Final overall survival analysis of the phase 3 HERITAGE study demonstrates equivalence of trastuzumab-dkst to trastuzumab in HER2-positive metastatic breast cancer.

PURPOSE: The phase 3 HERITAGE trial demonstrated that the biosimilar trastuzumab-dkst is well tolerated with similar efficacy (measured by overall response rate [ORR] and progression-free survival [PFS]) compared with originator trastuzumab combined with taxane followed by monotherapy in patients with HER2-positive metastatic breast cancer (MBC). Herein, we present final overall survival (OS) from HERITAGE. METHODS: HERITAGE is a multicenter, double-blind, randomized, parallel-group study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab plus taxane followed by continued monotherapy until disease progression. Overall survival was to be assessed at 36 months or after 240 deaths, whichever occurred first, as observed from time of randomization of last patient. RESULTS: At the final analysis (36 months), 242 patients in the intention-to-treat population had died during the study: 116 and 124 in the trastuzumab-dkst and trastuzumab groups, respectively, and 1 untreated patient from each treatment group. Median OS by Kaplan-Meier analysis was 35.0 months with trastuzumab-dkst and 30.2 months with trastuzumab. Evaluation of PFS showed a median of 11.1 months in both treatment groups. No new safety concerns were reported from week 48 until the end of the survival follow-up. CONCLUSION: This is the first phase 3 trial of a trastuzumab biosimilar to report long-term survival data similar to originator trastuzumab in patients with MBC. The comparable long-term OS between the trastuzumab-dkst and originator trastuzumab groups further supports the similarity of trastuzumab-dkst with originator trastuzumab and establishes trastuzumab-dkst as a safe and effective treatment option for patients with HER2-positive MBC. ClinicalTrials.gov NCT02472964; 6/16/2015.

Correlation between week 24 trastuzumab-dkst response and week 48 progression-free survival: the HERITAGE trial.

BACKGROUND: Trastuzumab-dkst is a biosimilar of trastuzumab. The phase 3 HERITAGE trial demonstrated equivalent overall response rate (ORR) with trastuzumab-dkst or originator trastuzumab at 24 weeks in patients with HER2-positive metastatic breast cancer receiving chemotherapy. We now present the correlation of ORR with progression-free survival (PFS) for maintenance monotherapy with trastuzumab-dkst vs trastuzumab at 48 weeks of treatment, and the safety, tolerability, and immunogenicity. METHODS: HERITAGE is a multicenter, double-blind, randomized, parallel-group, phase 3 study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab in combination with taxane followed by continued monotherapy until disease progression. The analysis included PFS at 48 weeks to support the primary efficacy endpoint of ORR and safety, tolerability, and immunogenicity of trastuzumab-dkst vs trastuzumab as maintenance monotherapy. RESULTS: Of 500 randomized patients, 342 entered the monotherapy phase; 214 patients received ≥48 weeks of treatment. There were no statistically significant differences between PFS, ORR, or interim overall survival at week 48 between trastuzumab-dkst and trastuzumab. Week 24 ORR was highly correlated with week 48 PFS (rb = 0.75). Cumulative treatment-emergent adverse events (TEAEs) and serious AEs were similar in both groups, with few grade ≥3 TEAEs. Immunogenicity was low and similar in both groups at 48 weeks. CONCLUSION: The correlation between ORR and PFS supports the design of first-line metastatic trials assessing biosimilar trastuzumab. Overall, trastuzumab-dkst and trastuzumab were well tolerated with similar efficacy, including ORR and PFS, in combination with a taxane followed by monotherapy.

Prognostic factors for long-term survival after adult liver transplantation.

PURPOSE: Prognostic factors for survival ≥ 15 years and life years lost after liver transplantation are largely unknown. METHODS: One thousand six hundred thirty primary adult liver transplants between 1983 and 2014 were analyzed. Risk factors for survival were identified with multivariable Cox regression and subsequently tested for their relevance as prognostic factors for observed 15-year survival using multivariable logistic regression and c statistics. The difference of life expectancy between a matched national reference population and survival in patients with post-transplant survival ≥ 15 years was calculated. RESULTS: Survival of ≥ 15 years was observed in 361 patients (22%). Sixty-nine adults died after more than 15 years losing a median of 15 years of life expectancy. One of those patients lived longer while 292 patients still have the chance to survive longer than their normal life expectancy. The indication primary sclerosing cholangitis (PSC) and later eras of transplantation were identified as significant independent protective factors while recipient age > 36.8 years, graft loss due to initial non-function or thrombosis, the indications hepatocellular carcinoma (HCC), hepatitis-C-virus-related cirrhosis (HCV-cirrhosis) and all other indications, donor age > 53 years, the number of surgical complications, and operative durations > 4.5 h were identified as significant independent risk factors limiting survival. All of these factors except the duration of operation had also a significant independent influence on observed 15-year survival (AUROC = 0.739). CONCLUSIONS: Recipients can exceptionally live longer than their normal life expectancy. Older recipients and patients with the indications HCC, HCV-cirrhosis, or other indications except PSC, should be transplanted with younger donor organs.

Statistical approach to quality assessment in liver transplantation.

PURPOSE: This study investigated the utility of retrospective two one-sided cumulative sum (CUSUM) charts combined with multivariable regression analysis in liver transplantation for transplant center benchmarking. METHODS: One thousand seven hundred and forty-nine consecutive adult primary liver transplants (January 1, 1983 to December 31, 2012) were analyzed retrospectively with two one-sided CUSUM chart analysis of 90-day mortality. RESULTS: Three eras and two subseries in latest era 3 were identified due to graphically delineated relevant shifts in mean 90-day mortality. Delineation of eras 1, 2, and 3 coincided with relevant changes in allocation policies. CUSUM analysis detected a resurgence of higher mean 90-day mortality in era 3 after results had improved continuously over 25 years. In era 3, two subseries were identified with improving mean 90-day mortality rates from 15.4% in subseries 1 to 8.9% in the following subseries 2. The quantitative influence of independent risk factors on 90-day mortality differed markedly between all identified eras and subseries as assessed with multivariable regression analysis deployed on era-specific subcohorts. CONCLUSION: The assessed methodology is able to identify meaningful center-specific eras and subseries of liver transplantation with striking alterations of the significance and weight of outcome drivers for post-transplant 90-day mortality over time. This warrants the introduction of prospective risk-adjusted two one-sided CUSUM chart analysis into quality management in liver transplantation in Germany with the goal to obtain alarm signals as early as possible.

Risk Balancing of Cold Ischemic Time against Night Shift Surgery Possibly Reduces Rates of Reoperation and Perioperative Graft Loss.

Background. This retrospective cohort study evaluates the advantages of risk balancing between prolonged cold ischemic time (CIT) and late night surgery. Methods. 1262 deceased donor kidney transplantations were analyzed. Multivariable regression was used to determine odds ratios (ORs) for reoperation, graft loss, delayed graft function (DGF), and discharge on dialysis. CIT was categorized according to a forward stepwise pattern ≤1h/>1h, ≤2h/>2h, ≤3h/>3h,…, ≤nh/>nh. ORs for DGF were plotted against CIT and a nonlinear regression function with best R2 was identified. First and second derivative were then implemented into the curvature formula k(x) = f''(x)/(1 + f'(x)2)3/2 to determine the point of highest CIT-mediated risk acceleration. Results. Surgery between 3 AM and 6 AM is an independent risk factor for reoperation and graft loss, whereas prolonged CIT is only relevant for DGF. CIT-mediated risk for DGF follows an exponential pattern f(x) = A · (1 + k · e(I · x)) with a cut-off for the highest risk increment at 23.5 hours. Conclusions. The risk of surgery at 3 AM-6 AM outweighs prolonged CIT when confined within 23.5 hours as determined by a new mathematical approach to calculate turning points of nonlinear time related risks. CIT is only relevant for the endpoint of DGF but had no impact on discharge on dialysis, reoperation, or graft loss.

Matched-pair analysis: identification of factors with independent influence on the development of PTLD after kidney or liver transplantation.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) adversely affects patients' long-term outcome. METHODS: The paired t test and McNemar's test were applied in a retrospective 1:1 matched-pair analysis including 36 patients with PTLD and 36 patients without PTLD after kidney or liver transplantation. Matching criteria were age, gender, indication, type of transplantation, and duration of follow-up. All investigated PTLD specimen were histologically positive for EBV. Risk-adjusted multivariable regression analysis was used to identify independence of risk factors for PTLD detected in matched-pair analysis. The resultant prognostic model was assessed with ROC-curve analysis. RESULTS: Patients suffering with PTLD had shorter mean survival (p = 0.004), more episodes of CMV infections or reactivations (p = 0.042), and fewer recipient HLA A2 haplotypes (p = 0.007), a tacrolimus-based immunosuppressive regimen (p = 0.052) and higher dosages of tacrolimus at hospital discharge (Tac dosage) (p = 0.052). Significant independent risk factors for PTLD were recipient HLA A2 (OR = 0.07, 95 % CI = 0.01-0.55, p = 0.011), higher Tac dosages (OR = 1.29, 95 % CI = 1.01-1.64, p = 0.040), and higher numbers of graft rejection episodes (OR = 0.38, 95 % CI = 0.17-0.87, p = 0.023). The following prognostic model for the prediction of PTLD demonstrated good model fit and a large area under the ROC curve (0.823): PTLD probability in % = Exp(y)/(1 + Exp(y)) with y = 0.671 - 1.096 × HLA A2-positive recipient + 0.151 × Tac dosage - 0.805 × number of graft rejection episodes. CONCLUSIONS: This study suggests prognostic relevance for recipient HLA A2, CMV, and EBV infections or reactivations and strong initial tacrolimus-based immunosuppression. Patients with risk factors may benefit from intensified screening for PTLD.

New Fixed-Dose Combinations of Fenofibrate/Simvastatin Therapy Significantly Improve the Lipid Profile of High-Risk Patients with Mixed Dyslipidemia Versus Monotherapies.

AIMS: Guidelines propose additional therapy to statin to treat elevated triglycerides (TG) and low high-density lipoprotein cholesterol (HDLC) in dyslipidemic patients. We evaluated the effects of new fixed-dose combinations (FDC) of fenofibrate/simvastatin on plasma lipids versus simvastatin or fenofibrate monotherapies. METHODS: Subjects with mixed dyslipidemia at high or very high cardiovascular risk on stable statin therapy for at least 3 months were included in a randomized, double-blind, active-control, parallel-group study. Patients were treated with FDC fenofibrate/simvastatin 145/20 mg or 145/40 mg, simvastatin 20 mg or 40 mg, or fenofibrate 145 mg for 12 weeks. Plasma lipids, C-reactive protein, and cystatin C were measured before and after treatments. Differences in % changes were compared between FDC fenofibrate/simvastatin and monotherapies. RESULTS: Significant differences between FDC fenofibrate/simvastatin and simvastatin monotherapies were observed for the % change of TG (LS mean difference [two-sided 95% CI]: -32.2% [-38.6%, -25.8%], P < 0.001) and HDL-C (7.5% [4.7%, 10.2%], P < 0.001). A significant difference between the FDC fenofibrate/simvastatin and fenofibrate was observed for LDLC % changes (-34.7% [-40.8%, -28.5%], P < 0.001). Significant differences between FDC fenofibrate/simvastatin and their respective monotherapies were also observed for Apo B and non-HDLC % changes. The FDC were well tolerated with a similar safety profile compared with monotherapies. CONCLUSIONS: FDC fenofibrate/simvastatin are effective and well-tolerated therapies to improve the TG and HDLC profile in high-risk patients with mixed dyslipidemia.