Treatment Discontinuation For Adverse Events Research Articles

Evaluation of discontinuation for adverse events of JAK inhibitors and bDMARDs in an international collaboration of rheumatoid arthritis registers (the ‘JAK-pot’ study)

BackgroundIn a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking the tumour necrosis factor...

Brief Report: Efficacy and Safety of Efavirenz, Raltegravir, and Dolutegravir in HIV-1/TB Coinfection. A Multicenter Retrospective Cohort Study in France.

There are limited data comparing the efficacy and safety of raltegravir and dolutegravir to that of efavirenz in HIV-1/tuberculosis (TB) coinfected patients. We conducted a 10-year retrospective study in 4 centers in France. We included all HIV-1/tuberculosis coinfected patients starting antiretroviral therapy with a rifampicin-based regimen, with a plasma HIV RNA level (VL) > 1000 copies/mL. The primary endpoint was the proportion of patients with virological success that is, with VL <50 copies/mL at W48 using an Intention-To-Treat analysis, using last-observation-carried-forward to impute missing data. We also assessed antiretroviral therapy safety, analyzing treatment discontinuation for adverse events. Between 2010 and 2020, 117 patients were included. Thirty-nine (33.3%) were treated with raltegravir and 2 nucleoside reverse transcriptase inhibitors (NRTIs), 19 (16.2%) with dolutegravir (and 2 NRTIs) and 59 (50.4%) with efavirenz (and 2 NRTIs). At W48, the primary endpoint was achieved in 24 patients (61.5%) in the raltegravir group, in 12 (63.2%) in the dolutegravir group, and in 41 (69.5%) in the efavirenz group using an Intention-To-Treat analysis ( P = 0.68). Emergence of drug resistance in patients with virological failure, defined as a VL >50 copies/mL, was observed in 3 patients with efavirenz and one patient with raltegravir. Rate of treatment discontinuation for drug-related adverse events was 10.3%, 10.6%, 16.9% for raltegravir, dolutegravir and efavirenz respectively ( P = 0.67). In this retrospective cohort study, raltegravir and dolutegravir yielded similar efficacy and safety results to efavirenz for the treatment of HIV-1/TB coinfected patients.

P188 Baricitinib effectiveness after a previous inadequate response to an alternative JAK inhibitor: results from the Swiss rheumatoid arthritis register

Abstract Background/Aims Previous research has suggested that switching between b/tsDMARDs with different mode of action may be more effective than switching agents within the same mechanism of action. Limited data exists about the impact of an inadequate response to a previous JAK-inhibitor (JAKi) on subsequent JAKi effectiveness. Methods This is a nested study within the Swiss Clinical Quality Management (SCQM) registry of RA patients. All patients initiating baricitinib treatment courses (BARI) between 01-09-2017 and 01-06-2020, with at least one follow-up visit, were included. We compared the time to treatment discontinuation, as a measure of drug effectiveness, of BARI with a previous history of an inadequate response (IR) to tofacitinib (“BARI-post-TOFA”) or without (“BARI-initial”). Tofacitinib IR was defined as previous tofacitinib treatment discontinuation for adverse events or for ineffectiveness. Baseline characteristics were compared using t-tests or χ2. We used Kaplan-Meier curve to display crude time to discontinuation and a Cox model to estimate adjusted hazard ratio (HR). Cox model was adjusted for potential confounding factors: age, BMI, concomitant csDMARD, concomitant steroid usage, baseline CDAI, disease duration, smoking status, line of therapy, gender and seropositivity to RF/ACPA. Results Of the 273 included BARI, 72 were initiated in patients with a history of a previous tofacitinib IR (Table 1). No differences were found between the “BARI-post-TOFA” and the “BARI-initial” groups in terms of time-to-discontinuation, as demonstrated by both the unadjusted Kaplan-Meier survival analysis (Log-rank p = 0.44) and the fully adjusted Cox analysis (Hazard Ratio BARI-post-TOFA vs BARI-initial = 0.76 (95% IC [0.42 - 1.34]; p = 0.34). Other covariates significantly associated with drug maintenance were active smoking (p = 0.03) and CDAI score (p &amp;lt; 0.01). Conclusion In this preliminary analysis, a history of prior tofacitinib IR did not appear to significantly impact subsequent drug maintenance of baricitinib. Disclosure B.T.P. Gilbert: Other; Invited speaker for Lilly Symposium SGR Congress Lausanne (2021). D.S. Courvoisier: None. D. Mongin: None. K. Lauper: None. V.A. Guimaraes: Other; Clinical Research Scientist Immunology at Eli Lilly (Suisse) S.A. R.B. Mueller: None. A. Finckh: Grants/research support; Invited speaker and consultant for Eli Lilly. Has received research grant from Eli Lilly.

A Randomized Study of Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Cyclophosphamide-Dexamethasone Induction in Newly Diagnosed Myeloma Patients Eligible for Transplant: High Efficacy in High- and Standard-Risk Patients

Background :Proteasome inhibitor-based induction is currently considered standard of care in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for high-dose therapy and transplant (MEL200-ASCT). The second-generation proteasome inhibitor Carfilzomib proved to be effective, either in combination with Lenalidomide-Dexamethasone (KRd) or with Cyclophosphamide-Dexamethasone (KCd) (Jakubowiak, Blood 2012; Bringhen, Blood 2014). Aim : The primary objective of this analysis was to compare the efficacy of KRd vs KCd induction in pts eligible for transplantation. The secondary aim was to evaluate the efficacy of KRd vs KCd in different subgroups of pts according to prognostic features, focusing specifically on high-risk pts. Methods : NDMM pts Results : At data cut-off, 309 pts were randomized to KRd vs 154 pts to KCd. Pts characteristics were well balanced: median age was 57 years in both groups, ISS Stage II/III was reported in 48% of pts in KRd and KCd, high-risk chromosomal abnormalities (del(17p) or t(4;14) or t(14;16)) were present in 30% of KRd pts and 34% of KCd pts. After 4 cycles of induction, the rate of ≥partial response (PR) was 96% with KRd vs 92% with KCd; ≥VGPR was 74% with KRd vs 61% with KCd (P=0.01), with 31% vs 20% of pts (P=0.03) achieving ≥near complete response (nCR) and 15% vs 6% (P=0.02) ≥complete response (CR) respectively in KRd and KCd; stable disease was reported in 3% of KRd vs 7% of KCd pts, with only 1% of pts in each group being primary refractory. Subgroup analysis of response rates showed the superiority of KRd vs KCd in terms of ≥VGPR in all the subgroups analyzed (Figure 1 - Panel A). Of interest, the rates of ≥VGPR, ≥nCR and ≥CR were comparable in high- and standard-risk pts treated with KRd (Figure 1 - Panel B). Six-month MRD results were available in a subset of pts (122 KRd and 53 KCd pts): MRD was negative in 66/122 (54%) KRd pts vs 16/53 (30%) KCd pts (P=0.005). Regarding safety, the rate of ≥1 grade 3-4 hematologic adverse events (AEs) was comparable between KRd and KCd (7% vs 6%), the most frequent being neutropenia (KRd 6% vs KCd 5%). The rate of ≥1 Grade 3-4 non-hematologic AEs was higher with KRd (32% vs 16%, P Conclusions :KRd induction showed a higher efficacy of KCd in terms of ≥VGPR, ≥nCR and ≥CR rates, with an acceptable safety profile. The superiority of KRd vs KCd was confirmed in high- and standard-risk groups, with response rates in high-risk pts treated with KRd comparable to the ones in standard-risk, suggesting the high efficacy of this regimen even in this subset of pts representing a current unmet medical need. Updated data will be presented at the meeting. Disclosures Gay: Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees; Roche: Membership on an entity9s Board of Directors or advisory committees; Mundipharma: Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria. Offidani: celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Oliva: Takeda: Honoraria; Celgene: Honoraria. Mancuso: Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Palumbo: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding. Musto: Janssen: Honoraria; Celgene: Honoraria. Boccadoro: Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Efficacy and toxicity of extended aromatase inhibitors after adjuvant aromatase inhibitors-containing therapy for hormone-receptor-positive breast cancer: a literature-based meta-analysis of randomized trials

Endocrine therapy with aromatase inhibitors (AIs) is the cornerstone of adjuvant systemic treatment for postmenopausal patients with hormone receptor-positive breast cancer. It has become clear that hormone receptor-positive breast cancer carries a consistent risk of relapse up to 15 years after diagnosis. Extended duration of adjuvant AIs therapy after completing initial standard adjuvant AIs-containing therapy may prevent late recurrence and death. We performed a meta-analysis to assess the real impact of the extended adjuvant therapy with AIs. A literature-based meta-analysis of the randomized controlled trials (RCTs) was undertaken. Relevant publications from PubMed, Embase, Cochrane Library, and abstracts from American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer (SABCS) symposia were searched. The endpoints were disease-free survival (DFS), overall survival (OS), local recurrence, distant recurrence, contralateral breast cancer, non-breast cancer-related death, and toxicity. Eight trials comprising 15,966 patients met the inclusion criteria. The pooled analysis revealed a significant improvement in DFS (RR = 0.79; 95% CI 0.68-0.91), distant recurrence (RR = 0.75; 95% CI 0.58-0.96), and contralateral breast cancer (RR = 0.53; 95% CI 0.40-0.70) in the extended AIs group. While there was not significant improvement in OS (RR = 1.00, 95% CI 0.99-1.01), non-breast cancer-related death (RR = 1.16, 95% CI 0.96-1.41), and local recurrence (RR = 0.82; 95% CI 0.64-1.06), the subgroup analysis showed that the patient with tumor size > 2cm (HR = 0.74, RD = - 0.31, P = 0.05 vs. HR = 0.85, RD = - 0.16, P = 0.20), node positive status (HR = 0.77, RD = - 0.27, P = < 0.0001 vs. HR = 0.89, RD = -0.12, P = 0.19) and previous chemotherapy use (HR = 0.75, RD = - 0.29, P = 0.003 vs. HR = 0.91, RD = -0.10, P = 0.44) would get a greater DFS benefit with extended AIs. Longer treatment with AIs was associated with an increased risk ratio of bone pain (RR = 1.26, RD = 0.04, P = 0.003), bone fractures (RR = 1.59, RD = 0.02, P = 0.002), osteoporosis (RR = 1.53, RD = 0.07, P = 0.005), myalgia (RR = 1.26, RD = 0.04, P = 0.02), and treatment discontinuation for adverse events (RR = 1.51, RD = 0.06, P = 0.0009). After initial standard AIs-containing adjuvant therapy, extended AIs therapy could further bring a DFS benefit for postmenopausal patients with early breast cancer, especially in the patients with high-risk characteristics.

A randomized, proof-of-concept clinical trial on repurposing chlorcyclizine for the treatment of chronic hepatitis C

Background & aimsChlorcyclizine HCl (CCZ) is a piperazine-class antihistamine with anti-hepatitis C virus (HCV) activity in vitro and in vivo. In a first-in-humans study for HCV, we evaluated the antiviral effects and safety of CCZ±ribavirin (RBV), characterized pharmacokinetic (PK) and viral kinetic (VK) patterns, and provide insights into CCZs mode of action against HCV. MethodsChronic HCV patients were randomized to CCZ (75 mg twice daily) or CCZ+weight-based RBV (1000/1200 mg daily) for 28 days. Therapy started with a loading dose of CCZ 150 mg ± RBV. Serial assessments of safety, liver tests, PK and VK markers were obtained. Results24 HCV patients were treated; 54% male, median age 56 years, median HCV RNA 6.30 log IU/ml, without baseline differences between groups. At the end of therapy, subjects treated with CCZ monotherapy did not show any significant or sustained reduction in viremia (p = 0.69), whereas 7/12 (58%) subjects treated with CCZ+RBV had a >3-fold decline in HCV RNA. Subjects who responded demonstrated monophasic (n = 2), biphasic (n = 2) and triphasic (n = 3) VK responses. Contrary to historical RBV monotherapy response, CCZ+RBV demonstrated a continued viral decline suggesting a possible synergistic effect of CCZ+RBV. Mathematical modeling predicts a median effectiveness of CCZ+RBV in blocking viral production (ε) of 59% (Interquartile range, IQR: 50%) and blocking infection (η) of 78% (IQR: 23%). Adverse events (AEs) were mild-moderate without treatment discontinuations for AEs. ConclusionsIn this human pilot study, CCZ demonstrated some anti-HCV effects, mostly in combination with RBV. More potent CCZ derivatives with optimal PK features may be more suitable for future therapeutic development. ClinicalTrials.gov number: NCT02118012.

Effects of blood pressure-lowering treatment on cardiovascular outcomes and mortality: 13 - benefits and adverse events in older and younger patients with hypertension: overview, meta-analyses and meta-regression analyses of randomized trials.

There is overwhelming evidence that blood pressure (BP)-lowering treatment can reduce cardiovascular outcomes also in the elderly, but some important aspects influencing medical practice are controversial as sufficient evidence has not been provided by single randomized controlled trials (RCTs), whereas evidence may result from a systematic search and meta-analysis of all available data. The following clinically relevant issues concerning the effects of BP lowering in older and younger individuals have been investigated: differences in benefits; the oldest and the youngest age range for which evidence of BP-lowering effects is available; the SBP level at which BP-lowering treatment should be initiated; the SBP and DBP levels treatment should be aimed at; differences in treatment burdens and harms. A database we previously identified of 72 BP-lowering RCTs in 260 210 patients was searched for separately reported data on older and younger individuals [cutoffs of 65 (primary analyses), 70, 75, 80, 60 and 55 years). The data were further stratified according to the levels of baseline (untreated) BP, and of on-treatment achieved SBP or DBP. Seven fatal and nonfatal outcomes were considered for benefits. Burdens and harms were investigated as permanent treatment discontinuations for adverse events, and hypotension/syncope. Risk ratios and absolute risk changes were calculated by a random effects model. Effects at older and younger ages were compared by heterogeneity test. Thirty-two RCTs provided data on 96 549 patients older than 65 years, and 31 RCTs on 114 009 patients younger than 65 years. All cardiovascular outcomes were significantly reduced by treatment both in older and younger individuals, without significant age-dependent differences in relative risk reduction but with significantly higher absolute risk reductions in older individuals. The extreme age ranges for which evidence of significant benefits of treatment were available was greater than 80 and less than 55 years. Only one RCT provided data on benefits of BP-lowering at age greater than 65 when treatment was initiated at SBP values in the grade 1 range, but more consistent evidence was provided when age was greater than 60 years. Both in patients older and younger than 65 years, significant reductions of cardiovascular outcomes were found at on-treatment SBP less than 140 mmHg and DBP less than 80 mmHg. There was no evidence that treatment discontinuations for adverse events or hypotension/syncope were more frequent at age greater than 65. Antihypertensive treatment should be recommended to all individuals with elevated BP, independent of age. The prudent recommendation to initiate treatment at SBP values 140-159 mmHg is supported at older age defined as greater than 60 years. SBP and DBP values lower than 140 mmHg and, respectively, 80 mmHg can be aimed at with incremental benefits without disproportionate burdens until age 80 years, above which available evidence is for benefits at on-treatment SBP 140-149 mmHg.

Effects of blood pressure-lowering treatment on cardiovascular outcomes and mortality: 14 - effects of different classes of antihypertensive drugs in older and younger patients: overview and meta-analysis.

The five major classes of blood pressure (BP)-lowering drugs have all been shown to significantly reduce the risk of major cardiovascular events when compared with placebo, and when directly (head-to-head) compared, no significant differences in their overall effectiveness have been detected, except for minor differences in cause-specific events. It is unknown, however, whether age-related differences exist and if some classes of drugs are differently effective in older or younger individuals. This clinically relevant question has been the object of a systematic search and meta-analysis of all available data. Two databases we had previously identified [72 placebo-controlled BP-lowering randomized clinical trials (RCTs) in 260 210 individuals and 50 RCTs head-to-head comparing treatments with BP-lowering drugs of different classes in 247 006 individuals) were searched for separately reported data on patients older or younger than 65 years, and the data were further stratified according to the class of drug [diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers] compared with placebo or with other drug classes. Seven fatal and nonfatal outcomes were considered for benefits. Adverse events were investigated as permanent treatment discontinuations for adverse events. Risk ratios and absolute risk changes were calculated by a random effects model. Effects at older and younger ages were compared by heterogeneity test. We identified 20 placebo-controlled RCTs on 55 645 older individuals and 21 on 99 621 younger individuals, and 21 head-to-head drug comparison RCTs on 94 228 older individuals and 27 on 100 232 younger individuals (for a total of 349 726 individuals). When compared with placebo, all five classes of BP-lowering drugs significantly reduced the risk of major cardiovascular events or stroke, with no significant difference between older and younger patients. However, in head-to-head comparisons, no significant difference was found between older and younger patients in the effects of diuretics, calcium antagonists, ACE inhibitors and angiotensin receptor blockers on all cardiovascular outcomes, whereas beta-blockers revealed an age-dependent effectiveness, being equally effective as the other agents at an age below 65 years, but less effective at an older age. Most BP-lowering classes are equally effective in preventing risk of fatal and nonfatal cardiovascular events both in older and younger patients, whereas beta-blockers, though being equally effective as the other agents in patients younger than 65, loose some of their effectiveness at an older age.

Toxicity of Extended Adjuvant Therapy With Aromatase Inhibitors in Early Breast Cancer: A Systematic Review and Meta-analysis.

A number of randomized controlled trials (RCTs) have reported improvement in breast cancer outcomes from extending treatment with aromatase inhibitors (AIs) beyond the initial five years after diagnosis. However, the toxicity profile of extended AIs is uncertain. We identified RCTs that compared extended AIs to placebo or no treatment using MEDLINE and a review of abstracts from key conferences between 2013 and 2016. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm (NNH) were computed for prespecified safety and tolerability outcomes including cardiovascular events, bone fractures, second cancers (excluding new breast cancer), treatment discontinuation for adverse events, and death without recurrence. All statistical tests were two-sided. Seven trials comprising 16 349 patients met the inclusion criteria. Longer treatment with AIs was associated with increased odds of cardiovascular events (OR = 1.18, 95% CI = 1.00 to 1.40, P = .05, NNH = 122), bone fractures (OR = 1.34, 95% CI = 1.16 to 1.55, P < .001, NNH = 72), and treatment discontinuation for adverse events (OR = 1.45, 95% CI = 1.25 to 1.68, P < .001, NNH = 21). Longer treatment with AIs did not influence the odds of either second malignancy (OR = 0.93, 95% CI = 0.73 to 1.18, P = .56) or deaths without breast cancer recurrence (OR = 1.11, 95% CI = 0.90 to 1.36, P = .34). Extended treatment with AIs is associated with an increased risk of cardiovascular events and bone fractures. There is no statistically significant increase in deaths without breast cancer recurrence among patients receiving longer treatment with AIs. These data should be taken into account when considering extended adjuvant AIs.

Effects of blood-pressure-lowering treatment in hypertension: 9. Discontinuations for adverse events attributed to different classes of antihypertensive drugs: meta-analyses of randomized trials.

Choice of antihypertensive drugs is also based on the expected burden of adverse events associated with each class of agents, and we have recently identified treatment discontinuation for adverse events as a measure of treatment tolerability frequently reported in randomized controlled trials (RCTs). To investigate whether all classes of blood pressure (BP) lowering drugs increase discontinuations for adverse events when compared with placebo and whether risk of discontinuation is similar for all classes when compared in head-to-head RCTs. RCTs of BP-lowering treatment were subdivided in groups according to class of drug compared with placebo or with other classes. Risk ratios and 95% confidence intervals of major cardiovascular events and of treatment discontinuations for adverse events were calculated (random-effects model). Thirty-eight placebo-controlled RCTs (147 788 patients) and 37 head-to-head RCTs (242 481 patients) provided comparative information on discontinuations for adverse events. All classes of drugs significantly increased discontinuations for adverse events over those occurring on placebo: risk ratio diuretics 2.23 (1.32-3.76), beta-blockers 2.88 (1.58-5.28), calcium antagonists 2.03 (1.17-3.56), angiotensin-converting enzyme inhibitors 2.78 (1.37-5.47), central agents 1.74 (1.24-2.45), with the single exception of angiotensin receptor blockers, which did not significantly increase adverse events over placebo [risk ratio 1.13 (0.78-1.62)]. Similarly, in head-to-head comparison RCTs with other classes, angiotensin receptor blockers were the only class associated with a significantly lower risk of adverse events [risk ratio 0.71 (0.58-0.87)] when head-to-head compared with other classes. Regression analysis also shows that incidence of discontinuations for adverse events is proportional to the number of antihypertensive and other cardiovascular drugs, which accounts for the high incidence of this outcome often found in groups randomized to placebo. Reduction of cardiovascular events by all classes of BP-lowering drugs is accompanied by increased treatment discontinuations for adverse events, except when angiotensin receptor blockers are used. Treatment discontinuations are also related to treatment often accompanying antihypertensive agents.

Effects of blood pressure lowering treatment in hypertension: 8. Outcome reductions vs. discontinuations because of adverse drug events - meta-analyses of randomized trials.

Previous meta-analyses of randomized controlled trials (RCTs) of blood pressure (BP)-lowering treatment provided overwhelming evidence that treatment markedly reduces risk of cardiovascular outcomes in hypertensive patients. However, adverse events associated with BP-lowering treatment have never been surveyed systematically. Identifying among BP-lowering RCTs those reporting a common and meaningful index of treatment-attributed adverse events, and describing the burden of these adverse events accompanying the benefits of mortality and morbidity reduction induced by treatment. The database consisted of the BP-lowering RCTs (active vs. placebo or less active treatment) we have described (70 RCTs, 255 970 participants, 1 091 964 patient-years). A common index of relevant adverse events was identified as permanent treatment discontinuation attributed to treatment adverse events. Risk ratios and 95% confidence intervals, standardized to a SBP/DBP reduction of 10/5 mmHg, of seven fatal and nonfatal outcomes and of treatment discontinuations for adverse events were calculated (random-effects model). The relationships of outcome reductions and discontinuation excess to SBP and DBP reductions were investigated by meta-regressions. Forty-four RCTs provided data on treatment discontinuations for adverse events and six more on serious adverse events because of treatment (179 949 patients, 719 796 patient-years). In these 50 RCTs, a significant 24% reduction of major cardiovascular event risk was associated with a significant 89% increase in the risk of discontinuations (33 major cardiovascular effects prevented and 84 excess discontinuations/1000 patients for 5 years). Metaregression analysis indicated that both outcome reductions and treatment discontinuation excess were significantly related to the extent of SBP and DBP reduction, but absolute treatment discontinuation excess disproportionally increased with larger BP reductions than increase in outcome risk reduction. Furthermore, a standard SBP reduction was found associated with a constant relative reduction, but a smaller absolute reduction of cardiovascular events, and a greater relative excess of treatment discontinuations when the achieved SBP was below 130 mmHg rather than in higher ranges. The burden of adverse events associated with BP-lowering treatment should be considered not to deny patients the overwhelming benefits of BP lowering, but whenever the extent of the BP lowering or the BP target to be achieved are discussed.

1BA The impact of pathological factors on long-term local control in the EORTC boost no-boost trial

patients (pts) with advanced renal cell carcinoma (RCC), treatment with cabozantinib was associated with encouraging clinical activity. The objective of the METEOR trial was to evaluate the efficacy and safety of cabozantinib compared to everolimus in pts with clear cell RCC and disease progression following treatment with one or more VEGFR tyrosine kinase inhibitors (TKIs). Methods: In this open-label phase 3 trial (NCT01865747), pts were randomized 1:1 to receive cabozantinib (60mg QD) or everolimus (10mg QD). Pts had measurable disease per RECIST 1.1, KPS 70%, and were stratified by MSKCC prognostic criteria and number of prior VEGFR TKIs. Patients must have progressed within 6 months of their prior VEGFR TKI. The primary endpoint was progression-free survival (PFS) per independent radiology committee (IRC). The trial was designed for an event-driven analysis of PFS events among the first 375 randomized pts to provide 90% power to detect a hazard ratio of 0.667 with a 2-sided 0.05 level of significance using a stratified log-rank test. Secondary efficacy endpoints include objective response rate (ORR) and overall survival (OS) among all randomized pts. Results: A total of 658 pts were randomized between Aug 2013 and Nov 2014. 71% pts had 1 and 29% pts 2 or more prior VEGFR TKIs. 46% pts were favorable, 41% intermediate, and 13% poor risk by MSKCC criteria. The study met the primary endpoint. The estimated median PFS among the first 375 randomized pts was 7.4 months for pts receiving cabozantinib, and 3.8 months for patients receiving everolimus, HR 0.58 (95% CI 0.45 to 0.75), p < 0.001. Prespecified subgroup analyses for PFS will be presented. The ORR in the PFS population was 21% with cabozantinib compared to 5% with everolimus (P < 0.001). At the interim analysis of OS (49% information fraction) among all 658 pts, the hazard ratio was 0.67 (95% CI 0.51 to 0.89), p = 0.0050, in favor of cabozantinib, not meeting the criteria for early rejection of H0 (p 0.0019). Medians for OS could not yet be estimated. The most common serious adverse events for pts receiving cabozantinib were abdominal pain (3%), pleural effusion (2.7%), diarrhoea (2.1%), and for pts receiving everolimus were anemia (3.7%), dyspnoea (3.7%), pneumonia (3.7%). Treatment discontinuation for adverse events occurred in 9.1% for cabozantinib and 10% for everolimus. Conclusions: Cabozantinib demonstrated improvement in PFS and ORR compared with everolimus in VEGFR TKI pretreated pts with advanced clear cell RCC. A trend of improved survival for pts receiving cabozantinib was observed at the interim analysis. The incidence of serious adverse events was similar in both arms. Conflict of interest: Ownership: Stock ownership: Anne Borgman-Hagey, Colin Hessel, Christian Scheffold, Gisela Schwab. Advisory Board: Tannir, Powles, Escudier. Corporate-sponsored Research:. Tannir, Roth, Motzer, Heng, Hammers, Choueiri. Other Substantive Relationships: Honoraria: Tannir, Escudier.

Quality-Of-Life (Qol), Tolerability, and Supportive Care Results: Necitumumab Phase 3 Squire Study

ABSTRACT Aim: Characterize QoL, tolerability, and supportive care of patients (pts) receiving necitumumab (N) + gemcitabine-cisplatin (GC) in the SQUIRE study. Methods: Pts with ECOG performance status (PS) 0-2, stage IV squamous NSCLC were randomized 1:1 to GC (G = 1250 mg/m2 IV days 1, 8; C = 75 mg/m2 IV day 1) + N (800 mg absolute dose IV), or GC alone (every 21 days up to 6 cycles). Pts treated with GC + N with no disease progression (PD) continued on N monotherapy until PD. Pt reported symptoms were measured by the Lung Cancer Symptom Scale (LCSS) prior to the start of each cycle (1-6) and every 6 weeks thereafter until PD. Physician reported PS was measured before every cycle. Tolerability was measured by number of cycles received, treatment discontinuation for adverse events (AEs), rates of serious AEs (SAEs), % of pts receiving N monotherapy post-induction. AEs (Safety Common Terminology Criteria [v3.0]) and supportive care data were collected while pts were on study. Results: 1093 pts were randomized (545 GC + N Arm, 548 GC Arm); 7 pts in each arm were not treated. 88.3% (GC + N) and 88.0% (GC) pts had a baseline and ≥ 1 post-baseline LCSS assessment. 95% CIs for the hazard ratios (HRs) for time to deterioration (TTD) of all 12 variables contained 1. The HR for TTD of PS by ≥1 point (cycles 1-6) was 0.861 (95% CI: 0.692-1.071). GC + N pts received a median of 6 cycles (interquartile [IQ] range 3-6) of GC, and a median of 6 cycles (IQ range 3-10) of N. GC pts received a median of 5 cycles (IQ range 3-6). Treatment discontinuation rates due to AEs were 13.6% (GC + N) and 14.6% (GC). SAEs were 47.8% (GC + N) and 37.5% (GC). The most common grade ≥3 AE was neutropenia, 24.3% (GC + N) and 27.5% (GC). 51% of GC + N pts continued on N monotherapy (median: 4 additional cycles). Select supportive care for treated patients is summarized in Table below. GC + N (538 pts) (%) GC (541 pts) (%) Concomitant medications 100 100 Transfusions 21.9 20.5 Hospitalizations 41.1 34.0 Colony stimulating factors 13.4 16.8 Erythropoietin 0.2 1.5 Conclusions: Long-term use of N was well tolerated. There were no major differences in AE rates, no detrimental effect overall of adding N to GC in terms of patients' QoL (symptoms and PS). Supportive care and associated resource use were modest. Disclosure: M. Reck: Member of Advisory Board: Hoffmann-La Roche, Lilly, AstraZeneca, BMS, Novartis, Pfizer, Boehringer – Ingelheim Honoraria for lectures: Hoffmann-La Roche, Lilly, AstraZeneca, BMS, Novartis, Pfizer, Boehringer-Ingelheim; M. Dediu: Consultant and Advisory Role (C) - Eli Lilly, Amgen, Boehringer-Ingleheim, Novartis. Speaker fee - TEVA, Boehringer-Ingelheim, MSD, GlaxoSmithkline, Amgen, Astra-Zeneca, Roche, Janssen, Eli Lilly, Pfizer; O. Molinier: Dr Olivier MOLINIER declares -consultant and advisory role for Eli Lilly and Roche -Speaker for Boehringer-Ingleheim; C. Schumann: Consultant and Advisory Role: -Eli Lilly, Pfizer, Roche, Boehringer-Ingelheim Speaker fee: -Eli Lilly, Novartis, Pfizer, Roche, Astra-Zeneca, Amgen, Boehringer-Ingelheim; J. Brown: I am an employee of Eli Lilly and Company and hold stock options and equity with Eli Lilly and Company; V. Soldatenkova: Employment: Lilly Deutschland GmbH, stock ownership. N. Chouaki: Employee of Eli Lilly and Company, I have stock ownership; N. Thatcher: Honoraria for advisory boards and speaker bureaus Eli Lilly and other companies. All other authors have declared no conflicts of interest.

Everolimus versus placebo in Japanese patients with advanced pancreatic neuroendocrine tumors (pNET): Japanese subgroup analysis of RADIANT-3.

289 Background: Everolimus demonstrated a statistically and clinically significant improvement in PFS over placebo in a multi-national, randomized, placebo-controlled, phase III trial in patients with advanced low- or intermediate-grade pNET with disease progression within the prior 12 months (RADIANT-3) (Ann Oncol [2010] 21[suppl 6]: NP doi:10.1093/annonc/mdq340). Forty patients were enrolled from Japanese sites and randomized (n=23: everolimus; n=17: placebo) in that study. The purpose of this report is to investigate the efficacy and safety in the Japanese subgroup. Methods: Subgroup analysis for the Japanese patients was performed comparing the efficacy and safety between everolimus 10mg/d orally plus best supportive care (BSC) and matching placebo plus BSC. The primary efficacy endpoint was progression-free survival (PFS). The safety was evaluated based on the incidence of adverse events (AEs). Results: Treatment with everolimus resulted in a significant prolongation by 16.62 months in median PFS (19.45 months for everolimus, 2.83 months for placebo), with 81% reduction in the hazard ratio of progression/death (HR 0.19 [95% CI: 0.08, 0.48]; one-sided unstratified log-rank test: p&lt;.001). The most common AE was stomatitis (73.9% everolimus vs 23.5% placebo); mostly grade 1/2. Grade 3/4 AEs occurred in 69.5% of the everolimus arm and 29.4% of the placebo arm, and amongst the most frequent included (% in everolimus vs % in placebo): neutropenia (17.4% vs 3%); anemia (8.7% vs 0%); pneumonitis (8.7% vs 0%); leukopenia (8.7% vs 0%). The remainder of grade 3/4 AEs was less than 3%. Median duration of exposure to everolimus was 57 weeks vs 47 weeks on placebo. Treatment discontinuation for AEs was 17% in the everolimus arm vs 0% in the placebo arm. Conclusions: Everolimus demonstrated a clinically meaningful improvement in PFS over placebo in Japanese patients. Everolimus was well tolerated in Japanese patients, and no new safety concerns were noted. This result suggests that everolimus can be a standard treatment for Japanese patients with advanced pNET. [Table: see text]

Abstract P2-16-13: Phase II Open Label Trial Bevacizumab in Combination with Paclitaxel and Gemcitabine as First Line in Patients with HER-2 Negative Recurrent or Metastatic Breast Cancer (AVALUZ): First Analysis

Abstract Background: The combination of bevacizumab with taxanes, capecitabine or anthracyclines has shown increased progression-free survival in patients with metastatic breast carcinoma. The aim of this study is to evaluate the efficacy and toxicity profile of the combination of bevacizumab with gemcitabine and paclitaxel, providing a preliminary analysis of response in patients included for whom at least one response assessment and the toxicity experienced in all patients treated. Methods: A Phase II multicenter, national, open-label study in patients diagnosed of recurrent or metastatic HER-2 negative breast carcinoma, treated with first-line bevacizumab 10 mg/kg, paclitaxel 150 mg/m2 and gemcitabine 2000 mg/m2 day 1 and 15 c/28d until disease progression, unacceptable toxicity, or medical decision. This abstract evaluates efficacy by the response rate and the toxicity profile of the combination in all cycles of all patients included. The primary end-point of the study is PFS. Toxicity is evaluated according to NCI CTC v 3.0 criteria. Results: From January 2009 to December 2009, 82 evaluable patients were recruited in 23 sites, with at least one response assessment available in 69. Median age 51.5 (26-81), ER+ 59 pts, PR+ 51 pts, triple negative patients 16 and previous chemotherapy (neoadj or adj) 58 pts. Of the 69 pts with response assessment, the last assessment is in cycle 3 for 31.88% of patients, cycle 6: 33.33%, cycle 9: 4.35%, cycle 12: 1.45% and at the end of treatment 29%. The median cycles administered per patient is 6 (1-14) and the relative median dose intensity is 0.93 for bevacizumab, 0.91 for paclitaxel, and 0.93 for gemcitabine. The overall response obtained was 69.57%, with a clinical benefit of 89.86% (CR 8.7% (6), PR 60.87% (42), SD 20.29%, and DP 10.14%). Of the 82 patients with a median follow-up of 7.19 m (0.16-13.98), grade 3-4 toxicity affected 41%, with treatment discontinuation for adverse events in 19.51%. Eighteen SAEs were reported: pyrexia (4), infection at catheter site (2), urine infection and a single case of angor, hypertension, pulmonary embolism, pleural effusion, febrile neutropenia, neutropenia, vomiting, diarrhoea, dehydration, atrial fibrillation, and dizziness. Toxicity was generally easily controlled. Conclusions: Although data from the primary study endpoint (PFS) are not yet available, the treatment regimen obtained a high overall response in patients treated and was well tolerated by this patient group. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-13.

Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis c genotype 1-infected slow responders

In hepatitis C virus (HCV) genotype 1 infection, the duration of interferon-based therapy is a critical determinant in achieving sustained virologic response (SVR). Slow or late responders to peginterferon and ribavirin may benefit from an extended treatment course. We sought to determine if therapy extension could improve response rates in a United States population of slow responders. Slow response was defined by achieving at least a 2-log decrement in HCV RNA from baseline, yet having detectable HCV RNA at 12 weeks and undetectable HCV RNA at 24 weeks (polymerase chain reaction, TaqMan, Roche; detection limit 10 IU/mL). Patients were treatment-naïve, chronically infected genotype 1-infected slow responders to 1.5 mug/kg/week of peginterferon-alpha2b and 800-1400 mg/day of ribavirin and were randomly assigned 1:1 to complete a total of 48 or 72 weeks of therapy. Dose reductions and treatment discontinuations for adverse events or laboratory abnormalities were similar between the 2 treatment arms. End-of-treatment response rates were similar in the 72-week group compared with those in the 48-week group (48% versus 45%; P value not significant). Overall, the rate of SVR was superior in patients treated for 72 weeks versus 48 weeks (38% versus 18%, respectively; P = 0.026). Extending the treatment duration from 48 weeks to 72 weeks in genotype 1-infected patients with slow virologic response to peginterferon-alpha2b and weight-based ribavirin significantly improves SVR rates. Treatment extension does not seem to increase the rate of dose reduction or therapy discontinuation.

Regimen Simplification to Atazanavir-Ritonavir Alone as Maintenance Antiretroviral Therapy After Sustained Virologic Suppression

The long-term adverse effects, expense, and difficulty of adherence to antiretroviral regimens have led to studies of simpler maintenance therapies. Maintenance therapy with ritonavir-boosted atazanavir alone is a possible option because of low pill burden, once-daily dosing, safety, and unique resistance profile. To assess whether simplified maintenance therapy with atazanavir-ritonavir alone after virologic suppression increases the risk of virologic failure (2 consecutive human immunodeficiency virus type 1 [HIV-1] RNA measurements of > or =200 copies/mL). Single-group, open-label, multicenter, 24-week pilot study of 36 HIV-infected adults with virologic suppression for 48 weeks or longer receiving their first protease inhibitor (PI)-based regimen. The study was conducted between September 1, 2004, and April 18, 2006, at 12 participating AIDS clinical trial units in the United States. Participants switched PIs to atazanavir-ritonavir at entry and discontinued nucleoside analog reverse transcriptase inhibitors (NRTIs) after 6 weeks. Virologic failure within 24 weeks of discontinuing NRTIs. Other measures included HIV-1 drug resistance, plasma atazanavir concentrations, adverse events, CD4 cell counts, plasma lipid levels, and HIV-1 RNA levels in seminal plasma. Thirty-six participants enrolled and 2 discontinued before simplification to atazanavir-ritonavir alone. Thirty-four patients were included in the analysis of the primary end point after 24 weeks: 1 withdrew voluntarily, and 33 continued the regimen. Virologic success (absence of failure) through 24 weeks of simplified therapy occurred in 91% (31 of 34 patients; lower 90% confidence interval limit = 85%). Three participants experienced virologic failure 12, 14, and 20 weeks after simplification, with plasma HIV-1 RNA levels of 4730, 1285, and 28 397 copies/mL, respectively. Resistance testing at failure did not identify PI resistance mutations. Plasma atazanavir concentrations at failure were low or below detection in 2 of 3 participants experiencing failure. There were no treatment discontinuations for adverse events after simplification; no significant changes in CD4 cell counts or plasma lipid levels; and no detectable HIV-1 RNA in seminal plasma from all 8 participants tested. These preliminary data suggest that simplified maintenance therapy with atazanavir-ritonavir alone may be efficacious for maintaining virologic suppression in carefully selected patients with HIV infection. These findings require confirmation in larger, randomized trials of this strategy. clinicaltrials.gov Identifier: NCT00084019.