity (RT) in patients with solid tumors treated with monoclonal antibodies (mAbs) directed against PD-1/PD-L1. Methods By searching the MEDLINE/PubMed, Cochrane Library, and ASCO Meeting abstracts, prospective studies were identified. Combined RRs and 95% confidence intervals (CIs) were calculated using fixed- or random-effects methods. Results Eleven articles were selected for this analysis, with a total of 5,722 patients who were used to evaluate RT. The incidence of anti-PD-1-related RT of all-grades and high-grades was low (1.4% and 0.2%, respectively). However, compared to controls, treatment with PD-1 inhibitors was associated with a significant increased risk of any grade RT (RR = 1.85, 95% CI, 1.07-3.20; p = 0.03) but not high-grade RT (RR = 1.57, 95% CI, 0.56-4.36; p = 0.39). Pembrolizumab significantly increased the risk of any-grade RT (RR = 4.91, p = 0.01) compared to the control arm, and a significant difference was found between nivolumab and pembrolizumab for developing RT of any grade (p = 0.04). Conversely, no differences were identified between the type of prior treatment (prior platinum-containing chemotherapy regimen vs. nonplatinum containing regimen). Conclusions Immune-mediated RT is a rare adverse event that is generally low in severity. Compared to standard therapies, anti-PD-1 mAbs significantly increase the risk of any grade, without conditioning the risk of high-grade RT. The type of PD-1 inhibitor could affect the risk of developing any-grade RT, while prior therapy with platinum-containing regimens does not affect the risk of developing RT.

49 - Outcome of Lower-Risk Patients with Myelodysplastic Syndromes without 5Q Deletion after Failure of Erythropoiesis Stimulating Agents

Knowledge of the real-world treatment patterns for non–small-cell lung cancer (NSCLC) can identify quality-of-care gaps and guide resource allocation needs. Our objective was to describe the treatment patterns for advanced NSCLC after first-line chemotherapy in the era before the approval of immunotherapeutic agents.The present was a retrospective observational study of adult patients with advanced NSCLC (stage IIIB/IV or metastatic recurrence) who had completed a platinum-containing regimen, with an appropriate tyrosine kinase inhibitor if positive for epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Eligible patients initiated second-line chemotherapy from November 2012 through October 2014, recorded in an oncology record system for U.S. community clinics.Of 6867 patients with advanced NSCLC, 4188 (61%) initiated and 2707 (39%) completed platinum therapy, with a tyrosine kinase inhibitor, if appropriate. Subsequently 1889 of 2707 (70%) received second-line chemotherapy, including 1173 within the study period (844 [72%] nonsquamous, 275 [23%] squamous, and 54 [5%] not otherwise specified). The mean ± standard deviation patient age was 66 ± 10 years; 54% were male. Of the 94 different second-line regimens, docetaxel was the most common, prescribed to 14% of the patients overall and 14% and 16% of the nonsquamous and squamous cohorts, respectively. The median duration was 64 days (range, 1-455 days) and 48 days (range, 1-210 days) for the nonsquamous and squamous cohorts, respectively. The median duration by regimen category was 15 to 85 days (overall range, 1-953 days).These findings show the diversity, short treatment duration, and lack of efficacy of second-line chemotherapy regimens for NSCLC in the community oncology setting.

Abstract P5-16-13: Predictive and prognostic value of Ki-67 expression in triple-negative breast cancer before and after neoadjuvant chemotherapy with weekly paclitaxel plus carboplatin

Abstract Background: Neoadjuvant chemotherapy (NCT) is one of the main treatment strategies for patients with locally advanced breast cancer. This study was designed to demonstrate the utility of a platinum-containing treatment regimen in the neoadjuvant setting and to identify the predictive or prognostic value of Ki-67 among patients with triple-negative breast cancer (TNBC) Methods: Data from 280 patients with stage II–III TNBC were collected. All patients underwent four cycles of NCT with paclitaxel (80 mg/m2) and carboplatin (AUC 2 mg*min/ml) on days 1, 8, and 15 of a 28-day cycle. Ki-67 values were evaluated in both biopsy and excision specimens. The clinical responses to NCT were evaluated based on MRI and ultrasound examinations in accordance with the response evaluation criteria in solid tumors (RECIST) version 1.1. The pathological evaluation of surgical specimens was conducted at by the Miller-Payne (MP) grading system. Logistic regression analysis was performed to identify independent predictors of pathological complete response (pCR). Survival analysis was performed to evaluate the prognostic value of various clinical and pathological variables. Results: The overall pCR rate was 33.9%. Both the categorical and linear Ki-67 were independently correlated with pCR (P&amp;lt;0.001). There were also statistically significant differences among Ki-67 categories with respect to clinical response (P&amp;lt;0.001), Miller-Payne (MP) grades (P&amp;lt;0.001), and node status (P&amp;lt;0.001). A significant reduction of Ki-67 after NCT was most likely observed in patients with a relatively better response. Among 185 patients with a residual tumor after NCT, the tumor cell proliferation significantly decreased from a median Ki-67 value of 20.0% before chemotherapy to 15% after chemotherapy. The mean absolute reductions in Ki-67 were 29.4%, 8.5%, and -10.2% in patients with an ideal response (MP 5/4), a partial response (MP 3) and a poor response (MP2/1), respectively. In the multivariate model for non-pCR patients, Ki-67 reduction presented an independent prognostic value for relapse of disease (HR=0.986, 95% CI: 0.978-0.994; P=0.001). Residual node involvement was also an independent predictor of patient outcome (HR=0.895, 95% CI: 0.355-2.259 for 1-3 nodes and HR=2.424, 95% CI: 1.048-5.608 for more than 4 nodes, using 0 nodes as a reference; P=0.002). Better survival was more frequently observed in patients with a greater reduction in the Ki-67 value and fewer involved nodes. Conclusions: The primary Ki-67 might help in further classifying TNBCs into subtypes with different responses to chemotherapy. The significant reduction of Ki-67 after treatment could indicate a favorable prognosis in non-pCR patients. Citation Format: Wang R-X, Chen S, Jin X, Shao Z-M. Predictive and prognostic value of Ki-67 expression in triple-negative breast cancer before and after neoadjuvant chemotherapy with weekly paclitaxel plus carboplatin [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 P5-16-13.

Abstract P6-09-09: Evaluation of tumor infiltrating lymphocytes (TILs) and their association with homologous recombination deficiency and BRCA1/2 mutation status in triple-negative breast cancer (TNBC): A pooled analysis

Background: TNBC patients with homologous recombination (HR) deficient tumors have significantly higher pathologic complete response (pCR, ypT0/is ypN0) rates when treated with platinum-based chemotherapy. TILs are prognostic and predictive of chemotherapy benefit in TNBC. Interestingly, recent data suggests that HR deficient TNBCs and BRCA1/2 mutant ovarian cancers may be enriched for immune cell infiltration. Thus, we performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HR deficiency status and tumor BRCA1/2 mutation status. Methods: 166 patients with TNBC and known HR deficiency status from the following clinical trials were available for analysis: PrECOG 0105 (N=72), NCT00580333 (N=32), NCT01372579 (N=26), TBCRC 008 (N=18) and NCT00148694 (N=18). Neoadjuvant chemotherapy regimens included 1) carboplatin, gemcitabine, iniparib, 2) cisplatin with or without bevacizumab 3) carboplatin, eribulin, 4) carboplatin, nab-paclitaxel, with or without vorinostat. HR deficiency status was defined as a high HRD score (42 or higher) and/or presence of a BRCA1/2 tumor mutation (tBRCA). Digitized pre-treatment core biopsy HE sTIL p=0.159). The same absent association was observed for tBRCA mutation status (iTIL p=0.607; sTIL p=0.315) and binary HRD score (iTIL p=0.879; sTIL p=0.364). Updated results with additional cases scored for TILs will be reported at time of presentation. Additional analyses assessing the relationship between TILs and pCR/residual cancer burden adjusting for HRD status and other clinical variables will also be included at the time of presentation. Conclusion: Several previous studies have reported that TILs are significantly associated with response to standard chemotherapy regimens when given in the neoadjuvant setting. Measures of genomic instability and DNA repair deficiency, including HRD, have been shown to be robust predictors of response to chemotherapy, including platinum containing regimens. It is unclear if TILs will be predictive in a similarly robust way for response to platinum-containing regimens. Results of this study suggest TIL density and HR deficiency status may be independent and non-overlapping. Final analysis including additional cases will be included in the final presentation.Background: TNBC patients with homologous recombination (HR) deficient tumors have significantly higher pathologic complete response (pCR, ypT0/is ypN0) rates when treated with platinum-based chemotherapy. TILs are prognostic and predictive of chemotherapy benefit in TNBC. Interestingly, recent data suggests that HR deficient TNBCs and BRCA1/2 mutant ovarian cancers may be enriched for immune cell infiltration. Thus, we performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HR deficiency status and tumor BRCA1/2 mutation status. Methods: 166 patients with TNBC and known HR deficiency status from the following clinical trials were available for analysis: PrECOG 0105 (N=72), NCT00580333 (N=32), NCT01372579 (N=26), TBCRC 008 (N=18) and NCT00148694 (N=18). Neoadjuvant chemotherapy regimens included 1) carboplatin, gemcitabine, iniparib, 2) cisplatin with or without bevacizumab 3) carboplatin, eribulin, 4) carboplatin, nab-paclitaxel, with or without vorinostat. HR deficiency status was defined as a high HRD score (42 or higher) and/or presence of a BRCA1/2 tumor mutation (tBRCA). Digitized pre-treatment core biopsy HE sTIL p=0.159). The same absent association was observed for tBRCA mutation status (iTIL p=0.607; sTIL p=0.315) and binary HRD score (iTIL p=0.879; sTIL p=0.364). Updated results with additional cases scored for TILs will be reported at time of presentation. Additional analyses assessing the relationship between TILs and pCR/residual cancer burden adjusting for HRD status and other clinical variables will also be included at the time of presentation. Conclusion: Several previous studies have reported that TILs are significantly associated with response to standard chemotherapy regimens when given in the neoadjuvant setting. Measures of genomic instability and DNA repair deficiency, including HRD, have been shown to be robust predictors of response to chemotherapy, including platinum containing regimens. It is unclear if TILs will be predictive in a similarly robust way for response to platinum-containing regimens. Results of this study suggest TIL density and HR deficiency status may be independent and non-overlapping. Final analysis including additional cases will be included in the final presentation. Citation Format: Telli ML, Badve S, Vinayak S, Silver DP, Isakoff SJ, Kaklamani VG, Gradishar WJ, Stearns V, Connolly RM, Ford JM, Adams S, Garber JE, Evans B, Timms K, Wenstrup R, Richardson AL. Evaluation of tumor infiltrating lymphocytes (TILs) and their association with homologous recombination deficiency and BRCA1/2 mutation status in triple-negative breast cancer (TNBC): A pooled analysis [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 P6-09-09.

Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer

Background:BRCA1/BRCA2 germ line (GL) mutation carriers with pancreatic adenocarcinoma (PDAC) may have distinct outcomes. We recently described an apparent more favourable prognosis of surgically resected BRCA-associated PDAC patients in a single-arm, uncontrolled, retrospective study. However, the prognostic impact of GL BRCA1/2 mutations in surgically resected PDAC has not been compared with a matched control population.Methods:A larger multi-centre, case–control retrospective analysis was performed. Cases were patients with surgically resected, BRCA1/2-associated PDAC from 2004 to 2013. Controls included surgically resected PDAC cases treated during the same time period that were either BRCA non-carriers, or had no family history of breast, ovarian or pancreatic cancers. Cases and controls were matched by: age at diagnosis (within ±5-year period) and institution. Demographics, clinical history, overall survival (OS) and disease-free survival (DFS) were abstracted from patient records. Statistical comparisons were assessed using χ2- and Fisher’s exact test, and median DFS/OS using Kaplan–Meier method and log-rank testing.Results:Twenty-five patients with BRCA1-(n=4) or BRCA2 (N=21)-associated resectable PDAC were identified. Mean age was 55.7 years (range, 34–78 years), 48% (n=12) were females and 76% (n=19) were Jewish. Cases were compared (1 : 2) with 49 resectable PDAC controls, and were balanced for age, ethnicity and other relevant clinical and pathological features. BRCA-associated PDAC patients received neoadjuvant, or adjuvant platinum-based treatment more frequently than controls (7 out of 8 vs 6 out of 14) and (7 out of 21 vs 3 out of 44), respectively. No significant difference in median OS (37.06 vs 38.77 months, P=0.838) and in DFS (14.3 vs 12.0 months, P=0.303) could be demonstrated between cases and controls. A trend to increased DFS was observed among BRCA-positive cases treated with neoadjuvant/adjuvant platinum-containing regimens (n=10) compared with similarly treated controls (n=7) (39.1 vs 12.4 months, P=0.255).Conclusions:In this retrospective analysis, the prognosis of surgically resectable BRCA-associated PDAC is no different than that of sporadic PDAC from the same institution. The role of platinum-based adjuvant therapy in this setting requires prospective investigation.

Systemic Immunotherapy for Urothelial Cancer: Current Trends and Future Directions.

Urothelial cancer of the bladder, renal pelvis, ureter, and other urinary organs is the fifth most common cancer in the United States, and systemic platinum-based chemotherapy remains the standard of care for first-line treatment of advanced/metastatic urothelial carcinoma (UC). Until recently, there were very limited options for patients who are refractory to chemotherapy, or do not tolerate chemotherapy due to toxicities and overall outcomes have remained very poor. While the role of immunotherapy was first established in non-muscle invasive bladder cancer in the 1970s, no systemic immunotherapy was approved for advanced disease until the recent approval of a programmed death ligand-1 (PD-L1) inhibitor, atezolizumab, in patients with advanced/metastatic UC who have progressed on platinum-containing regimens. This represents a significant milestone in this disease after a void of over 30 years. In addition to atezolizumab, a variety of checkpoint inhibitors have shown a significant activity in advanced/metastatic urothelial carcinoma and are expected to gain Food and Drug Administration (FDA) approval in the near future. The introduction of novel immunotherapy agents has led to rapid changes in the field of urothelial carcinoma. Numerous checkpoint inhibitors are being tested alone or in combination in the first and subsequent-line therapies of metastatic disease, as well as neoadjuvant and adjuvant settings. They are also being studied in combination with radiation therapy and for non-muscle invasive bladder cancer refractory to BCG. Furthermore, immunotherapy is being utilized for those ineligible for first-line platinum-based chemotherapy. This review outlines the novel immunotherapy agents which have either been approved, or are currently being investigated in clinical trials in UC.

OA18.02 Evaluation of a Modified Dosing Regimen (2-Weeks on/1-Week off) of Sunitinib as Part of a Phase II Trial in Thymic Carcinoma

Sunitinib is active in patients with recurrent thymic carcinoma (TC). We have previously reported an objective response rate of 26% and disease control rate (partial response and stable disease) of 91% in patients with TC when sunitinib is administered at a dose of 50 mg once daily for 4 weeks followed by 2 weeks off (4/2 dosing schedule). Grade 3 or 4 treatment-related adverse events (TEAEs) occurring in more than 10% of patients included fatigue, oral mucositis and lymphocytopenia (20% each), and hypertension (13%). Grade 3 decrease in left ventricular ejection fraction (LVEF) was observed in 8% of patients. Alternative dosing schedules have been evaluated in solid tumors to improve tolerability. As part of an ongoing phase II study (NCT01621568), we evaluated the clinical activity and tolerability of sunitinib in patients with TC using a 2-weeks-on/1-week-off (2/1) dosing regimen. Patients with progressive TC after at least one prior platinum-containing chemotherapy regimen, measurable disease, and adequate end organ function were enrolled and received sunitinib at a dose of 50 mg orally once daily using a 2/1 schedule until disease progression or development of intolerable adverse events. The primary objective was evaluation of response rate. Tumor assessments were performed every 6 weeks using RECIST version 1.1 and toxicity was assessed every 3 weeks using CTCAE version 4.0. Exploratory correlative studies including evaluation of immune cell subsets will be reported separately. Between July 8, 2014 and January 14, 2016, 15 patients were enrolled. Median age was 62 years (range, 41-76), and 33% were male. A median of 4 (range, 1 – 33+) cycles of sunitinib was administered. Among 13 evaluable patients, there was 1 (8%) partial response, 11 (85%) stable disease and 1 (8%) progressive disease. After a median follow-up of 16 months, the median progression-free survival was 5 months and median overall survival was 16 months. Grade 3 or 4 TEAEs occurring in more than 10% of patients included lymphocytopenia (40%), neutropenia and leucopenia (20% each), thrombocytopenia and oral mucositis (13% each). Grade 3 decrease in LVEF was observed in 1 (7%) patient. Sunitinib, administered using a 2/1 dosing schedule, has clinical activity in patients with TC, and the frequency of clinically significant TEAEs (fatigue, mucositis, hypertension) is acceptable. Studies are ongoing to identify novel immunological biomarkers of activity.

P2.03a-028 Phase I/II Trial of Carboplatin, nab-Paclitaxel and Bevacizumab for Advanced Non-Squamous Non-Small Cell Lung Cancer: Results of Phase I Part: Topic: Clinical Trials

Nanoparticle albumin-bound paclitaxel (nab-PTX) is a new formulation of paclitaxel and has demonstrated efficacy when combined with carboplatin (Cb), resulting in one of the standard platinum-containing chemotherapy regimens for patients (pts) with chemo-naïve advanced non-small cell lung cancer (NSCLC). The addition of anti-vascular endothelial growth factor antibody bevacizumab (BEV) to chemotherapy has been known an effective treatment option for non-squamous NSCLC. The efficacy and safety of the new triplet regimen: Cb + nab-PTX + BEV has not yet been assessed. We planned multicenter, open-label, phase I/II trial of Cb + nab-PTX + BEV (CARNAVAL study; TORG1424 / OLCSG1402). Eligible pts were chemo-naïve, aged ≥20 years, ECOG PS 0/1 with advanced non-squamous NSCLC. Pts received 4 to 6 cycles of Cb (AUC = 6, day1) + nab-PTX (dose level 1; 100mg/m2 on days 1, 8 or dose level 2; 100mg/m2 on days 1, 8, and 15) + BEV (15mg/kg, day1) followed by maintenance nab-PTX + BEV every 3 weeks until disease progression. The phase I part of the study used a 6+6 dose-escalation design to determine the maximum tolerated dose. Major dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for at least 4 consecutive days, febrile neutropenia, grade 4 thrombocytopenia, grade ≥3 non-hematologic toxicity (excluding nausea, vomiting, loss of appetite, fatigue, diarrhea, constipation, disorder of electrolyte, hypertension and hypersensitivity, if they are manageable), and grade 4 hypertension. DLT was assessed during 1st cycle. This study was registered at UMIN (ID: 000014560). From October 2014 to July 2015, 4 and 12 pts were enrolled at dose level 1 and 2 cohorts respectively. No DLT was observed at either level and recommended phase II dose (RP2D) was determined at dose level 2. Grade ≥3 adverse events (AEs) during the overall treatment period were as follows; neutropenia (13 pts), thrombocytopenia (4 pts), nausea, vomiting, anorexia (3 pts each), anemia, fatigue, hypertension (2 pts each), pneumonitis, liver disorder, hyponatremia, febrile neutropenia, skin ulcer, esophageal perforation (1 pt each). All AEs were manageable. RP2D of Cb + nab-PTX + BEV was determined at dose level 2 (nab-PTX; 100mg/m2 on days 1, 8 and 15 every 3 weeks). We have started phase 2 part of the trial at dose level 2 since November 2015.

Multi-institutional prospective study of nedaplatin plus S-1 chemotherapy in recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-containing regimens.

In this multi-institutional prospective study, we aimed to assess the safety and efficacy of nedaplatin plus S-1 (NS) chemotherapy for patients with recurrent and metastatic nasopharyngeal carcinoma (NPC) when platinum-containing regimens failed. A total of 52 recurrent and metastatic NPC patients who previously received, but failed with platinum-containing chemotherapy, had oral S-1 chemotherapy (twice daily from the first day to the fourteenth day) and nedaplatin (80 mg/ m2, day 1) every 3 weeks. The body surface area (BSA) decided the dose of S-1: 40 mg twice a day when BSA < 1.25 m2; 50 mg twice daily when 1.25 m2 ⩽ BSA < 1.5 m2; and 60 mg twice daily when BSA ⩾ 1.5 m2. Treatment was well tolerated. The main hematological adverse event was neutropenia. Five patients (9.6%) had grade 3 neutropenia. Three patients were found with grade 3 anemia (5.8%). One patient was found with grade 3 thrombocytopenia (1.9%). No patient was found with grade 3 or 4 nonhematological toxicity. The rates of complete response, partial response and overall response were 3.8%, 38.5% and 42.3%, respectively. Median time to progression was 6.2 months and median survival was 14.6 months. The rates of 1-year survival and 2-year survival were 63% and 27%, respectively. NS chemotherapy provides a satisfactory and safe clinical activity for patients with recurrent and metastatic NPC after platinum-containing chemotherapy failed.

48TiP - KEYNOTE-122: Phase 2 study of pembrolizumab versus standard-of-care chemotherapy in platinum-pretreated, recurrent or metastatic nasopharyngeal carcinoma

Aim/Background: Treatment for recurrent/metastatic nasopharyngeal carcinoma (NPC) that progresses on a platinum-based regimen includes gemcitabine, capecitabine, or docetaxel. Prolonged exposure to Epstein-Barr virus (EBV) in NPC leads to increased expression of PD-1, resulting in suppressed T-cell immunity and tumor surveillance. Pembrolizumab is a monoclonal anti–PD-1 antibody designed to block the interaction between PD-1 and PD-L1 and PD-L2. In the phase 1b KEYNOTE-028 study, pembrolizumab had an ORR of 22% (6/27) in heavily pretreated (≥3 lines) patients with NPC. KEYNOTE-122 (NCT02611960) is a multicenter, open-label, randomized phase 2 study designed to evaluate the efficacy and safety of pembrolizumab monotherapy versus chemotherapy in patients with platinum-pretreated, recurrent or metastatic NPC. Trial design: Key eligibility criteria include age ≥18 years, histologically confirmed nonkeratinizing differentiated NPC (WHO Class II) or undifferentiated NPC (WHO Class III), metastatic or recurrent disease, EBV positivity determined locally or centrally by EBV-encoded small RNA in situ hybridization, previous treatment with platinum-containing regimen, ECOG performance status 0-1, and measurable disease per RECIST v1.1. Patients will be randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 weeks (Q3W) or investigator’s choice of chemotherapy (capecitabine 1000 mg/m2 twice daily on days 1-14 of each 3-week cycle, gemcitabine 1250 mg/m2 once per week on days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m2 Q3W). Treatment will continue until disease progression, unacceptable toxicity, investigator decision, or 35 cycles of pembrolizumab. Response will be evaluated every 6 weeks for the first year of treatment and every 9 weeks thereafter per RECIST v1.1 by central imaging assessment. Primary end points are overall survival and progression-free survival per RECIST v1.1 by central imaging assessment; secondary end points include objective response rate and duration of response per RECIST v1.1 by central imaging assessment. Enrollment is ongoing and will continue until approximately 160 patients have enrolled. Clinical trial identification: ClinicalTrials.gov, NCT02611960 Legal entity responsible for the study: Merck & Co., Inc. Funding: Merck & Co., Inc. Disclosure: V. Lee: Received honoraria from Eli Lilly Asia Inc., and travel accommodations for international conference from Merck Sharp and Dohme. M-J. Ahn: Is on the advisory committee for AstraZeneca, ONO, Boehringer Ingelheim, Novartis, Lilly, BMS, and Merck. R.F. Swaby: I am a Merck employee and I own Merck stock. A.T.C. Chan: Research funding from Merck. All other authors have declared no conflicts of interest.

Evolution of Chemosensitivity and Resistance Assays as Predictors of Clinical Outcomes in Epithelial Ovarian Cancer Patients.

Epithelial ovarian cancer (EOC) is responsible for more cancer-related deaths than any other malignancy of the female reproductive system. The standard of care for advanced EOC involves a combination of cytoreductive surgery and platinum-based chemotherapy. Although a majority of patients respond to a platinum-containing regimen, many fail to respond to first-line treatment (platinum-refractory disease) or experience disease progression within 6 months of completing treatment (platinum-resistant disease). Even in patients who initially respond to platinum-based therapy, secondary development of platinum resistance is common. Many chemotherapeutic regimens with comparable efficacy and toxicities are available, leaving the determination of optimal therapy to the physician's discretion. There have been many efforts over the years to develop accurate predictors of outcomes in patients treated with chemotherapy to help inform treatment decisions. Predictive treatment markers are particularly relevant in a disease such as EOC, where a large number of similarly efficacious chemotherapy regimens are available. Chemosensitivity and resistance assays (CSRAs) are attractive approaches to interrogate the efficacy and complex biology of EOC. Some early predictive cellular tests, such as the early clonogenic assays, were limited by technical and logistical issues. Over time, changes in these assays have improved their prognostic and predictive value, but there is still a lack of widespread adoption due to methodological difficulties or limited clinical validation. Herein, we provide an overview of the evolution of CSRAs used to predict outcomes in patients treated with chemotherapy that have been evaluated for use in EOC, with a focus on the latest generation chemoresponse assay.

Abstract 2592: The role of surgery in the treatment of epithelioid trophoblastic tumor: A single institution case series

Abstract Objective: Epithelioid trophoblastic tumor (ETT) is a rare variant of gestational trophoblastic neoplasia (GTN) that develops from chorionic-type intermediate trophoblasts, simulates carcinoma, often presents many years following a pregnancy event, is associated with low or normal human chorionic gonadotropin (hCG) levels, and is relatively resistant to chemotherapy. Our aim was to identify the role of surgery in the management of both localized and metastatic ETT. Methods: A retrospective review of women with ETT treated at a gestational trophoblastic disease center from 2010-2015 identified five women. Medical records were abstracted for demographic data, clinical presentation, hCG levels, prior pregnancy information, disease sites, and treatment with chemotherapy and surgery. Results: The five women with ETT ranged in age from 28 to 48 years. Clinical presentation was abnormal uterine bleeding prompting dilation and curettage, which established the diagnosis of ETT in three women. One woman presented with repeated spontaneous pneumothorax requiring thoracoscopic resection, which identified a 6 cm ETT in the lung. Another woman was initially treated with methotrexate for a presumed ectopic pregnancy without a response. Two women had no identifiable antecedent pregnancy, two women had spontaneous abortions 19 and 72 months prior to the diagnosis of ETT, and one woman had a normal term delivery 48 months earlier. Four of five women had metastatic disease to the lungs. Three of these women underwent pulmonary wedge resection as well as hysterectomy followed by paclitaxel-cisplatin/paclitaxel-etoposide (TP/TE) chemotherapy, while the other woman was treated with etoposide, methotrexate, actinomycin D/etoposide, cisplatin (EMA/EP) chemotherapy and hysterectomy. The one woman with nonmetastatic disease was treated with hysterectomy only. All five women are currently without evidence of disease. Conclusions: Surgery, including hysterectomy and resection of metastatic disease, is an important component in the treatment of women with ETT. Adjuvant chemotherapy with a platinum-containing regimen, such as TP/TE or EMA/EP, should be used in women with metastatic disease. All five women with ETT in this series were cured using this approach, including the four with metastatic disease. Citation Format: Abigail Winder, Janelle Sobecki-Rausch, Kruti Maniar, Karen Novak, Julie Kim, John Lurain. The role of surgery in the treatment of epithelioid trophoblastic tumor: A single institution case series. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2592.

Abstract 2250: STK11 mutations in non-small cell lung cancer (NSCLC): descriptive analysis and prognostic significance

Abstract Background: STK11 (also called LKB1) is among the 3 most mutated genes in lung adenocarcinoma, but its prognostic and predictive significance in advanced NSCLC patients is still not clear. Recent preclinical and translational evidence suggest its role in conditioning KRAS mutant lung adenocarcinomas aggressiveness and response to targeted treatment. Materials and methods: This retrospective analysis, in a single center, included consecutive NSCLC patients who had undergone a platinum-containing regimen, for which standard or next generation (NGS) sequencing analyses of STK11 gene (exons 1-9) had been successfully performed. STK11 gene was considered mutated if effect on protein was predicted as deleterious. Clinical features along with EGFR (exons 18-21), KRAS (exons 2-4) and TP53 (exons 1-11) mutational status were correlated to STK11 status. Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for stage (advanced yes/no) and histology for progression-free survival (PFS), and smoking status, stage, EGFR/KRAS status and number of lines of chemotherapy for overall survival (OS). Results: Among the 302 patients included between November 2007 and January 2015, 63% were male, 16% non-smoker and median age was 60 year; 75% had an adenocarcinoma, 88% a stage IIIB or IV and 80% no previous treatment for advanced disease; 25 (8%) patients had a STK11 mutation, 30 (10%) an EGFR mutation and 81 (27%) a KRAS mutation. Deletions/insertions, missense and false-sense mutations mainly involved exon 4-6 of STK11. No statistical differences were observed between STK11 status and sex, smoking status, age, stage at diagnosis or histology (adenocarcinoma versus others). Among the 25 patients with STK11 mutation, 13 patients (52%) had a KRAS mutation, compared with 67 (24%) among those without STK11 mutation (p = 0.008). No correlation between STK11 and EGFR or TP53 mutational status was observed. Median follow-up time was 34.8 months (95% confidence interval [CI95]: 30.7-42.3). In univariate analysis, OS was shorter for STK11 mutated patients compared to wild type ones (p = 0.085; HR: 1.53; CI95: 0.94-2.49) with a median OS of 10.4 (CI95: 6.1-15.7) and 17.3 (CI95: 14.0-21.1) months for mutated and wild-type STK11 patients respectively. In multivariate analysis, the HR was 1.21 (CI95: 0.74-1.99; p = 0.45). Similar non-significant results were observed for PFS. Conclusion: We confirm the reported data of a positive correlation between STK11 and KRAS mutations. No correlation between STK11 status and PFS or OS in patients receiving platinum-based treatment was observed when taking into account other prognostic covariates. Citation Format: Francesco Facchinetti, Maria Virginia Bluthgen, Gabrielle Tergemina Clain, Laura Faivre, Jean-Pierre Pignon, David Planchard, Jean-Charles Soria, Benjamin Besse, Ludovic Lacroix. STK11 mutations in non-small cell lung cancer (NSCLC): descriptive analysis and prognostic significance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2250.

Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial

Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394. Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0-464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0-470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0-288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC. Bristol-Myers Squibb.

Treatment Patterns for Advanced Non–Small-cell Lung Cancer After Platinum-containing Therapy in U.S. Community Oncology Clinical Practice

BackgroundKnowledge of the real-world treatment patterns for non–small-cell lung cancer (NSCLC) can identify quality-of-care gaps and guide resource allocation needs. Our objective was to describe the treatment patterns for advanced NSCLC after first-line chemotherapy in the era before the approval of immunotherapeutic agents. Materials and MethodsThe present was a retrospective observational study of adult patients with advanced NSCLC (stage IIIB/IV or metastatic recurrence) who had completed a platinum-containing regimen, with an appropriate tyrosine kinase inhibitor if positive for epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Eligible patients initiated second-line chemotherapy from November 2012 through October 2014, recorded in an oncology record system for U.S. community clinics. ResultsOf 6867 patients with advanced NSCLC, 4188 (61%) initiated and 2707 (39%) completed platinum therapy, with a tyrosine kinase inhibitor, if appropriate. Subsequently 1889 of 2707 (70%) received second-line chemotherapy, including 1173 within the study period (844 [72%] nonsquamous, 275 [23%] squamous, and 54 [5%] not otherwise specified). The mean ± standard deviation patient age was 66 ± 10 years; 54% were male. Of the 94 different second-line regimens, docetaxel was the most common, prescribed to 14% of the patients overall and 14% and 16% of the nonsquamous and squamous cohorts, respectively. The median duration was 64 days (range, 1-455 days) and 48 days (range, 1-210 days) for the nonsquamous and squamous cohorts, respectively. The median duration by regimen category was 15 to 85 days (overall range, 1-953 days). ConclusionThese findings show the diversity, short treatment duration, and lack of efficacy of second-line chemotherapy regimens for NSCLC in the community oncology setting.

Phase II Study of a Non-Platinum–Containing Doublet of Paclitaxel and Pemetrexed with Bevacizumab as Initial Therapy for Patients with Advanced Lung Adenocarcinomas

IntroductionMany patients with lung cancers cannot receive platinum-containing regimens owing to comorbid medical conditions. We designed the PPB (paclitaxel, pemetrexed, and bevacizumab) regimen to maintain or improve outcomes while averting the unique toxicities of platinum-based chemotherapies. MethodsWe enrolled patients with untreated, advanced lung adenocarcinomas with measurable disease and no contraindications to bevacizumab. Participants received paclitaxel, 90 mg/m2, pemetrexed, 500 mg/m2, and bevacizumab, 10 mg/kg, every 14 days for 6 months and continued to receive pemetrexed and bevacizumab every 14 days until progression or unacceptable toxicity. ResultsOf the 44 patients treated, 50% were women; the median age was 61 years and 89% had a Karnofsky performance status of at least 80%. We genotyped 38 patients with the following results: Kirsten rat sarcoma viral oncogene homolog gene (KRAS), 16; anaplastic lymphoma receptor tyrosine kinase gene (ALK), three; B-Raf proto-oncogene, serine/threonine kinase gene (BRAF) V600E, two; erb-b2 receptor tyrosine kinase 2 gene (HER2)/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), one; epidermal growth factor receptor gene (EGFR) exon 20 insertion, one; and driver 15, none. A total of 23 patients achieved a PR (52%, 95% confidence interval: 37–68), including seven of 16 with KRAS-mutant tumors. The overall survival rate at 2 years was 43% with a median of 17 months (95% confidence interval: 10–29). Grade 3/4 treatment-related toxicities included elevated alanine transaminase level (16%), fatigue (16%), leukopenia (9%), anemia (7%), elevated aspartate transaminase level (7%), edema (5%), and pleural effusions (5%). Two patients died of respiratory failure without disease progression. ConclusionsThe PPB regimen produced a high response rate in patients with lung adenocarcinomas regardless of mutational status. Survival and toxicities were comparable to those in the phase II reports testing platinum-containing doublets with bevacizumab. These results justify use of the PPB regimen in fit patients in whom three-drug regimens including bevacizumab are appropriate.

Abstract OT1-03-17: ABRAZO: An international phase 2 (2-stage, 2-cohort) study of the oral PARP inhibitor talazoparib (BMN 673) in BRCA mutation subjects with locally advanced and/or metastatic breast cancer

Abstract Background: Cancer cells with deleterious mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/2) are deficient in the DNA double-strand break repair mechanism, rendering them highly dependent on the single-strand break repair pathway, which is initiated by poly-(ADP-ribose) polymerase (PARP) [1-3]. In cells with deleterious BRCA1/2 mutations, PARP inhibition is synthetically lethal because of accumulation of irreparable DNA damage [1-3]. Talazoparib (BMN 673) exhibits a novel two-pronged approach in treating BRCA1/2-mutant tumors: 1) potent catalytic inhibition of the PARP enzyme; and 2) trapping of PARP at sites of DNA damage [4-7]. The capacity to trap PARP-DNA complexes varies widely across PARP inhibitors and is not correlated with catalytic inhibition potency [4-7]. In preclinical models, trapping PARP on DNA is more potent at inducing cancer cell death than enzymatic inhibition of PARP alone [4,7]. Talazoparib is the most potent clinical-stage PARP inhibitor tested to date with the highest efficacy at trapping PARP-DNA complexes [7]. Talazoparib has shown single-agent antitumor efficacy in several solid tumor types and was generally well tolerated in a phase 1/2 clinical study [8]. Methods: This 2-stage, 2-cohort, phase 2 international study (ABRAZO) evaluates the safety and efficacy of talazoparib in patients with a deleterious germline BRCA1 or BRCA2 mutation with locally advanced and/or metastatic breast cancer. Eligible subjects will be assigned to one of two cohorts based on prior chemotherapy for metastatic disease. Cohort 1 (n=70) includes patients with a complete response (CR) or partial response (PR) to platinum-containing regimens for metastatic disease. Cohort 2 (n=70) includes patients who have received &amp;gt;2 prior chemotherapy regimens in the metastatic setting but have not had prior platinum therapy for locally advanced or metastatic disease (prior adjuvant or neoadjuvant therapy with a platinum is allowed). The primary objective is objective response rate (ORR). Secondary objectives include clinical benefit response (CBR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Health-related quality of life (QoL) assessments are an exploratory objective. Eligible subjects will receive oral talazoparib (1 mg/day, 21-day cycles) until disease progression or unacceptable toxicity. This trial is currently enrolling patients from the United States and Europe (NCT02034916). This study is funded by BioMarin Pharmaceutical Inc.