Current usage of pembrolizumab in triple negative breast cancer (TNBC).

INTRODUCTION: The use of immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 pathway has changed the landscape in the treatment of triple negative breast cancer (TNBC). The ICI pembrolizumab in combination with chemotherapy now forms a standard of care for the treatment of advanced PD-L1 positive TNBC and as part of neoadjuvant therapy for high-risk early-stage disease. Evidence in this space is rapidly advancing. AREAS COVERED: This review aims to highlight the evolving role of immunotherapy in TNBC management and to discuss current challenges. The studies in this review were searched from PubMed and ClinicalTrials.gov. EXPERT OPINION: The KEYNOTE-522 trial demonstrated that the addition of peri-operative pembrolizumab to neoadjuvant chemotherapy improves patient outcomes in early-stage TNBC. However, critical questions remain including how to select which patients truly gain benefit from the addition of pembrolizumab; the optimal duration of therapy, and the optimal adjuvant therapy depending on pathologic response.

Results From the First Multicenter, Open-label, Phase IIIb Study Investigating the Combination of Pertuzumab With Subcutaneous Trastuzumab and a Taxane in Patients With HER2-positive Metastatic Breast Cancer (SAPPHIRE).

INTRODUCTION: The primary objective of this study was to assess the safety and tolerability of combination pertuzumab, subcutaneous trastuzumab (Herceptin), and investigator's choice of taxane chemotherapy in previously untreated patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Efficacy was a secondary objective. PATIENTS AND METHODS: This study was an open-label, non-randomized study of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who had no previous systemic non-hormonal anti-cancer therapy for metastatic disease. The primary endpoints included adverse events (AE), serious AEs, and cardiac AEs. Secondary endpoints included overall response rate, progression-free survival, and overall survival. Patients were treated with pertuzumab and subcutaneous trastuzumab in 3-weekly cycles with taxane chemotherapy until disease progression, unacceptable toxicity, or withdrawal of consent and followed for a minimum of 24 months from initiation of study treatment. RESULTS: Fifty patients were enrolled and included in the analysis. All patients experienced at least 1 AE, with diarrhea, fatigue, peripheral neuropathy, alopecia, rash, and nausea the most common. Three patients experienced at least 1 grade 3 event of suspected cardiac origin (cardiac failure, cardiomyopathy, hypertension). Six patients withdrew from therapy owing to AEs (cardiac failure, drug hypersensitivity, decreased left ventricular ejection fraction, syncope, and bullous dermatitis). Taxane chemotherapy comprised nab-paclitaxel (74.0% of patients), docetaxel (28.0%), or paclitaxel (4.0%). The overall response rate was 73.3% (95% confidence interval, 58.1%-85.4%), the median progression-free survival was 17.0 months (95% confidence interval, 12.5-31.2 months), and the median overall survival was not reached. CONCLUSIONS: Subcutaneous trastuzumab in this combination has an acceptable safety and tolerability profile, including cardiac safety profile. Safety and efficacy appear similar to previous studies of intravenous trastuzumab in this combination.

Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer: The BOLERO-6 Randomized Clinical Trial.

Importance: Everolimus plus exemestane and capecitabine are approved second-line therapies for advanced breast cancer. Objective: A postapproval commitment to health authorities to estimate the clinical benefit of everolimus plus exemestane vs everolimus or capecitabine monotherapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Design: Open-label, randomized, phase 2 trial of treatment effects in postmenopausal women with advanced breast cancer that had progressed during treatment with nonsteroidal aromatase inhibitors. Interventions: Patients were randomized to 3 treatment regimens: (1) everolimus (10 mg/d) plus exemestane (25 mg/d); (2) everolimus alone (10 mg/d); and (3) capecitabine alone (1250 mg/m2 twice daily). Main Outcomes and Measures: Estimated hazard ratios (HRs) of progression-free survival (PFS) for everolimus plus exemestane vs everolimus alone (primary objective) or capecitabine alone (key secondary objective). Safety was a secondary objective. No formal statistical comparisons were planned. Results: A total of 309 postmenopausal women were enrolled, median age, 61 years (range, 32-88 years). Of these, 104 received everolimus plus exemestane; 103, everolimus alone; and 102, capecitabine alone. Median follow-up from randomization to the analysis cutoff (June 1, 2017) was 37.6 months. Estimated HR of PFS was 0.74 (90% CI, 0.57-0.97) for the primary objective of everolimus plus exemestane vs everolimus alone and 1.26 (90% CI, 0.96-1.66) for everolimus plus exemestane vs capecitabine alone. Between treatment arms, potential informative censoring was noted, and a stratified multivariate Cox regression model was used to account for imbalances in baseline characteristics; a consistent HR was observed for everolimus plus exemestane vs everolimus (0.73; 90% CI, 0.56-0.97), but the HR was closer to 1 for everolimus plus exemestane vs capecitabine (1.15; 90% CI, 0.86-1.52). Grade 3 to 4 adverse events were more frequent with capecitabine (74%; n = 75) vs everolimus plus exemestane (70%; n = 73) or everolimus alone (59%; n = 61). Serious adverse events were more frequent with everolimus plus exemestane (36%; n = 37) vs everolimus alone (29%; n = 30) or capecitabine (29%; n = 30). Conclusions and Relevance: These findings suggest that everolimus plus exemestane combination therapy offers a PFS benefit vs everolimus alone, and they support continued use of this therapy in this setting. A numerical PFS difference with capecitabine vs everolimus plus exemestane should be interpreted cautiously owing to imbalances among baseline characteristics and potential informative censoring. Trial Registration: ClinicalTrials.gov identifier: NCT01783444.

Spotlight on the utility of the Oncotype DX® breast cancer assay.

The Oncotype DX® assay was developed to address the need for optimizing the selection of adjuvant systemic therapy for patients with estrogen receptor (ER)-positive, lymph node-negative breast cancer. It has ushered in the era of genomic-based personalized cancer care for ER-positive primary breast cancer and is now widely utilized in various parts of the world. Together with several other genomic assays, Oncotype DX has been incorporated into clinical practice guidelines on biomarker use to guide treatment decisions. The Oncotype DX result is presented as the recurrence score which is a continuous score that predicts the risk of distant disease recurrence. The assay, which provides information on clinicopathological factors, has been validated for use in the prognostication and prediction of degree of adjuvant chemotherapy benefit in both lymph node-positive and lymph node-negative early breast cancers. Clinical studies have consistently shown that the Oncotype DX has a significant impact on decision making in adjuvant therapy recommendations and appears to be cost-effective in diverse health care settings. In this article, we provide an overview of the validation and clinical impact studies for the Oncotype DX assay. We also discuss its potential use in the neoadjuvant setting, as well as the more recent prospective validation trials, and the economic and utility implications of studies that use a lower cutoff score to define low-risk disease.

Denosumab: Prevention and management of hypocalcemia, osteonecrosis of the jaw and atypical fractures.

Denosumab, a bone-modifying agent, reduces the risk of skeletal-related events in patients with bone metastases from solid tumors and is generally well tolerated. However, hypocalcemia, osteonecrosis of the jaw (ONJ) and atypical fracture are potential and important toxicities of denosumab therapy that require attention. In pivotal phase III trials in patients with bone metastases from solid tumors, the incidence of hypocalcemia was 9.6% in denosumab-treated patients, with most events being asymptomatic, grade 2 and resolving by week 4. Established hypocalcaemia requires additional short-term calcium and vitamin D supplementation and, if severe, administration of intravenous calcium. ONJ was reported in 1.8% of patients receiving denosumab over 3 years in these trials. Involvement of an experienced oro-maxillary surgeon is important if ONJ is suspected. Atypical fractures were rare in a large study of denosumab using the dose and scheduling approved for the treatment of osteoporosis. To prevent toxicities, patients should maintain calcium and vitamin D supplementation, good oral hygiene and regular dental reviews throughout treatment. This article presents case studies from our clinical practice and discusses the pathophysiology of these toxicities along with guidance on prevention, diagnosis and management.

Hypocalcaemia in patients with metastatic bone disease treated with denosumab.

BACKGROUND: This analysis was performed to further characterise treatment-emergent hypocalcaemia in patients with bone metastases receiving denosumab. METHODS: Laboratory abnormalities and adverse events of hypocalcaemia in patients with metastatic bone disease were analysed using data from three identically designed phase 3 trials of subcutaneous denosumab 120 mg (n = 2841) versus intravenous zoledronic acid 4 mg (n = 2836). RESULTS: The overall incidence of laboratory events of hypocalcaemia grade ⩾ 2 was higher with denosumab (12.4%) than with zoledronic acid (5.3%). Hypocalcaemia events were primarily grade 2 in severity and usually occurred within the first 6 months of treatment. Patients who reported taking calcium and/or vitamin D supplements had a lower incidence of hypocalcaemia. Prostate cancer or small-cell lung cancer, reduced creatinine clearance and higher baseline bone turnover markers of urinary N-telopeptide of type I collagen (uNTx; > 50 versus ⩽ 50 nmol/mmol) and bone-specific alkaline phosphatase (BSAP; > 20.77 µg/L [median] versus ⩽ 20.77 µg/L) values were important risk factors for developing hypocalcaemia. The risk associated with increased baseline BSAP levels was greater among patients who had > 2 bone metastases at baseline versus those with ⩽ 2 bone metastases at baseline. CONCLUSION: Hypocalcaemia was more frequent with denosumab versus zoledronic acid, consistent with denosumab's greater antiresorptive effect. Low serum calcium levels and potential vitamin D deficiency should be corrected before initiating treatment with a potent osteoclast inhibitor, and corrected serum calcium levels should be monitored during treatment. Adequate calcium and vitamin D intake appears to substantially reduce the risk of hypocalcaemia.

The impact of a genomic assay (Oncotype DX) on adjuvant treatment recommendations in early breast cancer.

OBJECTIVES: To assess how the recurrence score of the Oncotype DX breast cancer assay influences adjuvant systemic treatment decisions in the multidisciplinary meeting (MDM) for patients with early breast cancer (EBC) in Australia. DESIGN, SETTING AND PARTICIPANTS: A before-and-after study at three academic medical centres in Melbourne with patients and physicians serving as their own controls. Paired systemic adjuvant treatment recommendations were made in multidisciplinary meetings (MDMs) before and after Oncotype DX testing. Medical oncologists and surgeons, treating patients with unifocal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-negative or node-positive early breast cancer. MAIN OUTCOME MEASURES: Changes in physician treatment recommendations. RESULTS: This study enrolled 151 eligible patients between 1 November 2010 and 30 September 2011. Of these, 101 patients (67%) had node-negative and 50 (33%) had node-positive tumours. Recurrence score information resulted in treatment recommendation changes for 24 patients with node-negative tumours (24%) and for 13 patients with node-positive tumours (26%). The proportional change from chemo-hormonal therapy (CHT) to hormonal therapy (HT) was significantly greater than from HT to CHT for patients with node-negative tumours (23% difference in proportions; P= 0.02), and of similar magnitude for patients with node-positive tumours (25% difference in proportions; P = 0.14). CONCLUSION: The Oncotype DX recurrence score has a major impact on adjuvant treatment decision making in the MDM setting.

Prevalence of excessive tearing in women with early breast cancer receiving adjuvant docetaxel-based chemotherapy.

PURPOSE: To define the incidence and impact of tearing in patients receiving adjuvant docetaxel-based chemotherapy and assess for lacrimal duct obstruction (LDO) as a causative factor. PATIENTS AND METHODS: Consecutive patients with early breast cancer recommended for docetaxel-based chemotherapy with no prior ocular symptoms were included. Before and after completion of chemotherapy, patients underwent lacrimal drainage evaluation by computed tomographic dacrocystography (CT-DCG) and ophthalmic assessment. Eye symptoms were assessed at baseline, during, and after completion of chemotherapy. RESULTS: Over a 22-month period, 100 patients were recruited. Asymptomatic LDO was present at baseline in 17% and 18% of patients, as assessed by ophthalmic review and CT-DCG, respectively. Overall, 86% of patients developed tearing, with no significant difference between those who did and did not have LDO (94% v 84%; P = .45). Blepharitis occurred in 37% and minor corneal epitheliopathy in 22% of patients, with neither condition predicting for the development of tearing. Impairment of visual activities was greatest after cycle one (70% of patients) but had decreased to < 5% by 4 months after treatment. CONCLUSION: Tearing occurs in the majority of patients receiving adjuvant docetaxel-based chemotherapy regimens and occurred similarly in patients with and without LDO. There was poor concordance between CT-DCG and ophthalmic examination in the detection of LDO. Tearing and other eye symptoms impaired visual activities, but in nearly all patients, both symptoms and functional impairment were mild and had resolved by 4 months after chemotherapy. Our study demonstrates docetaxel-related tearing is not caused by LDO, and as such, evaluation or stenting of the duct is not considered necessary.

A randomized phase 2 study of paclitaxel and carboplatin with or without conatumumab for first-line treatment of advanced non-small-cell lung cancer.

INTRODUCTION: This study evaluated the efficacy, safety, and pharmacokinetics of conatumumab combined with paclitaxel-carboplatin (PC) as first-line treatment for advanced non-small-cell lung cancer (NSCLC). METHODS: Patients (aged >18 years) with previously untreated advanced or recurrent NSCLC were randomized 1:1:1 (stratified by Eastern Cooperative Oncology Group performance status and disease stage) to receive up to six 3-week cycles of PC combined with conatumumab (arm 1, 3 mg/kg; arm 2, 15 mg/kg) or placebo (arm 3) every 3 weeks. The primary endpoint was progression-free survival (PFS). This study is registered with ClinicalTrials.gov (NCT00534027). RESULTS: Between August 8, 2007 and April 9, 2009, 172 patients were randomized (arm 1, n = 57; arm 2, n = 56; arm 3, n = 59). Median PFS was 5.4 months (95% confidence interval [CI] 4.1-6.3) in arm 1 (hazard ratio [HR] 0.84 [95% CI 0.57-1.24]; p = 0.41), 4.8 months (95% CI 3.2-6.5) in arm 2 (HR 0.93 [0.64-1.35]; p = 0.57), and 5.5 months (95% CI 4.3-5.7) in arm 3. There was an interaction between tumor histology and the effect of conatumumab on PFS (squamous HR 0.47 [0.23-0.94]; nonsquamous HR 1.08 [0.74-1.57]; interaction p = 0.039).The most common grade of three or more adverse events were neutropenia, anemia, and thrombocytopenia. There was no evidence of pharmacokinetic interactions between conatumumab and PC. Of 158 patients assessable for FCGR3A polymorphisms, conatumumab treatment was associated with a trend toward longer overall survival (HR 0.72 [0.43-1.23]) among V-allele carriers (V/V or F/V; n = 54) but not among F-allele homozygotes (n = 34; HR 1.37 [0.66-2.86]). CONCLUSION: Although well tolerated, the addition of conatumumab to PC did not improve outcomes in unselected patients with previously untreated advanced NSCLC.

Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial.

BACKGROUND: Insulin-like growth factors (IGF-1 and IGF-2) bind to the IGF-1 receptor (IGF-1R), increasing cell proliferation and survival. Ganitumab is a monoclonal IgG1 antibody that blocks IGF-1R. We tested the efficacy and safety of adding ganitumab to endocrine treatment for patients with hormone-receptor-positive breast cancer. METHODS: We did this phase 2 trial in outpatient clinics and hospitals. We enrolled postmenopausal women with hormone-receptor-positive, locally advanced or metastatic breast cancer previously treated with endocrine treatment. They were randomly assigned (2:1) with a central randomisation schedule to receive intravenous ganitumab 12 mg per kg bodyweight or placebo in combination with open-label intramuscular fulvestrant (500 mg on day 1, then 250 mg on days 15, 29, and every 28 days) or oral exemestane (25 mg once daily) on a 28-day cycle. Patients, investigators, study monitors, and the sponsor staff were masked to treatment allocation. Response was assessed every 8 weeks. The primary endpoint was median progression-free survival in the intention-to-treat population. We analysed overall survival as one of our secondary endpoints. The study is registered at ClinicalTrials.gov, number NCT00626106. FINDINGS: We screened 189 patients and enrolled 156 (106 in the ganitumab group and 50 in the placebo group). Median progression-free survival did not differ significantly between the ganitumab and placebo groups (3·9 months, 80% CI 3·6-5·3 vs 5·7 months, 4·4-7·4; hazard ratio [HR] 1·17, 80% CI 0·91-1·50; p=0·44). However, overall survival was worse in the the ganitumab group than in the placebo group (HR 1·78, 80% CI 1·27-2·50; p=0·025). With the exception of hyperglycaemia, adverse events were generally similar between groups. The most common grade 3 or higher adverse event was neutropenia-reported by six of 106 (6%) patients in the ganitumab group and one of 49 (2%) in the placebo group. Hyperglycaemia was reported by 12 of 106 (11%) patients in the ganitumab group (with six patients having grade 3 or 4 hyperglycaemia) and none of 49 in the placebo group. Serious adverse events were reported by 27 of 106 (25%) patients in the ganitumab group and nine of 49 (18%) patients in the placebo group. INTERPRETATION: Addition of ganitumab to endocrine treatment in women with previously treated hormone-receptor-positive locally advanced or metastatic breast cancer did not improve outcomes. Our results do not support further study of ganitumab in this subgroup of patients. FUNDING: Amgen.

Profile of cabozantinib and its potential in the treatment of advanced medullary thyroid cancer.

Medullary thyroid cancer is an uncommon malignancy for which until recently little effective treatment existed. It is often characterized by mutation and overexpression of the receptor tyrosine kinases RET (rearranged during transfection), VEGFR2 (vascular endothelial growth factor receptor 2) and MET (mesenchymal-epithelial transition factor), which make attractive targets for drug development. Cabozantinib is an orally bioavailable tyrosine kinase inhibitor which blocks MET, VEGRF2 and RET, and has shown considerable activity in medullary thyroid cancer in a Phase III trial, including in heavily pretreated patients. Its novel combination of vascular endothelial growth factor and MET inhibition is believed to address the MET escape pathway, which is thought to be the cause of nonsustained tumor responses resulting from inhibition of vascular endothelial growth factor alone.

Does immediate breast reconstruction compromise the delivery of adjuvant chemotherapy?

BACKGROUND: Immediate breast reconstruction (IBR) provides psychological benefit to many early breast cancer patients however concerns persist regarding its potential impact on chemotherapy delivery. We investigated the association between IBR, complications and adjuvant chemotherapy delivery. METHOD: Retrospective analysis of patients in an academic breast service, who underwent mastectomy, with or without reconstruction, and received adjuvant chemotherapy. RESULTS: Comparisons were made between 107 patients who received IBR and 113 who received mastectomy alone. Those receiving IBR were on average younger, with lower body mass index (BMI) and better prognoses. Overall complication rates were comparable (mastectomy alone: 45.1% versus IBR: 35.5%, p = 0.2). There was more return to surgery in the IBR group with 11.5% of tissue expanders requiring removal, whilst more seromas occurred in the mastectomy group. There was no significant difference in the median time to chemotherapy. CONCLUSION: We found no evidence that IBR compromised the delivery of adjuvant chemotherapy, although there was a significant incidence of implant infection.

Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer.

The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m(2) on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤ 33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m(2). Forty-six patients were enrolled and 45 received ≥ 1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.

Vandetanib for the treatment of non-small-cell lung cancer.

INTRODUCTION: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways. AREAS COVERED: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens. EXPERT OPINION: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.

Use of non-anthracycline regimens in early stage breast cancer in Australia.

Various factors have recently prompted a re-evaluation of the role of non-anthracycline regimens in early stage breast cancer (ESBC). Since 1990 anthracyclines have been a key component of chemotherapy regimens. However, there is increased understanding of the long-term, irreversible toxicities associated with these therapies, including cardiac failure and secondary leukemia. The development of the taxanes in the 1990s led to new adjuvant chemotherapy regimens and trials of various combinations in an effort to further increase survival and reduce toxicity. Concerns about cardiac toxicity were reinforced with the emergence of trastuzumab for the treatment of HER2-positive breast cancer. Trastuzumab alone causes cardiac toxicity and increases the risk of cardiac toxicity when combined with anthracyclines. These data, combined with recent results demonstrating the efficacy of non-anthracycline regimens in various disease settings, have generated interest in utilizing these therapies in patients with both HER2-positive and -negative tumors. This review outlines the evidence for the use of non-anthracycline adjuvant regimens in ESBC, including cyclophosphamide, methotrexate and 5-fluoruoracil, docetaxel, carboplatin and trastuzumab and docetaxel and cyclophosphamide, which have demonstrated equivalent efficacy and reduced toxicity compared to anthracycline-based regimens in various trials. The review also examines evidence for the use of non-anthracycline regimens in patients who previously had restricted access to these therapies due to their negative lymph node status. The wider availability of these regimens increases options when deciding upon adjuvant chemotherapy for patients with ESBC, especially in patients with a high risk of cardiac toxicity.

Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial.

PURPOSE: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This randomized, placebo-controlled phase III study assessed the efficacy of vandetanib plus pemetrexed as second-line therapy in advanced non-small-cell lung cancer. PATIENTS AND METHODS: Patients (N = 534) were randomly assigned to receive vandetanib 100 mg/d plus pemetrexed 500 mg/m(2) every 21 days (n = 256) or placebo plus pemetrexed (n = 278). Progression-free survival (PFS) was the primary end point; overall survival, objective response rate, disease control rate, time to deterioration of symptoms, and safety were secondary assessments. RESULTS: There was no significant difference in PFS between treatment arms (hazard ratio [HR], 0.86; 97.58% CI, 0.69 to 1.06; P = .108). Overall survival was also not significantly different (HR, 0.86; 97.54% CI, 0.65 to 1.13; P = .219). Statistically significant improvements in objective response rate (19% v 8%; P < .001) and time to deterioration of symptoms (HR, 0.71; P = .0052; median, 18.1 weeks for vandetanib and 12.1 weeks for placebo) were observed in patients receiving vandetanib. Adding vandetanib to pemetrexed increased the incidence of some adverse events, including rash, diarrhea, and hypertension, while showing a reduced incidence of nausea, vomiting, anemia, fatigue, and asthenia with no reduction in the dose intensity of pemetrexed. CONCLUSION: This study did not meet the primary end point of statistically significant PFS prolongation with vandetanib plus pemetrexed versus placebo plus pemetrexed. The vandetanib combination showed a significantly higher objective response rate and a significant delay in the time to worsening of lung cancer symptoms versus the placebo arm as well as an acceptable safety profile in this patient population.

Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.

PURPOSE: This randomized study compared denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand, with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases. PATIENTS AND METHODS: Patients were randomly assigned to receive either subcutaneous denosumab 120 mg and intravenous placebo (n = 1,026) or intravenous zoledronic acid 4 mg adjusted for creatinine clearance and subcutaneous placebo (n = 1,020) every 4 weeks. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary end point was time to first on-study SRE (defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). RESULTS: Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001). Reduction in bone turnover markers was greater with denosumab. Overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. An excess of renal AEs and acute-phase reactions occurred with zoledronic acid; hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred infrequently (2.0%, denosumab; 1.4%, zoledronic acid; P = .39). CONCLUSION: Denosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases.