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Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naive older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m(2) weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naive older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930.

Purpose Denosumab, an anti–RANK ligand monoclonal antibody, significantly increases bone metastasis–free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months. Patients and Methods A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died. Results In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets. Conclusion Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.

Denosumab is a fully human monoclonal antibody against RANK ligand (RANKL), an essential cytokine for the formation, function, and survival of osteoclasts. The role of excessive RANKL as a contributor to conditions characterized by bone loss or bone destruction has been well studied. With its novel mechanism of action, denosumab offers a significant advance in the treatment of postmenopausal osteoporosis; bone loss associated with hormone ablation therapy in women with breast cancer and men with prostate cancer; and the prevention of skeletal-related events in patients with bone metastases from solid tumors by offering clinical benefit to these patients in need.

Bone is a complex tissue that provides mechanical support for muscles and joints, protection for vital organs, a mineral reservoir that is essential for calcium homeostasis, and the environment and niches required for haematopoiesis. The regulation of bone mass in mammals is governed by a complex interplay between bone-forming cells termed osteoblasts and bone-resorbing cells termed osteoclasts, and is guided physiologically by a diverse set of hormones, cytokines and growth factors. The balance between these processes changes over time, causing an elevated risk of fractures with age. Osteoclasts may also be activated in the cancer setting, leading to bone pain, fracture, spinal cord compression and other significant morbidities. This Review chronicles the events that led to an increased understanding of bone resorption, the elucidation of the signalling pathway mediated by osteoprotegerin, receptor activator of NF-κB (RANK) and RANK ligand (RANKL) and its role in osteoclast biology, as well as the evolution of recombinant RANKL antagonists, which culminated in the development of the therapeutic RANKL-targeted antibody denosumab.

Background: Patients with breast cancer and bone metastases often experience skeletal-related events (SREs) and pain, which may impact health-related quality of life (HRQoL). Denosumab is a fully human monoclonal antibody against RANKL shown to be superior in delaying/preventing SREs and more effective in delaying moderate or severe pain in patients with advanced breast cancer compared with zoledronic acid (ZA). Previously reported results from this study population showed that both denosumab and ZA patients showed improvement or maintenance in HRQoL relative to baseline (BL), and a greater proportion of denosumab-treated patients had a clinically meaningful improvement in HRQoL. We now describe the effect of denosumab and ZA treatment on HRQoL among patients with varying degrees of pain at BL. Methods: Enrolled patients received subcutaneous (SC) denosumab 120 mg or intravenous (IV) ZA 4 mg every 4 weeks in a double-blind, double-dummy fashion. Pain was evaluated using the Brief Pain Inventory — Short Form (BPI). Patients were divided into 2 subgroups based on the level of pain reported at BL: no/mild pain or moderate/severe pain. Patients completed the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at BL, day 8, and before each monthly visit to assess overall HRQoL. Higher scores (range 0 to 108) represent better HRQoL. Improvement, maintenance, and worsening of HRQoL were assessed through month 18, when 30% of patients had dropped out due to death, disease progression, or withdrawal of consent. A change of ≥5 points (increase or decrease) in the FACT-G total score was considered a meaningful improvement. Results: Among patients who reported no/mild pain at baseline, more denosumab-treated patients had a ≥5-point increase in their FACT-G score from month 4 onwards. Over the 18 month period, an average of 4.1% more (range: −0.6% to 9.3%) denosumab-treated patients experienced meaningful improvement in HRQoL than ZA-treated patients. There were also fewer denosumab-treated patients experiencing ≥5-point decrease in HRQoL over 18 months (average of 2.4% fewer [range:-4.4% to 6.3% fewer]). Similar patterns were also noted for patients with moderate/severe pain at baseline. An average of 3.0% more (range:-1.7% to 7.9%) denosumab-treated patients had ≥5-point increase in FACT-G scores compared with ZA-treated patients over 18 months. A lower proportion of denosumab-treated patients (3.5% fewer [range: −1.1% to 11.5% fewer]) than ZA-treated patients had a decrease ≥5-points in their FACT-G score over 18 months. Conclusion: In patients with breast cancer and bone metastases, a greater proportion treated with denosumab than ZA had a meaningful improvement in HRQoL regardless of their pain level at BL. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-05.

Metastatic renal cell carcinoma (RCC) is a disease that is resistant to conventional systemic therapy. Nonmyeloablative allogeneic stem cell transplant has activity in patients with metastatic RCC. This approach has been used in related donor transplantation but there are limited data on outcomes in the setting of unrelated donor (URD) transplantation. This phase II trial assessed the efficacy, safety, and responses in 16 patients, 10 related and 6 URD transplants after a reduced intensity conditioning regimen and stem cell transplant as a treatment for metastatic RCC. Sixteen patients received a conditioning consisting of either fludarabine, cyclophosphamide (n=11) or fludarabine, total body irradiation (n=5) followed by transplantation from an HLA-matched sibling donor or a unrelated HLA-donor. Cyclosporine and mycophenolate mofetil were administered as posttransplant immunosuppression. Patients were monitored for engraftment by short tandem repeat for myeloid and lymphoid lineages and clinical response was assessed by serial imaging. All patients achieved donor chimerism, 7 patients developed acute, grades 2 to 3, graft-versus-host disease. Chronic graft-versus-host disease occurred in 6 patients and transplant-related mortality was 12%. Of the 10 related donors, 1 obtained a complete response, 3 had a partial response, and 3 had stable disease. In the 6 patients who underwent URD transplant, 1 obtained a complete response and 1 patient had stable disease. These results suggest that similar outcomes are possible where either related or URD were used as the stem cell source in reduced intensity stem cell transplant for metastatic RCC.

Few attempts have been made to examine the feasibility of safely administering low-molecular-weight-heparins (LMWHs) in the presence of concurrent thrombocytopenia. We retrospectively investigated the safety of low-dose LMWH in BMT patients, a population at risk of bleeding. In total, 26 patients received at least one dose of low-dose enoxaparin (ie1 mg/kg/day) during thrombocytopenia. s.c. enoxaparin 40 mg once daily was given in 85% of the cohort. The mean number of platelet days55 x 10(9) and20 x 10(9)/l were 16.5 days (95% CI=8.04-24.96) and 4.14 days (95% CI=2.35-5.93), respectively. The mean number of low-dose enoxaparin administration days when platelet55 x 10(9) and 20 x 10(9)/l were 9.89 days (95% CI=3.26-16.53) and 2.25 days (95% CI=0.57-3.93), respectively. Minor bleeding occurred in four patients (15%) whereas major episodes developed in two patients (8%). The latter two events occurred during the transition between full therapeutic (ie 1.5-2 mg/kg/day) and low-dose enoxaparin close to the onset of thrombocytopenia. The present case series, along with the discussed literature, descriptively suggests that low-dose enoxaparin may be safely administered at a platelet count in the range of 20 and 55 x 10(9)/l in BMT patients who weigh55 kg.

OBJECTIVE: To describe the evidence assessing the use of anti-thrombin III (AT-III) in the management of toxicity associated with hematopoietic stem-cell transplantation (HSCT)—conditioning regimens. DATA SOURCES: Clinical literature was accessed through conference proceedings, EMBASE, the Cochrane database, and MEDLINE (1966-December 2003). STUDY SELECTION AND DATA EXTRACTION: Case reports, small case series, case—control and cohort studies, and randomized controlled trials of AT-III in HSCT were evaluated. Publications examining AT-III use in the non-HSCT setting were also explored. Key search terms included AT-III, transplantation, and veno-occlusive disease (VOD). DATA SYNTHESIS: Severe VOD and ensuing multiple organ dysfunction is associated with high mortality in HSCT. A low AT-III level has been shown to correlate with the development of organ dysfunction. Phase II trials, case series, and one small, randomized, placebo-controlled study suggest a benefit when AT-III therapy is instituted early in the course of VOD/multiple organ dysfunction syndrome. In all of these reports, AT-III use was devoid of adverse events. CONCLUSIONS: Although further studies are needed to ascertain the optimal target level, method, and duration of administration, AT-III is still a viable alternative for the treatment of severe VOD and ensuing multiple organ dysfunction.

We conducted a randomized, double blind, placebo-controlled multi-institutional trial to assess the ability of amifostine to protect patients against acute lung injury associated with cyclophosphamide/cisplatin/carmustine (BCNU) (STAMP I), a BCNU-containing high dose chemotherapy regimen used with hematopoietic cell transplantation. Amifostine was administered in a dose of 740 mg/m2 for 2 doses preceding administration of BCNU, the presumed pulmonary-toxic component of the regimen. The trial was stopped after 79 patients were randomized and a planned interim analysis demonstrated that it was unlikely that pulmonary cytoprotection would be detected with further accrual. We conclude that amifostine, used in the dose and schedule we tested, does not reduce the incidence of acute lung injury produced by STAMP I. Further, we suggest that amifostine use with BCNU in other contexts and with clinically achievable doses is unlikely to protect the lung from BCNU-associated acute injury.

Systemic sclerosis (SSc) is a multisystem disease of presumed autoimmune pathogenesis for which no proven effective treatment exists. High-dose immunosuppressive therapy (HDIT) has been proposed as an investigational treatment for severe autoimmune diseases. Nineteen patients with poor-prognosis SSc underwent HDIT. The median age was 40 years (range, 23-61 years), the median modified Rodnan skin score (a measure of dermal sclerosis) was 31, and the median DLCO was 57%. Conditioning therapy involved 800 cGy total body irradiation (TBI) (± lung shielding to approximately 200 cGy), 120 mg/kg cyclophosphamide, and 90 mg/kg equine antithymocyte globulin. CD34-selected granulocyte–colony-stimulating factor–mobilized autologous blood stem cells provided hematopoietic rescue. With median follow-up at 14.7 months, the Kaplan-Meier estimated 2-year survival rate was 79%. Three patients died of treatment complications and one of disease progression. Two of the first 8 patients had fatal regimen-related pulmonary injury, a complication not found among 11 subsequent patients who received lung shielding for TBI. Overall, internal organ functions were stable to slightly worse after HDIT, and 4 patients had progressive or nonresponsive disease. As measured by modified Rodnan skin scores and modified health assessment questionnaire disability index (mHAQ-DI) scores, significant disease responses occurred in 12 of 12 patients evaluated at 1 year after HDIT. In conclusion, though important treatment-related toxicities occurred after HDIT for SSc, modifications of initial approaches appear to reduce treatment risks. Responses in skin and mHAQ-DI scores exceed those reported with other therapies, suggesting that HDIT is a promising new therapy for SSc that should be evaluated in prospective randomized studies.

BackgroundPatients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. MethodsIn this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. ResultsThe median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P

Background Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin’s lymphomas. Methods In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin’s lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety. Results The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin’s lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenstrom’s macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin’s lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%). Conclusions In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin’s lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.)

Fifty women with breast cancer metastatic to bone or bone marrow involvement on light microscopy at the time of initial evaluation were treated with high-dose chemotherapy (HDC) and peripheral blood progenitor cell (PBPC) transplantation with CD34(+) cell selection using the Isolex 300i system. All patients received induction chemotherapy. PBPC were mobilized with chemotherapy and granulocyte colony-stimulating factor. The median CD34(+) progenitor purity was 94.7% (range 72-98.7%) and recovery 38.4% (range 21-60%). Forty-eight hours after HDC with cyclophosphamide, cisplatin and carmustine, PBPC were reinfused. Median time to neutrophil count >0.5 x 10(9)/l was 9 (range 9-12) days and to platelet transfusion independence 11 (4-30) days. These data demonstrate that selected CD34(+) PBPCs allow rapid hematologic reconstitution after HDC. During follow-up, 23% of patients developed herpes zoster. Two patients developed cytomegalovirus infections. Three patients developed fungal infections. The development of these infections was not associated with steroid use but appeared more frequently in patients with diabetes mellitus. Seventy-four per cent of patients received steroids for pulmonary toxicity. Treatment-related mortality was 4%. Progression-free survival and overall survival at 35 months was 22.4% and 40.5%, with a median of 11.4 months and 15.4 months, respectively.

Autologous peripheral blood progenitor cell (PBPC) transplantation is increasingly employed in the outpatient setting, yet data on early complications following PBPC transplantation are scant. We evaluated 105 women with high-risk primary or metastatic breast cancer who were treated at a single institution during 1996-1997. The mean duration of neutropenia (absolute neutrophil count

This review focuses on certain of the principles involved in high-dose chemotherapy and radiation therapy along with autologous hematopoietic stem cell transplantation for the treatment of certain malignancies. In addition, the evidence, wherever possible based on randomized data, for the application of this approach in certain malignancies is reviewed. The malignancies highlighted include acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin disease, and breast cancer.

Each year in the USA, 180,000 new cases of breast cancer are diagnosed and about 44,000 women die of the disease. Current primary treatment consists of adjuvant chemotherapy and hormone therapy, and statistics show that combination chemotherapy favorably influences the outcomes in both node-negative and node-positive primary disease. However, a significant number of breast cancer patients succumb to the disease, and nearly every patient diagnosed with metastatic breast cancer will be dead within five years. High-dose chemotherapy (HDC) and peripheral blood progenitor cell transplantation (PBPCT) are based upon laboratory and clinical observations of the ability to modify growth properties of quiescent and replicating cancer cells. A large number of HDC and PBPCT regimens have been evaluated for treatment of metastatic breast cancer, and recent autologous bone marrow transplantation data indicate that three HDC regimens (CPB, CTCb and cytoxan and thiotepa) predominate. Unfortunately, negative media coverage surrounding and subsequent to the presentation of preliminary findings reported at the May 1999 American Society of Clinical Oncologists, that were not allowed adequate follow-up time for full analysis of treatment results, has had a detrimental effect on the ability to conduct trials in this area. Several randomized trials have been conducted in both the metastatic and high risk primary disease settings. Thorough analysis of these studies indicates an evaluable improvement in favor of HDC and PBPCT in three of the four randomized studies performed in metastatic breast cancer and two of the four high risk primary studies. Also, initial evaluations found that quality of life appeared comparable in patients receiving either HDC or not. Each randomized trial studied asks a different question and, depending on the intensity of HDC regimen, the intensity and duration of the standard dose chemotherapy control and the schedule of events in relation to induction chemotherapy, the outcomes may be quite variable. Still, certain general trends are indentifiable. HDC alone will not completely cure breast cancer and should be considered as part of an overall therapeutic plan. In some of these studies, significantly longer follow-up is required before definitive analysis can be completed.

(2000). High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Breast Cancer. Cancer Investigation: Vol. 18, No. 5, pp. 440-455.

Hormone-ablative therapies for breast cancer can cause marked and rapid reductions in circulating estrogen levels. Cancer treatment-induced bone loss (CTIBL) is generally more rapid and severe than bone loss associated with menopause in women or aging in women and men. In premenopausal women with breast cancer, CTIBL is mainly caused by chemotherapy with resultant ovarian failure, through the use of gonadotropin-releasing hormone (GnRH) agonists or by tamoxifen. In postmenopausal women, steroidal and nonsteroidal aromatase inhibitors (AIs) increase bone turnover, decrease bone mass, and increase fracture rate. Oral bisphosphonates and intravenous zoledronic acid can prevent bone loss in pre- and postmenopausal women. Subcutaneous denosumab has been shown to increase bone mineral density significantly in postmenopausal women receiving AIs. Finally, there is increasing evidence to support a disease modifying effect of bone-targeted treatment with improvements in disease-free and overall survival in some disease settings.

Purpose: Denosumab was shown to be superior to zoledronic acid in preventing skeletal related events (SRE) in patients with breast cancer and bone metastases in a randomized, double-blind phase III study. We evaluated further results from this study related to skeletal complications and health-related quality of life (HRQoL). Experimental Design: Patients were randomized 1:1 to receive subcutaneous denosumab 120 mg (n = 1,026) and intravenous placebo, or intravenous zoledronic acid 4 mg (n = 1,020) and subcutaneous placebo every 4 weeks. Analyses reported here include the proportion of patients with one or multiple on-study SREs, time to first radiation to bone, time to first SRE or hypercalcemia of malignancy, and change in HRQoL (functional assessment of cancer therapy–general). Results: Fewer patients receiving denosumab than zoledronic acid had an on-study SRE (31% vs. 36%, P = 0.006). The incidence of first radiation to bone was 12% (n = 123) with denosumab versus 16% (n = 162) with zoledronic acid. Denosumab prolonged the time to first radiation to bone by 26% versus zoledronic acid (HR, 0.74; 95% confidence interval [CI], 0.59–0.94, P = 0.012) and prolonged the time to first SRE or hypercalcemia of malignancy by 18% (HR, 0.82; 95% CI, 0.70–0.95; P = 0.007). Ten percent more patients had a clinically meaningful improvement in HRQoL with denosumab relative to zoledronic acid, regardless of baseline pain levels. Conclusions: Denosumab was superior to zoledronic acid in reducing bone-related complications of metastatic breast cancer and maintained HRQoL, providing an efficacious, well-tolerated treatment option for patients with bone metastases from breast cancer. Clin Cancer Res; 18(17); 4841–9. ©2012 AACR.

BACKGROUND: In this study, the authors evaluated the effect of denosumab versus zoledronic acid (ZA) on pain in patients with advanced breast cancer and bone metastases. METHODS: The prevention of pain, reduction in pain interference with daily life activities, and the proportion of patients requiring strong opioid analgesics were assessed in a randomized, double-blind, double-dummy phase 3 study comparing denosumab with ZA for preventing skeletal-related events in 2046 patients who had breast cancer and bone metastases. Patients completed the Brief Pain Inventory-Short Form at baseline and monthly thereafter. RESULTS: Fewer patients who received denosumab reported a clinically meaningful worsening of pain severity (≥2-point increase) from baseline compared with patients who received ZA, and a trend was observed toward delayed time to pain worsening with denosumab versus ZA (denosumab, 8.5 months; ZA, 7.4 months; P = .08). In patients who had no/mild pain at baseline, a 4-month delay in progression to moderate/severe pain was observed with denosumab compared with ZA (9.7 months vs 5.8 months; P = .002). Denosumab delayed the time to increased pain interference by approximately 1 month compared with ZA (denosumab, 16.0 months; ZA, 14.9 months; P = .09). The time to pain improvement (P = .72) and the time to decreased pain interference (P = .92) were similar between the groups. Fewer denosumab-treated patients reported increased analgesic use from no/low use at baseline to strong opioid use. CONCLUSIONS: Denosumab demonstrated improved pain prevention and comparable pain palliation compared with ZA. In addition, fewer denosumab-treated patients shifted to strong opioid analgesic use. Cancer 2012. © 2012 American Cancer Society.

Matthew Smith*, Boston, MA; Fred Saad, Montreal, Canada; Neal Shore, Myrtle Beach, SC; Stephane Oudard, Paris, France; Kurt Miller, Berlin, Germany; Bertrand Tombal, Bruxelles, Belgium; Paul Sieber, Lancaster, PA; Karim Fizazi, Villejuif, France; Peter Van Veldhuizen, Kansas City, MO; Ronaldo Damiao, Rio de Janeiro, Brazil; Gavin Marx, Wahroonga, Australia; Juan Morote, Barcelona, Spain; Amy Feng, Roger Dansey, Carsten Goessl, Thousand Oaks, CA

With increasing healthcare resource constraints, it has become important to understand the incremental cost-effectiveness of new medicines. Subcutaneous denosumab is superior to intravenous zoledronic acid (ZA) for the prevention of skeletal-related events (SREs) in patients with advanced solid tumors and bone metastases. This study sought to determine the lifetime cost-effectiveness of denosumab vs ZA in this setting, from a US managed-care perspective.A lifetime Markov model was developed, with relative rate reductions in SREs for denosumab vs ZA derived from three pivotal Phase 3 trials involving patients with castration-resistant prostate cancer (CRPC), breast cancer, and non-small-cell lung cancer (NSCLC), and bone metastases. The real-world SRE rates in ZA-treated patients were derived from a large commercial database. SRE and treatment administration quality-adjusted life year (QALY) decrements were estimated with time-trade-off studies. SRE costs were estimated from a nationally representative commercial claims database. Drug, drug administration, and renal monitoring costs were included. Costs and QALYs were discounted at 3% annually. One-way and probabilistic sensitivity analyses were conducted.Across tumor types, denosumab was associated with a reduced number of SREs, increased QALYs, and increased lifetime total costs vs ZA. The costs per QALY gained for denosumab vs ZA in CRPC, breast cancer, and NSCLC were $49,405, $78,915, and $67,931, respectively, commonly considered good value in the US. Costs per SRE avoided were $8567, $13,557, and $10,513, respectively. Results were sensitive to drug costs and SRE rates.Differences in pain severity and analgesic use favoring denosumab over ZA were not captured. Mortality was extrapolated from fitted generalized gamma function beyond the trial duration.Denosumab is a cost-effective treatment option for the prevention of SREs in patients with advanced solid tumors and bone metastases compared to ZA. The overall value of denosumab is based on superior efficacy, favorable safety, and more efficient administration.

Summary Background Giant-cell tumour (GCT) of bone is a primary osteolytic bone tumour with low metastatic potential and is associated with substantial skeletal morbidity. GCT is rich in osteoclast-like giant cells and contains mononuclear (stromal) cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. We investigated the potential therapeutic effect of denosumab, a fully human monoclonal antibody against RANKL, on tumour-cell survival and growth in patients with GCT. Methods In this open-label, single-group study, 37 patients with recurrent or unresectable GCT were enrolled and received subcutaneous denosumab 120 mg monthly (every 28 days), with loading doses on days 8 and 15 of month 1. The primary endpoint was tumour response, defined as elimination of at least 90% of giant cells or no radiological progression of the target lesion up to week 25. Study recruitment is closed; patient treatment and follow-up are ongoing. The study is registered with Clinical Trials.gov, NCT00396279. Findings Two patients had insufficient histology or radiology data for efficacy assessment. 30 of 35 (86%; 95% CI 70–95) of evaluable patients had a tumour response: 20 of 20 assessed by histology and 10 of 15 assessed by radiology. Adverse events were reported in 33 of 37 patients; the most common being pain in an extremity (n=7), back pain (n=4), and headache (n=4). Five patients had grade 3–5 adverse events, only one of which (grade 3 increase in human chorionic gonadotropin concentration not related to pregnancy) was deemed to be possibly treatment related. Five serious adverse events were reported although none were deemed treatment related. Interpretation Further investigation of denosumab as a therapy for GCT is warranted. Funding Amgen, Inc.

Four hundred fifteen patients with metastatic breast cancer with known hormone receptor status received primary treatment with tamoxifen. Measured values for the estrogen receptor (ER, i.e., with estrogen binding) followed a continuous distribution (range, 3 to 1000 fmol/mg of protein). These values correlated positively with age. The response to treatment with tamoxifen correlated with the ER level, with response rates of approximately 80% when the ER level was greater than 30.1 fmol/mg of protein. Two hundred eighteen (218 of 415, 52%) patients had progesterone receptor (PR) values greater than 10 fmol/mg. The PR positivity correlated with the ER level. Patients with PR levels greater than 10 fmol/mg of protein (124 of 226, 55%) had a significantly higher response rate than those with values less than 10 fmol/mg of protein (45 of 189, 24%). However, in a multivariate analysis including both receptor levels, age, site, and number of metastases, only the ER level was significant in predicting the response to treatment with tamoxifen. A quantitative estimation of the ER level thus is the best predictor of response to hormonal treatment with tamoxifen for advanced breast cancer.

Venoocclusive disease (VOD) is the most frequent cause of early nonrelapse mortality among patients receiving high-dose chemoradiotherapy and hematopoietic stem cell transplantation. Endothelial injury of sinusoids and hepatic veins following chemotherapy is considered the initial event in the development of VOD. Activation of the coagulation cascade and inflammatory processes following endothelial injury results in a hypercoagulable state and a localized consumption of the natural anticoagulants, antithrombin III, protein C and protein S. The resultant coagulopathy can lead to multiorgan dysfunction and death. The objective was to retrospectively study the largest series of patients that has received antithrombin III for the treatment of VOD following hematopoietic stem cell transplantation. A total of 48 patients were diagnosed with VOD post hematopoietic stem cell transplantation (median age, 39 years; range, 1-69 years); 38 of the 48 received a nonradiation-based conditioning regimen and 21 of 48 received a transplant from an unrelated donor. Treatment was primarily directed at early intervention rather than prophylactic therapy to correct the antithrombin III deficiency associated with VOD. We attempted to achieve antithrombin III levels greater than 120%. There was no significant treatment-related morbidity. The overall 100-day mortality for the treatment cohort was 17%, with 10% for the mild/moderate group and 39% for the severe group, respectively. In conclusion, the encouraging results of this study suggest that this antithrombin III treatment should be further considered in patients with severe VOD.

Idelalisib (ZYDELIG®, GS-1101) is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). We studied idelalisib in 2 registrational trials, one in relapsed chronic lymphocytic leukemia (CLL) and one in refractory, indolent non-Hodgkin lymphoma (iNHL). In the Phase 3 CLL trial (Furman 2014), patients with relapsed disease and multiple co-morbidities precluding the use of chemotherapy were randomized to receive blinded idelalisib 150 mg BID plus rituximab intravenously (at a dose of 375 mg per square meter, followed by 500 mg per square meter every 2 weeks for 4 doses and then every 4 weeks for 3 doses) for a total of 8 infusions or an oral placebo plus rituximab. A total of 220 patients were randomized, with a median age of 71 yrs (78% ≥65 yrs), median time since diagnosis of 8.5 yrs, and median number of 3 prior therapies (range: 1-12). Of these, 44% of pts had del17p/TP53 mutation. The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P Citation Format: Roger Dansey. Clinical validation of PI3Kδ as a therapeutic target in B-cell malignancy. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA18.

Doxorubicin plus paclitaxel has been shown to be an active regimen for metastatic breast cancer and is now frequently used as adjuvant therapy for high-risk primary breast cancer. Initial studies reported a higher than expected rate of cardiac toxicity with this regimen. We studied 105 patients with either high-risk primary breast cancer or metastatic breast cancer who were treated with doxorubicin (60 mg/m2) and 3-h infusions of paclitaxel (175 mg/m2) cycled every 3 weeks. Patients received three cycles of chemotherapy for high-risk primary or four cycles for metastatic disease. Patients then proceeded to high-dose chemotherapy (HDC) (STAMP I cyclophosphamide, cisplatin and carmustine) and peripheral blood progenitor cell transplantation (PBPCT). Patients underwent radionuclide multi-gated angiograms (MUGA) before and following induction chemotherapy and following HDC. During induction chemotherapy 40 (38%) of the patients had a reduction in left ventricular ejection fraction (LVEF). Fourteen had a decrease of 20% or greater and two were mildly symptomatic from CHF. There was additional reduction in the LVEF after HDC with a median value for LVEF of 59% (range, 20-78%). During HDC 10 patients developed clinical signs of congestive heart failure (CHF). Five patients responded to diuretic therapy and did not require any additional treatment. Four patients responded to vasodilation and/or digoxin with improvement in cardiac function. A clinically significant decrease in cardiac function was found in a small number of patients after induction chemotherapy and HDC with PBPCT. The majority of the patients tolerated this regimen without problems. Although there was a decline in LVEF as measured by radionuclide MUGA this did not prevent the majority of patients from proceeding with HDC. Bone Marrow Transplantation (2000).

High-dose chemotherapy is now frequently used for the treatment of primary and metastatic breast cancer. Two recent randomized trials have demonstrated that this treatment approach can result in extended disease-free and overall survival for patients with metastatic disease. However, treatment results have demonstrated that long term remissions from these treatments raise complex questions about traditional models of chemotherapy principles. A detailed analysis of the principles underlying high-dose therapy is presented in the context of principles of dose-response, the inverse rule and the total tumor cell kill hypotheses.

Introduction PI3Kδ signaling is critical for the proliferation and survival as well as for homing and tissue retention of malignant B cells. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in patients with heavily pretreated CLL. Methods This Phase 1 study evaluated idelalisib for relapsed/refractory CLL continuously given at 150 mg BID in combination with a total of 8 infusions of rituximab (R, 375 mg/m2 weekly x 8), or a total of 12 infusions of ofatumumab (O, 300mg initial dose either on Day 1 or Day 2 relative to the first dose of idelalisib, then 1,000 mg weekly x 7, then 1,000 mg every 4 wks x 4). Pts on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical response was evaluated according to published criteria (Hallek 2008; Cheson 2012). Results 40 pts (12F/28M) with a median (range) age of 66 (43-87) years and a WHO performance status of 0 (24, 60%) or 1 (16 40%) were enrolled. 19 pts received idelalisib in combination with R, 21 with O. Adverse disease characteristics (n, %) included Rai Stage III/IV (20, 50%), bulky lymphadenopathy (24, 60%), refractory disease (14, 35%), multiple prior therapies (median 2, range: 1-;9). Almost all patients (39, 98%) had at least 1 prior therapy containing R, and 3 of the 21 pts (14%) receiving idelalisib + O had received prior O. 63% of the pts receiving idelalisib + R, and 43% of the pts receiving idelalisib + O were refractory to R. Prior therapies also included alkylating agents (31, 78%, [bendamustine: 20, 50%]) and purine analogs (31, 78%, [fludarabine: 28, 70%]). Data available from 39 pts showed that 11 (28%) pts had evidence of del(17p) and/or TP53 mutations and 30 (75%) had unmutated IGHV. As of May 2013, the median (range) treatment duration was 18 (0-33) months. 23 (58%) pts have completed the primary study and enrolled into the extension study. A total of 14 pts (35%) were continuing idelalisib treatment on the extension study. The most common reasons for discontinuation either from the primary or extension study were disease progression (10, 25%) and adverse events (AEs) (9, 23%). There were 6 deaths reported on study; 3 pts experienced PD before death. Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea (53%/10%), cough (40%/3%), pyrexia (40%/3%), dyspnea (30%/3%), fatigue (25%/0%) nausea (25%/0%), rash (20%/0%), pneumonia (18%/15%), colitis (10%/10%) and pneumonitis (10%/7.5%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 30%/10%. Of those, only 1 pt discontinued the study because of (recurrent) TA elevation. The ORR (N=40) was 83% (33/40), with 3 CRs (8%), and a median (range) time to response of 1.9 (1.7-21.8) months. Median progression-free survival (PFS) for all patients (N=40) and duration of response (n=33) were 20 and 19 months, respectively. Median overall survival (OS) has not been reached. For the 11 pts with del(17p) and/or TP53 mutations, the response rate was 73% (8/11) and the median PFS and DOR were 19 months. Conclusions Combinations of idelalisib with therapeutic anti-CD20 antibodies such as rituximab or ofatumumab represent non-cytotoxic regimens with acceptable safety profiles and high activity resulting in durable tumor control in pts with heavily pretreated relapsed/refractory CLL. Phase 3 trials evaluating the efficacy of idelalisib in combination with R or O are ongoing (NCT01539512, NCT01659021). Disclosures: Furman: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. De Vos:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Fowler:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Coutre:Gilead Sciences: Research Funding.

Background Idelalisib (IDELA) is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues. Phase 1 trials demonstrated that IDELA is highly active as a single agent or in combination with rituximab (R) in heavily pretreated patients (pts) with CLL. Pts in these trials experienced reductions in disease-associated chemokines, improvement of organomegaly and cytopenias, profound reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Brown 2013; Barrientos 2013). Patients with early progression and significant co-morbidities have limited treatment options; single-agent rituximab is an option in these pts (NCCN 2013; Zelenetz 2013). Methods This Phase 3 study evaluated the efficacy and safety of IDELA + R vs placebo + R in pts with previously treated CLL. Eligibility criteria included the need for treatment per IWCLL guidelines, measurable lymphadenopathy, and CLL progression 6), renal dysfunction, or cytopenias due to poor marrow reserve. All pts received R at 375 mg/m2 [1st dose] and then 500 mg/m2q2 wks x 4, followed by q4 wks x 3 [8 doses total]) and were randomized to Arm A (n=110; IDELA 150 mg BID continuously) or Arm B (n=110; placebo BID continuously). Primary endpoint was progression-free survival (PFS). Response and progression in both arms were assessed by an independent review committee using standard criteria (Hallek 2008; Cheson 2012). Results were reviewed by an external Data Monitoring Committee (DMC). Results Results are from a pre-specified interim analysis after ∼50% of the total number of 119 planned events of CLL progression or death from any cause. Data cutoff was 30 Aug 2013. Pt characteristics (n=220) included a median age of 71 yrs (78% ≥ 65 yrs); CIRS > 6 in 85%; median creatinine clearance of 63.6 mL/min; and presence of anemia (73%), thrombocytopenia (61%), neutropenia (34%). Median time since diagnosis was 8.5 yrs, median number of prior therapies was 3 (range: 1-12), 44% had del(17p)/TP53 mutation, and 84% had unmutated IGHV. PFS in the IDELA + R arm was superior to placebo +R (HR [95% CI] = 0.15 [0.08, 0.28]; p = 3.0 x 1011). Median PFS of pts treated with IDELA + R was not reached and for placebo + R was 5.5 mos. At 24 wks, the PFS rate for IDELA +R was 93% compared to 46% for placebo + R. PFS strongly favored IDELA + R in all subgroups, including those with del(17p)/TP53 or unmutated IGHV. Pts treated with IDELA + R and with ≥1 post-baseline assessment also had a superior overall response rate (ORR) relative to those in the control arm (81% vs. 13%; odds ratio 29.9; p = 3.0 x 1019) and a higher lymph node response (LNR) rate (93% vs. 4%; odds ratio 264.5; p = 1.3 x 10-30). Relative to the control group, pts treated with IDELA +R also had a significant improvement in overall survival (OS): HR (95% CI) = 0.28 (0.09, 0.86), p = 0.018. Adverse events (AEs) occurring in ≥20% of pts (any Gr/Gr ≥3) by arm were: pyrexia (IDELA + R 29%/3%; placebo + R 16%/1%), fatigue (IDELA + R 24%/3%; placebo + R 27%/2%), nausea (IDELA + R 24%/0%; placebo + R 22%/0%), chills (IDELA + R 22%/2%; placebo + R 16%/0%), infusion-related reactions (IDELA + R 16%/0%; placebo + R 28%/4%), and cough (IDELA + R 15%/0%; placebo + R 25%/2%). Other selected AEs (any Gr/Gr ≥3) included diarrhea (IDELA + R 19%/4%; placebo + R 14%/0%) and rash (IDELA + R 10%/2%; placebo + R 6%/0%). Select lab abnormalities (any Gr/Gr ≥3) included ALT elevation (IDELA + R 31%/6%; placebo + R 9%/1%), anemia (IDELA + R 26%/6%; placebo + R 30%/14%), neutropenia (IDELA + R 55%/34%; placebo + R 49%/22%), and thrombocytopenia (IDELA + R 17%/10%; placebo + R 26%/16%). The most common SAEs were pneumonia (6.4%), pyrexia (6.4%), and febrile neutropenia (4.5%) in IDELA + R, and pneumonia (8.4%), febrile neutropenia (5.6%), and dyspnea (3.7%) in placebo + R. AEs led to study drug discontinuation in 9 pts (8.2%) in IDELA + R and 11 pts (10.3%) in placebo + R. Based on a review of efficacy and safety, the DMC recommended stopping the study early. Conclusions IDELA + R demonstrated statistically significant improvement with acceptable safety over placebo + R in PFS, ORR, LNR and OS in heavily pretreated pts with relapsed CLL, including those with adverse genetic features. Disclosures: Furman: Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Consultancy, Research Funding. Coutre:Gilead Sciences: Research Funding. Cheson:Gilead Sciences: Research Funding. Pagel:Gilead Sciences: Research Funding. Hillmen:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Ghia:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Eradat:Gilead Sciences: Research Funding. Ervin:Gilead Sciences: Research Funding. Lamanna:Gilead Sciences: Research Funding. Hallek:Gilead Sciences: Research Funding. Coiffier:Gilead Sciences: Research Funding. Pettitt:Gilead Sciences: Research Funding. Ma:Gilead Sciences: Research Funding. Stilgenbauer:Gilead Sciences: Honoraria, Research Funding. Aiello:Gilead Sciences: Employment. Johnson:Gilead Sciences: Employment, Equity Ownership. Miller:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment, Equity Ownership. O'Brien:Gilead Sciences: Research Funding.

Background PI3K-delta signaling is critical for proliferation, survival, homing and tissue retention of malignant B cells. Idelalisib is a selective, oral inhibitor of PI3Kδ that has been previously shown to be safe and tolerable and has demonstrated considerable activity as monotherapy or in combination with other agents in patients with relapsed/refractory (R/R) CLL. We provide an update on the safety and efficacy of a phase 1 study of idelalisib (IDELA) 150mg po BID administered continuously on a 28-day cycle in combination with two chemo-immunotherapy regimens: bendamustine/rituximab (IDELA+BR) and chlorambucil/rituximab (IDELA+ChR). Methods Twenty-nine adult subjects (15/14 IDELA+BR; IDELA+ChR) with R/R CLL requiring treatment were enrolled between April and Aug 2011 for the IDELA+BR cohort and Mar and Jul 2012 for the IDELA+ChR cohort. Median age 64 yrs (Min, Max: 41, 82), gender M/F (%) 65/35, WHO PS (%) 0/1/2 59/38/3, current Binet stage (%) A/B/C 21/28/41, and 62% of subjects had bulky adenopathy (presence of ≥1 node with diameter ≥5 cm). Median number of prior therapies was 3 (Min, Max: 1, 9). Thirty-five percent of subjects had refractory disease (not responding to a standard regimen or progressing within 6 month of the last course of a standard regimen) and 55% of subjects were refractory to rituximab. The treatment schedule was as follows: IDELA+BR (IDELA 150 mg BID po d1-28 until progression or withdrawal, rituximab 375 mg/m2 IV on d1 of cycles 1-6, bendamustine 70 or 90 mg/m2 intravenously on d1 and d2 of cycles 1-6). For the IDELA+RCh cohort (IDELA 150 mg BID po on d1-28 until progression or withdrawal, chlorambucil 10 mg/m2 po once a d1-7 of cycles 1-12, rituximab 375 mg/m2 IV d1 of cycles 1-6). Response was assessed by the investigators based on scheduled CT evaluations and clinical criteria following IWCLL 2008. Results The data cut-off date for this analysis was May 2013. Objective response rates for the 2 cohorts were 89.7% (95% CI (%): 72.6-97.8). Median time to response in both cohorts was 1.9 months. For IDELA+BR, the ORR was 86.7% (95% CI (%): 59.5-98.3) (CR 6.7%, PR 80%), neither median DOR nor median PFS have been reached and median exposure was 18.4 months (Min, Max: 1.2, 24.7). For IDELA+ChR, the ORR was 92.9% (95% CI (%): 66.1-99.8) (CR 14.3%, PR 78.6%), neither median DOR nor median PFS has been reached, and median exposure was 7.7 months (Min, Max: 1.9, 11.1). Commonly reported treatment-emergent AEs (≥20% of all subjects) and lab abnormalities of interest for IDELA+BR were (total(%)/≥grade 3 (%)): pyrexia (46.7/0) diarrhea (26.7/13.3), fatigue (20/0), neutropenia (86.7/60), thrombocytopenia (26.7/6.7), transaminase elevations (26.7/0), anemia (33.3/13.3). For IDELA+ChR, common TEAEs were: pyrexia (57.1/7.1), diarrhea (64.3/7.1), fatigue (42.9/21.4), neutropenia (64.3/42.9), thrombocytopenia (42.9/21.4), transaminase elevations (50.0/21.4), and anemia (42.9/14.3). Conclusion The combination of IDELA+BR or IDELA+ChR is tolerable and demonstrates strong activity with an ORR of 89.7%. Median PFS and DOR have not been reached in the IDELA+BR or the IDELA+ ChR cohorts. The ability to induce responses in this particularly difficult-to-treat patient population with refractory disease, the non-overlapping toxicity with these agents, and the ease of administration makes this an option in this patient population. These results support further studies with these chemo-immunotherapy regimens in patients with CLL. Disclosures: Barrientos: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Wagner-Johnston:Gilead Sciences: Research Funding. De Vos:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Dansey:Gilead Sciences: Employment. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Adewoye:Gilead Sciences: Employment. Furman:Gilead Sciences: Research Funding.

Background Myelofibrosis (MF) is characterized by activation of the JAK-STAT pathway, with the JAK2 V617F mutation found in 50-60% of patients. Although JAK inhibitors, such as FDA-approved ruxolitinib, have been effective in reducing splenomegaly and mitigating symptoms, patients uniformly exhibit “disease persistence” which is equated with a lack of hematologic or molecular remissions, or with loss of clinical improvement over time. Prior studies using cell lines or primary patient samples have shown that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is dysregulated in MPNs and is a potential therapeutic target (Kamishimoto et al, Cell Signal 2011; Huang et al, ASH 2009 Abstract 1896; Vannucchi et al, ASH 2011 Abstract 3835; Khan et al, Leukemia 2013). In CLL and other B-cell malignancies, the PI3K pathway is constitutively upregulated and is dependent on PI3Kδ. Idelalisib is a δ-isoform-specific PI3K inhibitor that is efficacious in patients with CLL and indolent NHL. Herein, the specific aims of our study were: 1) to determine whether the PI3Kδ isoform is expressed in progenitor cells from MF patients, and 2) to evaluate the inhibitory effects of idelalisib on basal and thrombopoietin (TPO)-stimulated AKT/S6RP phosphorylation (p-AKT/p-S6RP) in cell lines and in primary samples from MF patients who were either on chronic ruxolitinib (RUX) therapy or were not exposed to ruxolitinib (RUX-naïve or off-therapy at the time of sample collection). Methods To evaluate isoform expression, CD34+ cells from the peripheral blood of MF patients were sorted by FACSAria and cell lysates were analyzed by Simple Western using Peggy (ProteinSimple) with recombinant protein as a positive control. For cell line studies, BaF3/MPL W515L and UT-7/TPO cells were stimulated with recombinant human TPO and incubated with idelalisib. Whole cell lysates were analyzed by Western blot to quantify the % of p-AKT and p-S6RP levels compared to idelalisib-untreated cells. For MF patient samples, PBMCs were isolated from the whole blood of MF patients who were either RUX-naïve or on chronic RUX therapy and treated for 2 hours with idelalisib. Antibodies specific to p-AKT Ser473 and pS6RP Ser235/236 were used to quantify the proportion of p-AKT and pS6RP in basal and TPO-stimulated CD34+/CD3-/CD14-/CD19-/CD66- gated cells. Results The PI3Kδ isoform was found to be the predominant isoform expressed in 3 of 3 RUX-naïve and 4 of 4 chronic RUX patients tested; PI3Kβ was expressed at lower levels and no PI3Kα or γ was detected (Figure 1). In BaF3/MPL cells, p-AKT levels decreased by 51%, 64% and 67%, with 0.1, 1.0, 2.0 µM idelalisib, respectively, when compared to idelalisib-untreated cells; p-S6RP levels decreased by 24%, 27%, and 41%, respectively. Similarly, for UT-7/TPO cells, p-AKT decreased by 11%, 44%, and 55%, and p-S6 decreased by 13%, 28% and 48%, respectively. In CD34+ cells from RUX-naïve patients (n=3), p-AKT and p-S6RP levels decreased with increasing concentrations of idelalisib (0.02, 0.2, 2 µM). All patients on chronic RUX treatment demonstrated decreased p-AKT (n=3) and p-S6RP (n=4 basal, n=3 TPO-induced; patient 4 was only tested for basal) levels with increasing concentrations of idelalisib in both basal (Figure 2A) and TPO-stimulated (Figure 2B) assays. All 4 chronic RUX and 2 of 3 RUX-naïve patients tested carried the JAK2 V617F mutation. Conclusions The PI3Kδ isoform was identified as the predominant isoform expressed in CD34+ cells from MF patients. In both cell lines and patient samples, idelalisib inhibits the PI3K/AKT pathway, with a dose-dependent decrease of p-AKT and p-S6RP. Inhibition was observed for both RUX-naïve and chronic RUX-treated patients. Studies are underway to evaluate the effects of idelalisib on progenitor colony formation and induction of cell cycle arrest and apoptosis. * Meadows and Nguyen are first co-authors Disclosures: Meadows: Gilead: Employment, Equity Ownership. Queva:Gilead: Employment, Equity Ownership. Lannutti:Gilead, Acetra, Effector: Consultancy, Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Kashishian:Gilead: Employment, Equity Ownership. Jun:Gilead: Employment, Equity Ownership. Coutre:Gilead: Research Funding. Dansey:Gilead: Employment, Equity Ownership. Gotlib:Gilead: Consultancy, Research Funding.

Background PI3K-delta (δ) is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib (IDELA) is a potent and selective orally administered inhibitor of PI3Kδ with demonstrated activity in patients with R/R CLL as a single agent (Brown, ASCO 2013), in combinations with cytotoxic chemotherapy or with anti-CD20 mAbs, and in triplet combinations with chemotherapy and anti-CD20 mAbs (Barrientos ASCO 2013; Coutre EHA 2013; Barrientos EHA 2013). This report summarizes the Phase 1 combination experience of IDELA with cytotoxic chemotherapies. Methods Subjects were sequentially enrolled into one of 3 regimens of IDELA in combination with either (1) Bendamustine (B), 90 mg/m2 IV days 1,2 every 28 days x 6 cycles (N=15, enrolled Apr 2010-Nov 2011); (2) Fludarabine (F), 40 mg/m2 orally days 1-5, every 28 days x 6 cycles (N=12, enrolled Apr 2011-Aug 2011), or (3) Chlorambucil (Ch), 10 mg/m2 orally days 1-7, every 28 days x minimum of 3 and maximum of 12 cycles (N=18, enrolled Mar 2012-Aug 2012). IDELA was dosed at 150 mg po BID continuously. Response assessment was investigator determined, using scheduled CT scans and clinical criteria and applying IWCLL 2008 guidelines. Results 45 subjects were enrolled. The median age was 65 years; 73% Rai III/IV; median 3 prior regimens, (range 1-9); 58% refractory to last therapy. Prior therapy included rituximab (93%), F (82%), an alkylating agent (80%), and B (38%). 44% of B cohort subjects had prior B, and 75% of F cohort had prior F. Adverse prognostic factors: 42% del(17p)/TP53 mutated; 84% IGHV unmutated; 26% NOTCH1 mutated. As of May 1, 2013, the median idelalisib exposure for the B, F and Ch cohorts was 10.6 mo (range 1-32.5), 13.1 mo (2-22.4), and 11.1 mo (0.9-12.9), respectively. 18 (40%) subjects remain on treatment. Of the 27 discontinuations (D/C), 8 were for AEs, including diarrhea in 4 (9%); febrile neutropenia led to D/C in only 1. The most common (≥10% overall) Grade ≥3 AEs were febrile neutropenia (22%) and diarrhea (16%). Treatment-emergent Grade≥3 lab abnormalities in B/F/Ch/total (%) were neutropenia in 67/58/73/67, thrombocytopenia in 22/17/33/24, anemia in 28/17/20/22 and ALT/AST increased in 22/25/0/16. 42 subjects were evaluable for response. The ORR was 78% for the entire group of 45. Best responses (PR%/CR%) were 78/0 with B, 92/0 with F, and 60/7 with Ch; all non-responding subjects had stable disease. Among 42 subjects with genetic data, the ORR in the 19 with either del(17p) and/or TP53 mutation was 70% vs. 83% among 23 subjects with neither. The median time to response was 1.9 mos for each regimen. Median duration of response (mos) / median PFS (mos) was 26.6/19.9 for B, NR/NR for F, NR/NR for Ch, and 26.6/28.5 for the entire group (NR: not reached). Conclusions IDELA can be combined with the cytotoxic single agents B, F and Ch with acceptable safety. In this heavily pretreated group of patients, many with refractory disease and adverse genetic markers, the ORR of 78% and estimated DOR and PFS of 28.5 months are indicative of significant clinical activity. Disclosures: De Vos: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Furman:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Dansey:Gilead Sciences: Employment. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Dubowy:Gilead Sciences: Employment. Coutre:Gilead Sciences: Research Funding.

Background Idelalisib (IDELA) is a potent, competitive PI3Kδ inhibitor currently in Phase 3 clinical development. In numerous Phase 1/2 studies, IDELA alone or in combination with other therapies demonstrated clinical efficacy in patients with various hematologic malignancies (e.g., indolent non-Hodgkin lymphoma [iNHL] and chronic lymphocytic leukemia [CLL]) and overall safety of IDELA has been characterized in these patients. The relationship between IDELA plasma exposures and its inactive circulating metabolite, GS-563117, and clinical efficacy and safety findings were evaluated. Methods IDELA and GS-563117 plasma exposure were generated using population pharmacokinetic (PK) models for IDELA and GS-563117 based on data from several phase 1/2 clinical studies. Efficacy and safety data from 2 clinical studies, a Phase 1 dose ranging study (101-02; 50 mg to 350 mg BID, 150 mg and 300 mg QD) and a Phase 2 study (101-09), were included in the PK/PD analyses. Efficacy endpoints including best overall response rate (BOR), duration of response (DOR), progression free survival (PFS), sum of products of the greatest perpendicular diameters (SPD) of index lesions, and lymph node response rate (LNR) were evaluated against IDELA plasma exposure (AUCtau and Ctau). Safety endpoints evaluated included neutropenia, diarrhea, skin rash, infection, and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation (vs. plasma exposure of IDELA and GS-563117, specifically AUCtau and Cmax). Results Over a wide dose/exposure range in Study 101-02, median SPD response increased with IDELA exposure (Ctau) quartiles, before reaching a plateau at the third quartile (Q3: range ∼280-405 ng/mL), which encompasses the mean IDELA Ctau at 150 mg BID dose (381 [56%] ng/mL). IDELA exposures were less than dose proportional and modestly higher at doses >150 mg BID (eg. Ctau ∼48% higher at 350 mg vs. 150 mg BID). No relationships were observed between the incidence rate (yes/no) of Grade 3 or 4 AST or ALT elevation or the severity (Grade 1 to Grade 4) of elevation over the range of IDELA plasma exposure. Taken together, these data supported the selection of 150 mg BID for further development. No relevant association was observed between IDELA exposure (Ctau: median (Q1, Q3) = 294 (203, 437) ng/mL) vs. any of the efficacy endpoints evaluated in Study 101-09, indicating the absence of exposure-efficacy relationships at 150 mg BID (Table 1). In Study 101-09, no association was observed between IDELA or GS-563117 plasma exposures vs. incidence of neutropenia, diarrhea, rash, infection, or Grade 3 or 4 AST or ALT elevation. Conclusions There were no exposure-response relationships observed for efficacy or safety endpoints at IDELA 150 mg BID, which was selected based on comprehensive exposure-response analyses over a wide dose/exposure range. These data support the use of IDELA 150 mg BID as a monotherapy for treating patients with hematologic malignancies. Disclosures: Jin: Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Fang:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment, Equity Ownership. Newcomb:Gilead Sciences: Employment, Equity Ownership. Dansey:Gilead: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

TPS7133 Background: PI3K-delta is critical for the activation, proliferation and survival of B cells and plays a role in homing and retention of B cells in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and alters trafficking of malignant B cells in lymphoid tissues (Lannutti, 2011). Phase 1 trials demonstrated that idelalisib is highly active in heavily pretreated pts with CLL as a single agent or in combination with rituximab (R), bendamustine (B), or BR: pts experienced reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Coutre et al, 2012; Sharman et al, 2011). Methods: Study will enroll 390 pts with previously treated CLL who have measurable lymphadenopathy, have received prior therapy containing a purine analog or B and an anti-CD20 monoclonal antibody, are not refractory to B, have experienced CLL progression within 36 months from the completion of the last prior therapy, and are currently sufficiently fit to receive cytotoxic therapy. Pts are randomized in a 1:1 ratio to Arm A or B. On Arm A, subjects receive idelalisib continuously at 150 mg BID + R at 375 mg/m2 (1st dose) and then 500 mg/m2 every 4 weeks for 6 cycles + B at 70 mg/m2 on Days 1 and 2 of each 4-week cycle for 6 cycles. On Arm B, subjects receive placebo instead of idelalisib. Stratification factors address IGHV mutational status, del(17p)/p53 mutation status, and refractory vs relapsed disease. The primary endpoint is PFS and key secondary endpoints include ORR, lymph node response rate, CR rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set. The study was initiated in June 2012 and a data monitoring committee has begun regular review of data. Clinical trial information: NCT01569295.

8501 Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown monotherapy activity in recurrent MCL (Kahl, ICML 2011). Methods: This phase 1 study is evaluating the activity of continuous idelalisib (Id), 150 mg BID, in combination with everolimus (E) (10 mg PO qD) (Id+E regimen), with bortezomib (V) (1.3 mg/m2 SC day 1, 8, 15 per 28 day cycle) (Id+V regimen), or with rituximab (R) (375 mg/m2, on Day 1) and bendamustine (B) (90 mg/m2x 2), for 6 cycles (Id+BR regimen). Investigators assessed response according to standard criteria (Cheson 2007). Results: Study enrolled 22 patients with relapsed/refractory MCL. Results are from 14 Jan 2013 data cutoff. The 3 cohorts included Id+E (N=12), Id+V (N=6), and Id+BR (N=4). Patients were 73% male, median age [range] of 68 [47E79] years, 32% with refractory disease and 73% stage III/IV. The median [range] number of prior therapies was 3 [1E7]. The median [range] duration of treatment was 2.5 [0.5-8.3+] months. Overall response rate (ORR) was 10/22 (46%), with 2 CR (9%). The ORR/CR for Id+E, was 25%/0%, Id+V was 50%/0%, and Id+BR was 100%/50%. The median duration of response (mDOR) and median PFS (mPFS) were not reached. Most common adverse events included (total%/≥G3%) diarrhea (41/9), fatigue (41/0), rash (27/14), cough (27/0), decreased appetite (23/0), and epistaxis (23/0). Lab abnormalities included (total%/≥G3%) thrombocytopenia (82/27), neutropenia (32/14), and ALT/AST elevations (50/5). Conclusions: Preliminary data indicates idelalisib-based combination therapy is active in patients with relapsed/refractory MCL. All combinations were tolerable. These data support further clinical development in larger trials to further characterize safety and response duration. Clinical trial information: NCT01088048.

8500 Background: PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in recurrent iNHL (Kahl, ICML 2011), as well as combination therapy (Fowler, ASCO 2012). Methods: This phase I study evaluated the activity of continuous (48 weeks) idelalisib (Id), 100/150 mg BID, in combination with rituximab (R) (375 mg/m2 weekly x 8 doses) (Id+R), with bendamustine (B) (90 mg/m2 x 2, for 6 cycles) (Id+B), or in combination with R (375 mg/m2 monthly x 6) and B (90 mg/m2 x 2), for 6 cycles (Id+BR). Investigators assessed response according to standard criteria (Cheson 2007). Patients who continued to benefit were able to enroll on an extension study. Results: Study enrolled 78 pts with relapsed/refractory iNHL, with 34 (44%) pts continuing on treatment in the ongoing extension protocol. The 3 cohorts included Id+R (N=30), Id+B (N=34), and Id+BR (N=14). Pts were 67% male, median age [range] of 62 [37E84] years, 41% with refractory disease, 88% stage III/IV, and 36% of FL with high FLIPI scores. The median [range] number of prior therapies was 3 [1E10]. The median [range] duration of treatment was 10.6 [0.5-29.2] months. Overall response rate (ORR) was 63/78 (81%), with 22/78 (28%) CR. The ORR/CR for Id+R was 77%/20%, Id+B was 85%/29%, and Id+BR was 79%/43%. At 20 months, the PFS was 66%. For responders, 73% were progression-free at 20 months. Most common adverse events included (total%/≥G3%) pyrexia (56/4), fatigue (45/4), nausea (41/0), rash (40/8), cough (37/0), diarrhea (36/8), chills (18/0), URI (18/1), and pneumonia (17/15). Lab abnormalities included (total%/≥G3%) ALT/AST elevations (56/17). Conclusions: Idelalisib-based combination therapy is highly active and well tolerated in patients with relapsed/refractory iNHL. These data support further clinical development. Phase III trials evaluating the efficacy of idelalisib in combination with R, or BR in iNHL are ongoing (NCT01732913, NCT01732926). Clinical trial information: NCT01732913, NCT01732929.

TPS8618 Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). Phase I trials demonstrated that idelalisib is highly active in pts with heavily pretreated iNHL: pts experienced reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (de Vos et al, 2011). Methods: 450 pts with previously treated iNHL, who have measurable lymphadenopathy, require therapy for iNHL, have received prior anti-CD20-antibody-containing therapy and chemotherapy, and who have iNHL that is not refractory to bendamustine (B) are randomized in a 2:1 ratio into Arm A or B. In Arm A, pts receive idelalisib at 150 mg BID continuously + rituximab (R) at 375 mg/m2 every 28 days for 6 cycles + B at 90 mg/m2 on days 1 and 2 of each 28-d cycle. In Arm B, pts receive placebo BID instead of idelalisib. Stratification factors include tumor type (follicular lymphoma vs others), tumor burden (high vs low), and time since completion of last prior therapy for iNHL (

TPS8617 Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). Phase 1 trials demonstrated that idelalisib is highly active in pts with heavily pretreated iNHL: pts experienced reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy, and durable clinical benefit with acceptable safety profile (de Vos et al, 2011). Methods: 375 pts with previously treated iNHL, who have measurable lymphadenopathy, have received prior anti-CD20-antibody-containing therapy, and who have iNHL that is not refractory to rituximab (R) are randomized in a 2:1 ratio into Arm A or Arm B. In Arm A, pts receive idelalisib at 150 mg BID continuously + R at 375 mg/m2 (weekly x 4 then every 8 weeks x 4). In Arm B, pts receive placebo BID instead of idelalisib. Stratification factors include tumor type (follicular lymphoma vs others), tumor burden (high vs low), and time since completion of last prior therapy for iNHL (

4510 Background: Denosumab, an anti-RANK-ligand monoclonal antibody, has been shown to prolong BMFS by a median 4.2 months and with a 15% risk reduction vs. placebo in men with non-metastatic CRPC and baseline PSA value ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤10.0 months. To determine the efficacy of denosumab in men at greatest risk for bone metastases, we evaluated BMFS in a subset of men with PSADT ≤6 months (previously reported in Smith MR, et al: J Clin Oncol. 23:2918-2925, 2005). Methods: 1,432 men with non-metastatic CRPC (baseline medians: PSA: 12.3 ng/mL, PSADT: 5.1 months, ADT duration: 47.1 months) were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or placebo. The first patient enrolled February 2006; primary analysis cut-off was July 2010, when >660 men had developed bone metastasis or died. The primary endpoint was BMFS (time to first bone metastasis or death from any cause). BMFS results are presented for men with baseline PSADT ≤6 months. Results: Median BMFS in the placebo group of men with PSADT ≤6 months was 6.5 months shorter than for the placebo group in the full population (18.7 months vs. 25.2 months), indicating that these men are at particularly high risk. In this group of men with PSADT ≤6 months, denosumab prolonged BMFS by a median of 7.2 months and with a 23% reduction in risk compared with placebo (Table). Conclusions: Patients with shortened PSADT are at higher risk of developing bone metastasis and denosumab is markedly effective at prolonging BMFS in this subset of patients. [Table: see text]

Background Bone is a common site of distant recurrence in women with early-stage breast cancer. Cancer cells are thought to stimulate osteoclast-mediated bone resorption, which releases growth factors and cytokines that promote tumor growth. RANK Ligand (RANKL) is the key mediator of osteoclast-induced bone destruction. In preclinical studies, RANKL inhibition reduced the incidence of bone and lung metastases, suppressed tumor progression, and prolonged survival of tumor-bearing mice. Effects were additive with hormonal, chemotherapy, or targeted therapies. Denosumab is a fully human monoclonal antibody against RANKL, approved in the U.S. for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In patients with castrate-resistant prostate cancer, denosumab significantly improved bone metastasis-free survival (BMFS) compared to placebo. The D-CARE trial evaluates BMFS effects of denosumab in women with stage II or III breast cancer. Methods: Women with node-positive or locally advanced (T3 or T4) disease, and known hormone and HER-2 receptor status are eligible. Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination must be planned with curative intent. Women with a prior history of breast cancer (other than ductal carcinoma in situ [DCIS] or lobular carcinoma in situ [LCIS]) or distant metastasis, oral bisphosphonate (BP) use within 1 year or any intravenous BP use are excluded. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 mos, then every 3 mos, for a total of 5 yrs treatment. All patients receive vitamin D (≥ 400 IU) and calcium (≥ 500 mg) supplements. Primary endpoint of this event-driven trial is BMFS. Secondary endpoints include disease-free (DFS) and overall survival. The study is powered for both, BMFS and DFS. Safety, quality of life assessments and biomarkers are additional endpoints. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154 began enrolling patients in June 2010. PG and DF are supported in part by the Avon Foundation, NY. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-01-03.

272 Background: Patients with breast cancer and bone metastases often experience skeletal-related events (SREs) and pain, which can impact health-related quality of life (HRQoL). Denosumab is superior to zoledronic acid (ZA) in preventing SREs and more effective in delaying moderate or severe pain in patients with advanced breast cancer. We now describe the effect of denosumab or ZA treatment on HRQoL in these patients. Methods: Patients enrolled in this double-blind, double-dummy study were randomized to receive denosumab (120 mg SC) or ZA (4 mg IV) every 4 weeks. Patients completed the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline (BL), day 8, and each monthly visit to assess overall HRQoL. Higher scores (range 0 to 108) reflect a better HRQoL. Changes in HRQoL were summarized through month 18, when 30% of patients had died or dropped out due to disease progression or withdrawal of consent. Increases or decreases of ≥ 5 points in the FACT-G total score were considered clinically meaningful. Pain was evaluated by the Brief Pain Inventory–Short Form (BPI-SF). HRQoL was assessed in subgroups with no/mild pain or moderate/severe pain at BL. Results: The BL mean (SD) FACT-G score was similar for denosumab (n = 956) 72.7 (16.4) and ZA (n = 952) 73.6 (16.5) groups and increased from BL to month18 for both groups reflecting improved HRQoL. An average of 3.2% more (range 0.9% to 6.8%) denosumab-treated patients than ZA-treated patients experienced a ≥ 5-point increase in HRQoL from months 1 to 18. Fewer denosumab than ZA-treated patients reported a ≥ 5-point decrease in HRQoL (average 2.7% fewer; range 0.6% to 5.8%). Among patients with no/mild pain at BL, an average of 4.1% more (range -0.6% to 9.3%) denosumab-treated patients had a ≥ 5-point increase in FACT-G score from month 4 to 18. In this same subgroup, fewer denosumab-treated patients had a ≥ 5-point decrease in HRQoL over 18 months (average 2.4% fewer; range -4.4% to 6.3%). Similar patterns in FACT-G scores were noted for the subgroup with moderate/severe pain at BL. Conclusions: In patients with advanced breast cancer, a greater proportion treated with denosumab than ZA had a meaningful improvement in HRQoL regardless of BL pain level.

TPS152 Background: Bone is a common site of distant recurrence in women with early-stage breast cancer. Cancer cells are thought to stimulate osteoclast-mediated bone resorption, which releases growth factors and cytokines that promote tumor growth. RANK Ligand (RANKL) is the key mediator of osteoclast-induced bone destruction. In preclinical studies, RANKL inhibition reduced the incidence of bone and lung metastases, suppressed tumor progression, and prolonged survival of tumor-bearing mice. Effects were additive with hormonal, chemotherapy, or targeted therapies. Denosumab is a fully human monoclonal antibody against RANKL, approved in the U.S. for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In patients with castrate-resistant prostate cancer, denosumab significantly improved bone metastasis-free survival (BMFS) compared to placebo. The D-CARE trial evaluates BMFS effects of denosumab in women with stage II or III breast cancer. Methods: Women with node-...

TGFbeta superfamily, antagonizes TGFbeta signaling and counteracts EMT. Here, we have studied the involvement of cancer stem cells (CSCs) in invasiveness and bone metastasis. Furthermore, we evaluated if members of the TGFbeta-superfamily, particularly TGFbeta and BMPs (BMP2, BMP7 and a BMP2/7 heterodimer), can affect bone metastasis formation and whether this putative modification is mediated via CSCs. Our data demonstrate that BMP2/7 heterodimers are more potent inhibitors of TGFbeta-induced Smad signaling than its homodimeric counterparts (BMP2 and BMP7). BMP2/7 strongly inhibited basal and TGFbeta-induced migration of human osteotropic breast and prostate cancer cells (MDA-MB-231, PC3M-Pro4 resp.). Furthermore, TGFbeta significantly increased the size of the CSC subpopulation in both breast and prostate cancer. In contrast, BMPs (particularly BMP2/7) significantly inhibited the size of the CSC subpopulation under basal conditions and antagonized the stimulatory effects of TGFbeta. Strikingly, pretreatment of cancer cells with BMPs in a preclinical model, significantly inhibited the formation and growth of bone metastasis. Collectively, our data support the notion of migrating CSCs in bone metastasis and describe heterodimeric BMP2/7 as a powerful TGFbeta antagonistwith anti-metastatic potency.

1024 Background: Treatment with bisphosphonates in pts with metastatic breast cancer prevents osteoclast-mediated skeletal related events (SREs) and reduces pain. Denosumab, an investigative fully human monoclonal antibody against RANKL, was superior to ZA in delaying and preventing SREs in a recently completed randomized trial of breast cancer pts with bone metastases. Here, we describe pain outcomes from this study. Methods: Eligible breast cancer pts received either subcutaneous denosumab 120 mg or intravenous ZA 4 mg every 4 weeks in a double-bind, double-dummy design. Pts completed the Brief Pain Inventory to assess pain severity and interference with daily functioning at baseline (BL), day 8, and before each monthly visit through end of study. Analyses included all randomized pts (N=2,046) and were performed through week 73, when 30% of pts had dropped out due to death, disease progression, or consent withdrawal. Worst-pain severity ratings were dichotomized to no/mild (0-4) and moderate/severe (5-1...

1025 Background: Bone metastases in patients (pts) with breast cancer can lead to skeletal related events (SREs), pain, and decreased HRQL. Denosumab, an investigative fully human monoclonal antibody against RANKL, was previously shown to be superior in delaying SREs and more effective in delaying moderate or severe pain in pts with advanced breast cancer compared with ZA. Here, we assess HRQL in this head-to-head study of metastatic breast cancer pts. Methods: Eligible pts received subcutaneous (SC) denosumab 120 mg or intravenous (IV) ZA 4 mg every 4 weeks in a double-blind, double-dummy fashion. Pts completed Functional Assessment of Cancer Therapy-General (FACT-G) questionnaires at baseline (BL), day 8, and before each monthly visit to assess overall HRQL. Higher scores (range 0–108) represent better HRQL. Improvement, maintenance, and worsening of HRQL were assessed through week 73, when 30% of pts had dropped out due to death, disease progression, or consent withdrawn. Results: BL mean FACT-G total ...