Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021).

BACKGROUND: Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer. METHODS: COSMIC-021 is an ongoing, multicentre, open-label, phase 1b study with a dose-escalation stage followed by tumour-specific expansion stages. Expansion cohort 6 in metastatic castration-resistant prostate cancer was enrolled at 42 cancer research centres in France, Italy, the Netherlands, Spain, and the USA. Eligible patients were aged 18 years or older and had metastatic castration-resistant prostate cancer with radiographic soft tissue progression following treatment with either enzalutamide or abiraterone, or both; measurable soft tissue disease per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received oral cabozantinib 40 mg per day and intravenous atezolizumab 1200 mg once every 3 weeks. Study treatment continued until progressive disease or unacceptable toxicity. All enrolled patients were assessed for efficacy and safety. The primary endpoint was objective response rate per RECIST version 1.1 as assessed by the investigator. This study is registered with ClinicalTrials.gov, NCT03170960. FINDINGS: Between April 24, 2018, and Aug 31, 2020, 132 patients were enrolled and received at least one dose of study treatment. At data cutoff (Feb 19, 2021), median duration of follow-up was 15·2 months (IQR 9·6-21·7). Objective response rate was 23% (95% CI 17-32; 31 of 132 patients), with three (2%) confirmed complete responses and 28 (21%) confirmed partial responses. 72 (55%) of 132 patients had grade 3-4 treatment-related adverse events, with the most common being pulmonary embolism (11 [8%] patients), diarrhoea (nine [7%]), fatigue (nine [7%]), and hypertension (nine [7%]). There was one grade 5 treatment-related adverse event (dehydration). 74 (56%) of 132 patients had serious adverse events of any causality. 28 (21%) of 132 patients had treatment-related adverse events leading to discontinuation of either study drug. INTERPRETATION: Cabozantinib plus atezolizumab showed promising antitumour activity in patients with metastatic castration-resistant prostate cancer after novel hormonal therapy with an acceptable safety profile, supporting further evaluation of this combination. FUNDING: Exelixis.

A phase III, randomized, open-label study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy in patients with metastatic castration-resistant prostate cancer.

Cabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy - a population with a significant unmet need for treatment options. Trial Registration Clinical Trial Registration: NCT04446117 (ClinicalTrials.gov) Registered on 24 June 2020.

Patient-reported outcomes of multiple myeloma patients treated with panobinostat after ≥2 lines of therapy based on the international phase 3, randomized, double-blind, placebo-controlled PANORAMA-1 trial.

The phase 3 PANORAMA-1 trial led to regulatory approvals of panobinostat (PAN) in combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of multiple myeloma after ≥2 prior regimens, including BTZ and an immunomodulatory drug. Patient-reported outcomes (PROs) were assessed in PANORAMA-1, with data available for 73 patients in the PAN + BTZ + DEX arm and 74 patients in the placebo (PBO) + BTZ + DEX arm. Per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), global health status/quality of life (QoL) scores initially declined with PAN + BTZ + DEX during the first 24 weeks before approaching baseline scores and remaining steady during the next 24 weeks, with no difference between arms at Week 48. The EORTC QLQ-Myeloma module (EORTC QLQ-MY20) demonstrated initial improvements and subsequent stabilization of disease symptom scores in both arms and initial worsening and subsequent improvement of side effects of treatment scores, with the initial worsening more pronounced and recovery less pronounced with PAN + BTZ + DEX. Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scores remained relatively stable and similar between the arms. Overall, these PRO findings support the addition of PAN to the BTZ+DEX regimen as an efficacious treatment option, with limited symptomatology and impact on patients' QoL. The reported results are based on a descriptive analysis of the data. No formal statistical tests have been performed.

REACT expanded-access program in patients with metastatic renal cell carcinoma: real-world data from a European subanalysis.

AIM: RAD001 Expanded Access Clinical Trial (REACT) provided everolimus to patients with metastatic RCC before its commercial availability. This retrospective subgroup analysis evaluated eventual differences, mainly in safety, between the large European population (n = 906; 66.3%) and the overall population (n = 1367). PATIENTS & METHODS: REACT enrolled patients from 34 countries who received everolimus 10 mg/day until progression/discontinuation or commercial availability. RESULTS: Baseline characteristics, except race/ethnicity, were similar. Incidences of grade 3/4 adverse events were 50.7/11.3% in the European population and 48.8/12.8% in the overall population. A similar percentage of the European and overall populations achieved stable disease (∼ 51%) and completed treatment (20.6 and 19.7%). CONCLUSION: These results do not suggest differences for the European population and support everolimus as a worldwide standard of care for VEGFR-refractory metastatic RCC (NCT00655252).

Everolimus plus octreotide long-acting repeatable in patients with colorectal neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-2 study.

INTRODUCTION: The incidence of colorectal neuroendocrine tumors (NETs) is increasing, and patients with this disease have particularly poor prognoses. Treatment options are limited, and survival times have not improved in the past decade. METHODS: A post hoc analysis of the efficacy and tolerability of everolimus plus octreotide long-acting repeatable (LAR) was conducted in patients with colorectal NETs enrolled in the phase III RAD001 in Advanced Neuroendocrine Tumors, Second Trial (RADIANT-2) study. The primary endpoint (progression-free survival [PFS]), secondary endpoints (including objective response rate), and safety were assessed. RESULTS: Patients with colorectal NETs receiving everolimus plus octreotide LAR had a significantly longer median PFS (29.9 months; n = 19) than did those receiving placebo plus octreotide LAR (6.6 months; n = 20). Everolimus plus octreotide LAR treatment also significantly reduced the risk for disease progression (hazard ratio: 0.34; 95% confidence interval: 0.13-0.89; p = .011). Although no objective responses were observed, tumor shrinkage was more frequently noted in the everolimus plus octreotide LAR arm than in the placebo plus octreotide LAR arm (67% vs. 37%, respectively). The combination of everolimus plus octreotide LAR was generally well tolerated by patients with colorectal NETs; rash and stomatitis were the most commonly reported adverse events. CONCLUSIONS: Everolimus plus octreotide LAR treatment had significant benefits and improved outcomes for patients with advanced colorectal NETs compared with placebo plus octreotide LAR treatment. Results of this exploratory analysis are consistent with those reported from the RADIANT-2 primary analysis. These findings support additional investigations of everolimus plus octreotide LAR in patients with colorectal NETs.

Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study.

PURPOSE: COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non-clear cell (ncc) renal cell carcinoma (RCC). METHODS: This phase Ib study (NCT03170960) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety. RESULTS: A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs. CONCLUSION: The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes.

Phase II study of bryostatin 1 and vincristine for aggressive non-Hodgkin lymphoma relapsing after an autologous stem cell transplant.

Bryostatin 1, isolated from a marine bryozoan, enhances the efficacy of cytotoxic agents through modulation of the protein kinase C pathway and is active in combination with vincristine for diffuse large B-cell lymphoma. Further, the apoptotic frequency of peripheral blood T lymphocytes as determined by flow cytometry may predict which patients will respond to this combination. We tested the efficacy and safety of bryostatin 1 50 microg/m(2) given over 24 hr and vincristine 1.4 mg/m(2) on days 1 and 15 every 28 days in aggressive B-cell non-Hodgkin lymphoma (NHL) relapsing after autologous stem cell transplantation. End points included tumor response, toxicity, and survival. Responses were correlated with an increase in apoptotic frequency of CD5+ cells by flow cytometry using annexin V staining. Fourteen patients were enrolled with 13 being evaluable for a response. The overall response rate was 31% with two patients achieving a complete response. The most common toxicities were Grade 3 lymphopenia (seven patients), Grade 3 to 4 neutropenia (two patients), and Grade 3 hypophosphatemia (two patients). Median progression-free and overall survivals for all patients were 5.7 and 21.4 months, respectively. One patient demonstrated an increase in T-cell apoptotic frequency, also achieving a complete response. Bryostatin 1 and vincristine have efficacy in select patients with aggressive NHL. Future investigations of agents targeting the protein kinase C pathway may benefit from early response assessment using flow cytometry to evaluate T-cell apoptosis.

Outcomes of patients with stable heart failure undergoing elective noncardiac surgery.

OBJECTIVE: To evaluate modern surgical outcomes in patients with stable heart failure undergoing elective major noncardiac surgery and to compare the experience of patients with heart failure who have reduced vs preserved left ventricular ejection fraction (EF). PATIENTS AND METHODS: We retrospectively studied 557 consecutive patients with heart failure (192 EF less than or equal to 40% and 365 EF greater than 40%) and 10,583 controls who underwent systematic evaluation by hospitalists in a preoperative clinic before having major elective noncardiac surgery between January 1, 2003, and March 31, 2006. We examined outcomes in the entire cohort and in propensity-matched case-control groups. RESULTS: Unadjusted 1-month postoperative mortality in patients with both types of heart failure vs controls was 1.3% vs 0.4% (P equals .009), but this difference was not significant in propensity-matched groups (P equals .09). Unadjusted differences in mean hospital length of stay among heart failure patients vs controls (5.7 vs 4.3 days; P less than .001) and 1-month readmission (17.8% vs 8.5%; P less than .001) were also markedly attenuated in propensity-matched groups. Crude 1-year hazard ratios for mortality were 1.71 (95% confidence interval [CI], 1.5-2.0) for both types of heart failure, 2.1 (95% CI, 1.7-2.6) in patients with heart failure who had EF less than or equal to 40%, and 1.4 (95% CI, 1.2-1.8) in those who had EF greater than 40% (P less than .01 for all 3 comparisons); however, the differences were not significant in propensity-matched groups (P equals .43). CONCLUSION: Patients with clinically stable heart failure did not have high perioperative mortality rates in association with elective major noncardiac surgery, but they were more likely than patients without heart failure to have longer hospital stays, were more likely to require hospital readmission, and had a substantial long-term mortality rate.

Apoptosis mechanisms related to the increased sensitivity of Jurkat T-cells vs A431 epidermoid cells to photodynamic therapy with the phthalocyanine Pc 4.

To examine the clinical applicability of Pc 4, a promising second-generation photosensitizer, for the photodynamic treatment of lymphocyte-mediated skin diseases, we studied the A431 and Jurkat cell lines, commonly used as surrogates for human keratinocyte-derived carcinomas and lymphocytes, respectively. As revealed by ethyl acetate extraction and absorption spectrophotometry, uptake of Pc 4 into the two cell lines was linear with Pc 4 concentration and similar on a per cell basis but greater in Jurkat cells on a per mass basis. Flow cytometry showed that uptake was linear at low doses; variations in the dose-response for uptake measured by fluorescence supported differential aggregation of Pc 4 in the two cell types. As detected by confocal microscopy, Pc 4 localized to mitochondria and endoplasmic reticulum in both cell lines. Jurkat cells were much more sensitive to the lethal effects of phthalocyanine photodynamic therapy (Pc 4-PDT) than were A431 cells, as measured by a tetrazolium dye reduction assay, and more readily underwent morphological apoptosis. In a search for molecular factors to explain the greater photosensitivity of Jurkat cells, the fate of important Bcl-2 family members was monitored. Jurkat cells were more sensitive to the induction of immediate photodamage to Bcl-2, but the difference was insufficient to account fully for their greater sensitivity. The antiapoptotic protein Mcl-1 was extensively cleaved in a dose- and caspase-dependent manner in Jurkat, but not in A431, cells exposed to Pc 4-PDT. Thus, the greater killing by Pc 4-PDT in Jurkat compared with A431 cells correlated with greater Bcl-2 photodamage and more strongly to the more extensive Mcl-1 degradation. Pc 4-PDT may offer therapeutic advantages in targeting inflammatory cells over normal keratinocytes in the treatment of T-cell-mediated skin diseases, such as cutaneous lymphomas, dermatitis, lichenoid tissue reactions and psoriasis, and it will be instructive to evaluate the role of Bcl-2 family proteins, especially Mcl-1, in the therapeutic response.

Dexmedetomidine sedation for laryngeal framework surgery.

OBJECTIVES: Sedation for laryngeal framework surgery has lacked easy modulation between appropriate pain control, airway protection, and the alertness appropriate for vocal testing. Our objective was to determine whether dexmedetomidine hydrochloride could safely and effectively be used as the sole intravenous anesthetic agent in conjunction with local anesthesia for laryngeal framework procedures. METHODS: We undertook a prospective review of 14 patients who underwent laryngeal framework surgery with dexmedetomidine anesthesia in 2004 and 2005. All dexmedetomidine doses, sedation levels, and vital signs, including blood pressure, heart rate, respiratory rate, and oxygen saturation level, were recorded every 15 minutes by the anesthesiologist throughout the duration of the procedures. Operative conditions were noted by the surgeon, focusing special attention on airway protection, patient arousability, and patient comfort. RESULTS: Dexmedetomidine sedation produced hemodynamic and respiratory values that were maintained near preoperative values, and overall pharyngeal-laryngeal integrity provided superior operating conditions for the patient and the operating surgeon. CONCLUSIONS: We believe that dexmedetomidine provides excellent sedative and operative conditions for awake laryngeal framework procedures. Coupled with local anesthesia, dexmedetomidine produced virtually no undesirable hemodynamic or respiratory effects, while allowing for adequate sedation the majority of the time. The operative conditions were markedly improved over those of previous standard monitored anesthesia regimens.

Treatment-free interval as a metric of patient experience and a health outcome of value for advanced multiple myeloma: the case for the histone deacetylase inhibitor panobinostat, a next-generation novel agent.

BACKGROUND: Patients with relapsed or relapsed/refractory multiple myeloma (RRMM) face poor treatment options by the time third-line therapy is required, despite advances in overall survival in recent years. Treatment free interval (TFI) and opportunities to maintain quality of life (QoL) have been cited as additional measures of efficacy that can be utilized in personalized treatment decisions. METHODS: The clinical health outcomes data from PANORAMA-1, the pivotal phase-3 trial comparing panobinostat-bortezomib-dexamethasone (PAN-BTZ-DEX) with placebo (PBO)-BTZ-DEX in RRMM patients treated with 1 to 3 prior regimens, retrospectively assessed TFI as a health outcome measure and metric of patient treatment experience relevant to the RRMM population. RESULTS: PAN-BTZ-DEX shows promise for prolonged TFI (mean TFI, 7.49 months; 95% CI, 6.02 to 8.71) compared to PBO-BTZ-DEX (mean TFI, 3.86 months; 95% CI, 3.08 to 4.60) for heavily pre-treated advanced RRMM patients), due to the short duration of therapy and extended progression free-survival. Further, QoL during the TFI was similar to baseline. CONCLUSIONS: PAN-BTZ-DEX provides a treatment regimen with prolonged TFI benefits previously not available for RRMM patients. TFI has not been traditionally measured in clinical trials, but should be assessed in prospective data collection given its value to payers, providers, and patients.

Impact of prior chemotherapy use on the efficacy of everolimus in patients with advanced pancreatic neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-3 trial.

OBJECTIVE: The aim of this study was to evaluate efficacy and safety of everolimus in patients with pancreatic neuroendocrine tumors (pNET) by prior chemotherapy use in the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3). METHODS: Patients with advanced, progressive, low- or intermediate-grade pNET were prospectively stratified by prior chemotherapy use and World Health Organization performance status and were randomly assigned (1:1) to everolimus 10 mg/d (n = 207) or placebo (n = 203). RESULTS: Of the 410 patients, 204 (50%) were naive to chemotherapy (chemonaive). Baseline characteristics were similar for patients with or without prior chemotherapy. Everolimus significantly prolonged median progression-free survival regardless of prior chemotherapy use (prior chemotherapy: 11.0 vs 3.2 months; hazard ratio, 0.34; 95% confidence interval, 0.25-0.48; P < 0.0001) (chemonaive: 11.4 vs 5.4 months; hazard ratio, 0.42; 95% confidence interval, 0.29-0.60; P < 0.0001). Stable disease was the best overall response in 73% of everolimus-treated patients (151/207). The most common drug-related adverse events included stomatitis (60%-69%), rash (47%-50%), and diarrhea (34%). CONCLUSIONS: As more treatment options become available, it is important to consider the goals of treatment and to identify patients who would potentially benefit from a specific therapy. Findings from this planned subgroup analysis suggest the potential for first-line use of everolimus in patients with advanced pNET.

Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2.

BACKGROUND: The addition of mTOR inhibitor everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase 3 study (BOLERO-2) in patients with hormone-receptor-positive (HR(+)) breast cancer refractory to letrozole or anastrozole. The safety and efficacy of anticancer treatments may be influenced by ethnicity (Sekine et al. in Br J Cancer 99:1757-62, 2008). Safety and efficacy results from Asian versus non-Asian patients in BOLERO-2 are reported. METHODS: Patients were randomized (2:1) to 10 mg/day EVE + EXE or placebo (PBO) + EXE. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, clinical benefit rate, and safety. RESULTS: Of 143 Asian patients, 98 received EVE + EXE and 45 received PBO + EXE. Treatment with EVE + EXE significantly improved median PFS versus PBO + EXE among Asian patients by 38 % (HR = 0.62; 95 % CI, 0.41-0.94). Median PFS was also improved among non-Asian patients by 59 % (HR = 0.41; 95 % CI, 0.33-0.50). Median PFS duration among EVE-treated Asian patients was 8.48 versus 4.14 months for PBO + EXE, and 7.33 versus 2.83 months, respectively, in non-Asian patients. The most common grade 3/4 adverse events (stomatitis, anemia, elevated liver enzymes, hyperglycemia, and dyspnea) occurred at similar frequencies in Asian and non-Asian patients. Grade 1/2 interstitial lung disease occurred more frequently in Asian patients. Quality of life was similar between treatment arms in Asian patients. CONCLUSION: Adding EVE to EXE provided substantial clinical benefit in both Asian and non-Asian patients with similar safety profiles. This combination represents an improvement in the management of postmenopausal women with HR(+)/HER2(-) advanced breast cancer progressing on nonsteroidal aromatase inhibitors, regardless of ethnicity.

Everolimus plus octreotide long-acting repeatable in patients with advanced lung neuroendocrine tumors: analysis of the phase 3, randomized, placebo-controlled RADIANT-2 study.

BACKGROUND: The incidence of neuroendocrine tumors (NETs) has increased approximately fivefold since the 1980s. A similar increase in the incidence of lung NETs has been reported, but therapy has not been optimized. METHODS: This exploratory subanalysis evaluated the efficacy and safety of everolimus plus octreotide long-acting repeatable (LAR) in a cohort of patients with low- to intermediate-grade advanced lung NET from the phase 3, randomized, placebo-controlled RADIANT-2 (RAD001 in Advanced Neuroendocrine Tumors) study. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival, change from baseline in biomarker levels, and safety outcomes. RESULTS: Patients were randomly assigned to everolimus plus octreotide LAR (n 5 33) or placebo plus octreotide LAR (n 5 11). Median PFS was 13.63 months in the everolimus plus octreotide LAR arm compared with 5.59 months in the placebo plus octreotide LAR arm (relative risk for progression: HR, 0.72; 95% CI, 0.31­1.68; P 5 .228). More patients receiving everolimus plus octreotide LAR (67%) experienced minor tumor shrinkage (not partial response as per RECIST [Response Evaluation Criteria in Solid Tumors]) than those receiving placebo plus octreotide LAR (27%). Most frequently reported adverse events (AEs) included stomatitis, rash, diarrhea, and asthenia. This was consistent with the overall RADIANT-2 trial and the safety profile of everolimus. CONCLUSIONS: This exploratory subgroup analysis of the RADIANT-2 trial indicates that in patients with advanced lung NET, the addition of everolimus to octreotide LAR improves median PFS by 2.4-fold compared with placebo plus octreotide LAR. These clinically significant observations support the continued evaluation of everolimus treatment regimens in this patient population. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00412061

Safety of everolimus by treatment duration in patients with advanced renal cell cancer in an expanded access program.

OBJECTIVE: To retrospectively analyze the effects of treatment duration on outcomes of everolimus treatment of patients in the RAD001 Expanded-Access Clinical Trial in RCC (REACT) program. METHODS: Patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor received everolimus (10 mg once daily), with dosing interruption or modifications allowed for toxicity. All serious and grade 3/4 adverse events and grade 1/2 adverse events leading to a change in drug administration were reported. Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors. RESULTS: The study stratified 1367 evaluable patients into treatment duration groups of <3 months, ≥3 and <6 months, ≥6 months and <1 year, and ≥1 year. Pneumonia, noninfectious pneumonitis, and hyperglycemia occurred more frequently in patients receiving everolimus for ≥1 year but did not result in treatment discontinuations. First occurrence of adverse events presented early in the treatment course for most patients. Treatment duration of ≥6 months was associated with improved disease control rates. CONCLUSION: Everolimus is well tolerated in patients with metastatic renal cell carcinoma for treatment durations≥1 year and not associated with cumulative toxicity.

Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2.

BACKGROUND: Postmenopausal women with hormone receptor-positive (HR(+)) breast cancer in whom disease progresses or there is recurrence while taking a nonsteroidal aromatase inhibitor (NSAI) are usually treated with exemestane (EXE), but no single standard of care exists in this setting. The BOLERO-2 trial demonstrated that adding everolimus (EVE) to EXE improved progression-free survival (PFS) while maintaining quality of life when compared with EXE alone. Because many women with HR(+) advanced breast cancer are elderly, the tolerability profile of EVE plus EXE in this population is of interest. PATIENTS AND METHODS: BOLERO-2, a phase III randomized trial, compared EVE (10 mg/d) and placebo (PBO), both plus EXE (25 mg/d), in 724 postmenopausal women with HR(+) advanced breast cancer recurring/progressing after treatment with NSAIs. Safety and efficacy data in elderly patients are reported at 18-month median follow-up. RESULTS: Baseline disease characteristics and treatment histories among the elderly subsets (≥ 65 years, n = 275; ≥ 70 years, n = 164) were generally comparable with younger patients. The addition of EVE to EXE improved PFS regardless of age (hazard ratio, 0.59 [≥ 65 years] and 0.45 [≥ 70 years]). Adverse events (AEs) of special interest (all grades) that occurred more frequently with EVE than with PBO included stomatitis, infections, rash, pneumonitis, and hyperglycemia. Elderly EVE-treated patients had similar incidences of these AEs as did younger patients but had more on-treatment deaths. CONCLUSION: Adding EVE to EXE offers substantially improved PFS over EXE and was generally well tolerated in elderly patients with HR(+) advanced breast cancer. Careful monitoring and appropriate dose reductions or interruptions for AE management are recommended during treatment with EVE in this patient population.

Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study.

BACKGROUND: Everolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraLEveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2 months, respectively) and independent (11.0 versus 4.1 months, respectively) central assessment in postmenopausal women with HR(+), HER2(-) ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%). METHODS: Prespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases. FINDINGS: At a median follow-up of 18 months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8 months) and in those without visceral metastases (N=318; 9.9 versus 4.2 months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8 months with EVE+EXE versus 2.8 months with PBO+EXE. Among patients with visceral metastases and ECOG PS ≥1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5 months). INTERPRETATION: Adding EVE to EXE markedly extended PFS by ≥4 months among patients with HR(+) HER2(-) ABC regardless of the presence of visceral metastases.

Optimisation of the tumour response threshold in patients treated with everolimus for metastatic renal cell carcinoma: analysis of response and progression-free survival in the RECORD-1 study.

BACKGROUND AND OBJECTIVES: Objective response as determined by Response Evaluation Criteria in Solid Tumors (RECIST) is low among patients with metastatic renal cell carcinoma (mRCC) treated with targeted agents, despite significantly improved progression-free survival (PFS). A modified response threshold may be more clinically meaningful than RECIST for identifying patients who may derive a PFS benefit from targeted therapy. PATIENTS AND METHODS: We performed a retrospective analysis of data from the phase III RECORD-1 trial of everolimus versus placebo in patients with mRCC who had failed sunitinib or sorafenib (ClinicalTrials.gov identifier: NCT00410124). A series of tumour response thresholds, defined by the best change in the sum of the longest tumour diameters (ΔSLD) of target lesions, was evaluated to distinguish 'responders' from 'non-responders' with respect to significant improvement in PFS. RESULTS: The optimal threshold for determining a response to everolimus was -5% ΔSLD. At this threshold, median PFS was 8.4 months in responders and 5.0 months in non-responders (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.6-3.7). CONCLUSION: In patients who have failed vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy, everolimus affords superior PFS to placebo, regardless of change in tumour burden. However, a ≥ 5% reduction in SLD is a better predictor of PFS benefit than the classical ≥ 30% reduction used with RECIST.

Topical application of activity-based probes for visualization of brain tumor tissue.

Several investigators have shown the utility of systemically delivered optical imaging probes to image tumors in small animal models of cancer. Here we demonstrate an innovative method for imaging tumors and tumor margins during surgery. Specifically, we show that optical imaging probes topically applied to tumors and surrounding normal tissue rapidly differentiate between tissues. In contrast to systemic delivery of optical imaging probes which label tumors uniformly over time, topical probe application results in rapid and robust probe activation that is detectable as early as 5 minutes following application. Importantly, labeling is primarily associated with peri-tumor spaces. This methodology provides a means for rapid visualization of tumor and potentially infiltrating tumor cells and has potential applications for directed surgical excision of tumor tissues. Furthermore, this technology could find use in surgical resections for any tumors having differential regulation of cysteine cathepsin activity.

Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial.

BACKGROUND: Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy. OBJECTIVE: To evaluate the efficacy and safety of everolimus in elderly patients (those ≥ 65 and ≥ 70 yr of age) enrolled in RECORD-1. DESIGN, SETTING, AND PARTICIPANTS: The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n=416). INTERVENTION: Everolimus 10mg once daily (n=277) or placebo (n=139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity. MEASUREMENTS: Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety. RESULTS AND LIMITATIONS: In RECORD-1, 36.8% of patients were ≥ 65 yr and 17.5% were ≥ 70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation. CONCLUSIONS: Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.