Efficacy In Terms Of Progression-free Survival Research Articles

The Integration of Efficacy and Safety Outcomes Identifies the Net Clinical Benefit of Targeted Agents in Upfront Therapy of Chronic Lymphocytic Leukemia: Results of Network Meta-Analysis

In the absence of head-to-head randomized trials, indirect comparisons of therapy with targeted agents (TAs) across trials may well be informative in the management of chronic lymphocytic leukemia (CLL). However, such published analyses have mostly described progression-free survival (PFS) and provided sparse data on overall survival (OS) or toxicity. We, therefore, conducted a network meta-analysis (NMA) of published upfront CLL TA studies which incorporated a variety of efficacy and safety outcomes, in an attempt to predict the net benefit of TAs. We searched MEDLINE, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) assessing the efficacy and safety of Bruton kinase inhibitors (BTKis) and venetoclax-based regimens in treatment-naïve CLL. Efficacy outcomes (PFS, OS, time to next treatment [TTNT], overall response rate [ORR], complete remission [CR], minimal residual disease [MRD]), safety, and toxicity were evaluated. The surface under the cumulative ranking curve (SUCRA) was obtained for each treatment. The SUCRA provides a numeric representation (range from 0 to 100%), allowing for an overall ranking. The closer the SUCRA value to 100%, the higher the likelihood that therapy is in the top rank, whereas the closer to 0 the SUCRA value, the more likely treatment is in the bottom rank. Nine RCTs met the criteria of low risk for bias according to the Cochrane Handbook for Systematic Reviews of Interventions. Five were excluded because they lacked a common comparator arm (RESONATE2, ALLIANCE, ECOG-ACRIN, FLAIR, SEQUOIA). Four trials were suitable for network analysis (ILLUMINATE, ELEVATE-TN, CLL14, GLOW). Chlorambucil-obinutuzumab (CO) was the control arm across these studies (n=610). In all, these included 1547 patients and evaluated ibrutinib-obinutuzumab (IO) (ILLUMINATE; n=113), venetoclax-obinutuzumab (VO) (CLL14; n=216), acalabrutinib (A) monotherapy (ELEVATE-TN; n=179), A plus obinutuzumab (AO)(ELEVATE-TN; n=179) ibrutinib-venetoclax (IV)(GLOW; n=195). In this NMA, we used the longest published follow-up for each trial (GLOW 27.7 months, CLL14 52,4 months, ILLUMINATE 45 months, ELEVATE-TN 46.9 months). Patients with disrupted TP53 were excluded from the GLOW study and hence from our analysis. AO had the highest probability of efficacy in terms of PFS (SUCRA,0.9923), OS (SUCRA, 0.9010), and ORR (SUCRA,0.8670). In contrast, venetoclax-based regimens had the highest likelihood of achieving a better quality clinical and MRD responses. IV ranked first in terms of CR (SUCRA 0.9208) and VO in terms of undetectable MRD (SUCRA,0.9020). In the analysis of TTNT, IO was preferable (SUCRA,0.9810)(Tab 1). We developed a ranking chart for efficacy outcomes. The average (Av) SUCRA for PFS, OS, ORR, and CR was used to create an efficacy rankogram (k ranks ranged from 1 to 6). In the aggregate efficacy analysis, AO ranked first (Av SUCRA,0.8544) and CO last (Av SUCRA, 0.0575). The full Av SUCRA ranking order was AO, IV, VO, IO, A, CO (Av SUCRA, 0.8544, 0.5793,0.5747,0.4456,0.3864, 0.0575) (Fig 1). When outcomes of toxicity were included, the ranking order changed. The average SUCRA values for toxicities (assessed by the common terminology criteria adverse events (CTCAE) as grade 3 and above, which included neutropenia, infections, diarrhoea, and atrial fibrillation facilitated the development of a safety rankogram in which reduced toxicity is associated with an increased SUCRA value. The toxicity SUCRA ranking selected A first. The full toxicity SUCRA ranking is as follows : A, CO, AO, IV VO and IO (Av SUCRA; 0.70160.6650,0.4390,0.4377, 0.4325 and 0.3242)(Fig 2). A mixed efficacy-toxicity (E-T) rankogram was generated from the efficacy and toxicity Av SUCRA scores; this showed that AO ranked first followed by A, CO, IV, VO, and IO (ET-Av SUCRA: 0.6467, 0.5440,0.5247,0.5085,0.5035, 0.3850)(Fig 3). This is the first NMA that can aid the selection of upfront therapy in CLL patients with intact TP53. In patients who are physically fit a model based solely upon efficacy may be able to inform treatment decisions.On the other hand , a model based exclusively on toxicity outcomes may guide therapy selection in unfit patients. If a combined efficacy/toxicity model is utilized , it identifies a preference for acalabrutinib-based regimens. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of autologous transplantation on survival in patients with newly diagnosed multiple myeloma who have high-risk cytogenetics: A meta-analysis of randomized controlled trials.

Despite routine evaluation of cytogenetics in myeloma, little is known regarding the impact of high-dose therapy (HDT) consolidation on overall survival (OS) or progression-free survival (PFS) in patients who have high-risk cytogenetics. The authors performed a meta-analysis of randomized controlled trials (RCTs) to assess the heterogeneity of HDT efficacy according to cytogenetic risk. All RCTs in patients who had newly diagnosed myeloma from 2000 to 2021 that compared upfront HDT versus standard-dose therapy (SDT) consolidation were included. The primary objective was to assess the difference in HDT efficacy between standard-risk and high-risk cytogenetics in terms of the OS or PFS log(hazard ratio) (HR). The pooled OS and PFS HR was calculated according to cytogenetic-risk subgroup using a random-effects model, and heterogeneity (I2 ) (the percentage of total observed variability explained by between-study differences) was assessed using an interaction test. After screening 3307 citations, 6 RCTs were included for PFS analysis, and 4 were included for OS analysis. The median follow-up ranged from 3.1 to 7.8 years. The pooled OS HR for HDT versus SDT consolidation in patients with standard-risk and high-risk cytogenetics was 0.90 (95% confidence interval [CI], 0.70-1.17; I2 = 0%) and 0.66 (95% CI, 0.45-0.97; I2 = 0%), respectively. The difference in HDT efficacy in terms of OS between standard-risk and high-risk patients was statistically significant in favor of the high-risk group (P for interaction = .03). The pooled PFS HR for HDT versus SDT was 0.65 (95% CI 0.56-0.76; I2 = 0%) versus 0.52 (95% CI, 0.33-0.83; I2 = 55%), respectively. The difference in HDT efficacy in terms of PFS between standard-risk and high-risk patients was not significant (P for interaction = .25). The magnitude of OS benefit with upfront HDT is cytogenetics-dependent. Patients with high-risk cytogenetics should preferably receive upfront rather than delayed HDT consolidation. Upfront autologous stem cell transplantation improves overall survival in patients with newly diagnosed myeloma harboring high-risk cytogenetics.

Stereotactic body radiotherapy to lymph nodes in oligoprogressive castration-resistant prostate cancer patients: a post hoc analysis from two phase I clinical trials.

The prognosis of prostate cancer (PC) is generally favorable but the incidence of metastases is relatively high after the treatment of the primary tumor, especially in high-risk patients. Fractionated stereotactic body radiotherapy (SBRT) or single fraction stereotactic body radiosurgery (SRS) are emerging treatment options in this setting. However, data on SBRT/SRS in patients with metastatic castration-resistant PC (mCRPC) are largely lacking, particularly in subjects with nodal lesions. Therefore, we evaluated outcomes and toxicity recorded in mCRPC patients with nodal oligoprogression. Patients included in this analysis had ≤ 5 metastatic sites without visceral lesions and underwent SBRT/SRS on nodal metastases. Thirty-eight patients carrying out 61 nodal metastases were analyzed. The median SRS dose was 20Gy (range 12-24Gy) and the most common schedule was 20Gy (44.8%). The median SBRT dose was 45Gy (range 20-50Gy) and the most common regimen was 45Gy in 5 fractions (37.9%). Thirty-seven patients (97.4%) showed only grade 0-1 acute toxicity while one patient reported grade 2 dysphagia. In terms of late toxicity, one grade 2 laryngeal, one grade 1 skin and one grade 1 gastrointestinal toxicities were recorded. Two-year actuarial local control (LC), distant progression-free survival, progression-free survival (PFS) and overall survival were 94.0, 47.2, 47.2, and 90.2%, respectively. Two-year next line systemic therapy-free survival (NEST-FS) was 67.7%. In conclusion, the efficacy in terms of LC of SBRT/SRS in patients with nodal metastases from PC was confirmed. Moreover, this analysis suggests the efficacy in terms of PFS and NEST-FS also in the setting of oligoprogressive PC. In fact, about one-third of patients were free from progressive disease and two-third of subjects did not require hormonal therapy switch or discontinuation three years after treatment.

Adherence, persistence and efficacy of dasatinib and nilotinib in the treatment of patients resistant or intolerant to imatinib with chronic myeloid leukemia in chronic phase: an Italian multicenter study over two years in real life

Background The use of dasatinib and nilotinib in the treatment of patients with chronic myeloid leukemia represents a valid therapeutic option for patients resistant or intolerant to imatinib. In this multicentre study, adherence, persistence and efficacy in real life over two years of treatment were evaluated. Materials and methods Adherence to treatment was calculated as the ratio between the dose received and the prescribed dose. The dose received was calculated using pharmacy refill data. The persistence with treatment was calculated as the difference between the end and the beginning of the treatment. Efficacy was assigned as Progression-Free Survival (PFS) and Events-Free Survival (EFS) and represented through the Kaplan-Meier curve. Results The number of patients analysed was 117, 70 treated with dasatinib and 47 with nilotinib. Adherence to treatment for dasatinib and nilotinib at two years was 0.91 and 0.82 respectively. Persistence at two years was 77% while the PFS was 92% for both drugs in the study. Conclusion Adherence to the treatment calculated over two years showed a superiority of dasatinib over nilotinib. Nevertheless, the efficacy in terms of PFS and EFS is superimposable between the two drugs in the study.

Open-label, multicenter, randomized phase II study on docetaxel plus bevacizumab or pemetrexed plus bevacizumab for treatment of elderly (aged ≥75 years) patients with previously untreated advanced non-squamous non-small cell lung cancer: TORG1323.

BackgroundThe effectiveness of bevacizumab monotherapy in elderly patients with non-squamous non-small cell lung cancer (NSCLC) is unclear. The efficacy of the combinations for elderly patients was explored.MethodsUntreated patients (≥75 years; performance status 0–1) with stage IIIB, IV, or recurrent non-squamous NSCLC were included. Patients with epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) gene rearrangements were eligible even if they received tyrosine kinase inhibitors. Patients were randomized 1:1 to receive docetaxel (50 mg/m2) (DB) or pemetrexed (500 mg/m2) (PB) with bevacizumab (15 m/kg). The primary endpoint was progression-free survival (PFS). Treatment was administered every 3 weeks until disease progression or unacceptable toxicity.ResultsOverall, 103 patients (DB: n=51; PB: n=52) were enrolled. In the DB and PB arms, median ages [range] were 78 [75–88] and 79 [75–94] years, respectively; median PFS were 6.1 and 4.6 months, respectively [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.66–1.61]; and response rates were 43%, and 40%, respectively (P=0.840). Grade ≥3 leukopenia, neutropenia, and fatigue incidences were significantly higher in the DB arm. Febrile neutropenia incidence did not differ significantly (16% vs. 12%, P=0.578). One patient in the PB arm died from a ruptured abdominal aortic aneurysm. Quality of life (QoL) analysis revealed less deterioration in the PB arm.ConclusionsIn previously untreated elderly patients with non-squamous NSCLC, PB shows feasibility, better QoL, and promising efficacy in terms of PFS, and an objective response rate for further analysis (UMIN000012786).

First-line tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer: a network meta-analysis.

BackgroundEGFR-tyrosine kinase inhibitors (EGFR-TKIs) including afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib have proven efficacy in terms of progression-free survival (PFS) in patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, an overall view for comparing efficacy and toxicity on a meta-level is lacking. This study compared efficacy and toxicity of first-line treatment with five different EGFR-TKIs by conducting a network meta-analysis (NMA).MethodsA systematic review was performed, aiming to find eligible literature. Data of PFS, overall survival (OS), objective response rate (ORR), and adverse events were extracted. An NMA based on Bayesian statistics was established to synthesize the efficacy and toxicity of all treatments.ResultsThirteen randomized controlled trials, including data from 3,539 patients with EGFR-mutated NSCLC, were analyzed. Rank probabilities showed that osimertinib had a potentially better efficacy in terms of PFS and OS compared to all other TKIs. For ORR, afatinib and osimertinib showed a trend of superiority compared to the other four TKIs. Furthermore, there was a high risk of diarrhea and rash for patients treated with afatinib or dacomitinib as well as a moderate risk for treatment with erlotinib, gefitinib, and osimertinib.ConclusionOur study showed a favorable efficacy of osimertinib in terms of PFS and OS compared to all other EGFR-TKIs in patients with NSCLC harboring activating EGFR mutations. Furthermore, gefitinib, erlotinib, and osimertinib were associated with fewer toxicities compared to the other TKIs. Therefore, osimertinib is indicated as a preferable first-line TKI in patients with activating EGFR-mutated NSCLC.

Evaluation of the Effectiveness and Safety of Pixantrone for the Treatment of Multiply Relapsed or Refractory Aggressive Non Hodgkin B-Cell Lymphoma (aNHL) an Observational Multicentre Retrospective Study in a Real World Population

BACKGROUND: The objective of this study was to evaluate the effectiveness and safety of pixantrone as a rescue treatment for NHL patients in a real world population in Spain and Italy as data on the use of this drug in everyday clinical practice is still scarce.METHODS: The study included patients aged ≥18 years with histologically proven relapsed or refractory B-cell aNHL who were treated according to pixantrone's product information. Primary endpoint was progression-free survival (PFS). Secondary endpoints included the proportion of patients with complete response (CR), partial response (PR), overall response rate (ORR), overall survival (OS), as well as safety.RESULTS: 79 patients were included in 52 centers. At diagnosis, mean age was 65 years (95% CI 62-68) and 83% had ECOG 0-1. At pixantrone treatment initiation, 82% of patients presented Ann Arbor stage III-IV, and 64% an International Prognostic Index (IPI) Score ≥3; 85% were refractory and 15% relapsed. Median number of previous therapies was 3 (range 1-5). Patients received a median of two cycles of pixantrone (range 1-6). ORR was 29% with 13.2% CR and 15.8% PR. Median PFS and OS were 2.8 months (95% CI 2.1-3.6) and 4 months (95% CI 3.6-4.4), respectively. There was a trend towards better PFS in relapsed vs refractory patients (12.5 vs 2.6 months, respectively, p=0.059). Patients who received two or more cycles of pixantrone had 38% ORR (CR 17.5%; PR 19.3%). Adverse reactions to pixantrone were reported in 63% of patients. The most frequent toxicities were hematological (67.1%) and gastrointestinal (12%). No febrile neutropenia or clinical cardiotoxicity was reported.CONCLUSIONS: Although a high percentage of patients with very poor prognostic factors was included in this study (82% Ann Harbor III-IV, 63% IPI ≥3, and 85% refractory), treatment with pixantrone appears to be effective. There was a trend to better efficacy in terms of PFS in relapsed vs refractory patients. In those patients who received ≥2 cycles, pixantrone was more effective compared to those who received less than two cycles, with ORR similar to the pivotal study. Pixantrone treatment resulted active and well tolerated in real world clinical practice.Keywords: Refractory non-Hodgkin lymphoma; Relapsed non-Hodgkin lymphoma; Salvage therapy; pixantrone. DisclosuresSancho:Roche: Speakers Bureau; Janssen: Speakers Bureau; Kern Pharma: Speakers Bureau; Roche: Honoraria; Gilead: Honoraria; Celgene: Speakers Bureau; Mundipharma: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Bristol-Myers: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees. Grasso Cicala:Servier: Employment. Spione:Servier: Employment. Zinzani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau.

Efficacy and Safety of Afatinib for EGFR-mutant Non-small Cell Lung Cancer, Compared with Gefitinib or Erlotinib.

PurposeWe tried to evaluate whether there are any specific features in treatment outcomes of firstline afatinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), compared with gefitinib or erlotinib.Materials and MethodsWe analyzed patients treated with first-line afatinib, gefitinib, or erlotinib for advanced EGFR-mutant NSCLC at Samsung Medical Center between 2014 and 2016.ResultsIn total, 467 patients received first-line afatinib (n=165), gefitinib (n=230), or erlotinib (n=72). Afatinib was used more often in patients with tumors harboring deletion in exon 19 (Del19), whereas the gefitinib group had more elderly, females, and never smokers. The median progression-free survival (PFS) time for afatinib, gefitinib, and erlotinib was 19.1 months, 13.7 months, and 14.0 months, respectively (p=0.001). The superior PFS of afatinib was more remarkable in subgroups of Del19 or uncommon EGFR mutations. Overall toxicity profiles of the three drugs were comparable, though more grade 3 or 4 toxicities were detected in afatinib (7.3%) compared with gefitinib (2.6%) or erlotinib (1.8%). The common grade 3 or 4 toxicities of afatinib included diarrhea (3.0%), paronychia (2.4%), and skin rash (1.8%). Dose modification was more frequently required in patients treated with afatinib (112/165, 68%), compared with gefitinib (5/230, 2%) and erlotinib (4/72, 6%). Interestingly, however, dose reduction in the afatinib group did not impair its efficacy in terms of PFS (dose reduction vs. no reduction group, 23.5 months vs. 12.4 months).ConclusionFirst-line afatinib showed satisfactory efficacy data and manageable toxicity profiles.

Association of ABCG2 polymorphism with clinical efficacy of imatinib in patients with gastrointestinal stromal tumor.

Imatinib is a substrate of drug transporters and metabolizing enzymes, including members of the cytochrome P450 (CYP) system. Differences in imatinib pharmacokinetics among individuals might be influenced by genetic polymorphisms and be associated with variable clinical imatinib efficacy. This study sought to test how genetic polymorphisms can affect the clinical efficacy of imatinib and its blood levels in GIST patients. A total of 209 GIST patients who had received imatinib 400 mg daily were genotyped for six single-nucleotide polymorphisms in three genes (CYP3A5 6986A>G; ABCB1 1236C>T, 2677G>A/T, and 3435C>T; and ABCG2 34G>A and 421C>A) via blood samples. Progression-free survival (PFS) and imatinib plasma trough levels were evaluated and compared according to genotypes. With a median follow-up of 39.6 months (range 16.7-97.5 months), the estimated 5-year PFS rate was 67.5 % (95 % CI 59.9-75.1). Among the CYP3A5, ABCB1, and ABCG2 genotypes, ABCG2 421C>A was associated with PFS. The 5-year PFS rate in patients with the AA variant of ABCG2 421C>A (92.3 %; 95 % CI 77.8-100.0) was significantly superior to that of patients with CC/CA genotypes (65.0 %; 95 % CI 56.9-73.1; p = 0.047). For the imatinib trough levels, there were no statistically significant differences when comparing polymorphisms among all genotypes, even after adjusting for clinical factors, including sex, age, body surface area, hemoglobin, albumin, and creatinine clearance. The ABCG2 421C>A genetic variation could influence clinical efficacy in terms of PFS in patients with advanced GIST undergoing imatinib therapy.

Comparison of the Efficacy and Safety of S-1-Based and Capecitabine-Based Regimens in Gastrointestinal Cancer: A Meta-Analysis

PurposeOral fluoropyrimidine (S-1, capecitabine) has been considered as an important part of various regimens. We aimed to evaluate the efficacy and safety of S-1-based therapy versus capecitabine -based therapy in gastrointestinal cancers.MethodsEligible studies were identified from Pubmed, EMBASE. Additionally, abstracts presented at American Society of Clinical Oncology (ASCO) conferences held between 2000 and 2013 were searched to identify relevant clinical trials. The outcome included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and advent events.ResultsA total of 6 studies (4 RCTs and 2 retrospective analysis studies) containing 790 participants were included in this meta-analysis, including 401 patients in the S-1-based group and 389 patients in the capecitabine-based group. Results of our meta-analysis indicated that S-1-based and capecitabine-based regimens showed very similar efficacy in terms of PFS (HR 0.92, 95% CI 0.78–1.09, P = 0.360), OS (HR 1.01, 95% CI 0.84–1.21, P = 0.949), ORR (HR 1.04, 95% CI 0.87–1.25, P = 0.683) and DCR (HR 1.02, 95% CI 0.94–1.10, P = 0.639). There was also no significant difference in toxicity between regimens other than mild more hand–foot syndrome in capecitabine-based regimens.ConclusionBoth the S-1-based and capecitabine-based regimens are equally active and well tolerated, and have the potential of backbone chemotherapy regimen in further studies of gastrointestinal cancers.

881 - Sequential Use of Treatment Options in Advanced Renal-Cell Carcinoma (RCC): A Retrospective Analysis of 42 Patient Cases

ABSTRACT The best sequence of targeted therapy options has not been sufficiently defined and also the significance of Cytokine (Cy) in TKI (Sorafenib-So, Sunitinib-Su) and mTOR era. The objective of this study was to describe the clinical activity of sequence options in 2nd line treatment. Methods Retrospective study of 42 patients receiving TKI or Everolimus (EV) treatment after progression on first-line therapy. Sequence of systemic targeted treatment consisted of an Cy-TKI-sequence (n = 20; Cy-So, n = 12; Cy-Su, n = 8), TKI-TKI-sequence (n = 15; Su-So, n= 11; So-Su, n = 4) or an TKI-EV-sequence (n = 7; Su-EV, n = 7). We measured response to treatment (RECIST 1.0). Progression free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method. Results Sequence treatment groups did not significantly differ by gender, MSKCC prognostic group, or ECOG PS. Best response to 2nd line therapy included CR (Su: n = 2, sequential therapy after Cy), PR (So: n = 3, after Cy) and SD (EV: n = 5, after TKI; TKI: n = 13; So: n = 5 after Cy, Su: n= 3 after So, n= 5 after Cy). The estimated 2nd line PFS was 5.2 months for EV and 5.86 months for So sequential therapy after Su, 6.56 months for So sequential Cy, 6.7 months for Su sequential therapy after So, 6.54 months for Su sequential Cy. The estimated OS was longer for the group of patients receiving the Cy-TKI-sequence (49.87 months; 95% CI:16–26 for the group Cy-So and 40.36 months; 95% CI:16–26 for the group Cy-Su) and TKI-EV sequence (40.72 months; 95%CI:32–48) than for those receiving the TKI-TKI sequence So-Su (33.36 months, 95%CI:21–62) and Su-So (16.32 months, 95%CI:13–37). However, the TKI-TKI group was characterized by a relatively short first-line PFS (6.12 months of the Su-So group to 12.37 So-Su compared to 12.8 months of the TKI-EV group) which may at least in part explain the observed OS difference. Conclusions Common sequence treatment options may have comparable efficacy in terms of PFS and response. The observed differences in OS await further confirmation in prospective randomized trials. Disclosure All authors have declared no conflicts of interest.

Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial

Anthracyclines and taxanes are active cytotoxic drugs in the treatment of early metastatic breast cancer. It is yet unclear whether addition of capecitabine to the combination of these drugs improves the treatment outcome. Patients with advanced breast cancer were randomized to first-line chemotherapy with a combination of epirubicin (Farmorubicin(®)) and paclitaxel (Taxol(®)) alone (ET) or in combination with capecitabine (Xeloda(®), TEX). Starting doses for ET were epirubicin 75mg/m(2) plus paclitaxel 175mg/m(2), and for TEX epirubicin 75mg/m(2), paclitaxel 155mg/m(2), and capecitabine 825mg/m(2) BID for 14days. Subsequently, doses were tailored related to side effects. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), time to treatment failure (TTF), objective response (OR), safety and quality of life (QoL). 287 patients were randomized, 143 to ET and 144 to TEX. Median PFS was 10.8months for patients treated with ET, and 12.4months for those treated with TEX (HR 0.84, 95% CI 0.65-1.07, P=0.16); median OS was 26.0months for women in the ET versus 29.7months in the TEX arm (HR 0.84, 95% CI 0.63-1.11, P=0.22). OR was achieved in 44.8% (ET) and 54.2% (TEX), respectively (χ(2) 3.66, P=0.16). TTF was significantly longer for patients treated with TEX, 6.0months, versus 5.2months following ET (HR 0.73, 95% CI 0.58-0.93, P=0.009). Severe hematological side effects related to epirubicin and paclitaxel were evenly distributed between the treatment arms, mucositis, diarrhea, and Hand-Foot syndrome were significantly more frequent in the TEX arm. Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into clinically relevant improvement of the outcome.

Second-line sequential therapy in patients with metastasized renal cell carcinoma (mRCC): Retrospective comparison of common treatment options following failure of receptor tyrosine kinase inhibitor therapy.

e15059 Background: Everolimus (EV) is an efficacious treatment option after failure of receptor tyrosine kinase inhibitor (rTKI) therapy in mRCC patients. However, the best sequence of targeted therapy options has not been sufficiently defined. The objective of this study was to describe the clinical activity of sequence options in 2nd line treatment, i.e. rTKI followed by EV vs. rTkI followed by another rTKI. Methods: Retrospective study of 108 patients receiving rTKI or everolimus treatment after progression on first-line rTKI therapy at 2 German academic centres. Sequence of systemic targeted treatment consisted of an rTKI-rTKI-sequence (n=46; sunitinib-sorafenib, n= 35; sorafenib-sunitinib, n=11) or an rTKI-EV sequence (n=62). Median progression free survival (PFS) and median overall survival (OS) were determined for the two sequence treatment options using the Kaplan-Meier method. Response to treatment was assessed according response evaluation criteria in solid tumors (RECIST) 1.0. Results: Sequence treatement groups (rTKI-rTKI vs. rTKI-EV) did not significantyl differ by gender, MSKCC prognostic group, or ECOG performance status. Best response to 2nd line therapy included partial response (EV: n=2, 3%; rTKI: n=5, 11%; p=.11) and stable disease (EV: n=30, 48%; rTKI: n=15, 33%; p=.21) for a disease control rate of 51.5% (EV) and 43.4% (rTKI), respectively. The estimated 2nd line PFS was 3.6 months (92% CI: 1.8 – 5.4) for Everolimus and 4.0 months (3.2 – 4.9) for rTKI sequential therapy. The estimated OS was longer for the group of patients receiving the rTKI-EV sequence (43 months; 95% CI: 33.9 – 52.1) than for those receiving the rTKI-rTKI sequence (29 months, 95% CI: 18.6 – 39.5; p = .03). However, the rTKI-rTKI group was characterized by a relatively short first-line PFS (6.6 months compared to 10.6 months of the rTKI-EV group) which may at least in part explain the observed OS difference. Conclusions: Common sequence treatment options may have comparable efficacy in terms of PFS and response rate. The observed differences in OS await further confirmation in prospective randomized trials.