Log-Rank Test vs MaxCombo and Difference in Restricted Mean Survival Time Tests for Comparing Survival Under Nonproportional Hazards in Immuno-oncology Trials: A Systematic Review and Meta-analysis.

Importance: The log-rank test is considered the criterion standard for comparing 2 survival curves in pivotal registrational trials. However, with novel immunotherapies that often violate the proportional hazards assumptions over time, log-rank can lose power and may fail to detect treatment benefit. The MaxCombo test, a combination of weighted log-rank tests, retains power under different types of nonproportional hazards. The difference in restricted mean survival time (dRMST) test is frequently proposed as an alternative to the log-rank under nonproportional hazard scenarios. Objective: To compare the log-rank with the MaxCombo and dRMST in immuno-oncology trials to evaluate their performance in practice. Data Sources: Comprehensive literature review using Google Scholar, PubMed, and other sources for randomized clinical trials published in peer-reviewed journals or presented at major clinical conferences before December 2019 assessing efficacy of anti-programmed cell death protein-1 or anti-programmed death/ligand 1 monoclonal antibodies. Study Selection: Pivotal studies with overall survival or progression-free survival as the primary or key secondary end point with a planned statistical comparison in the protocol. Sixty-three studies on anti-programmed cell death protein-1 or anti-programmed death/ligand 1 monoclonal antibodies used as monotherapy or in combination with other agents in 35 902 patients across multiple solid tumor types were identified. Data Extraction and Synthesis: Statistical comparisons (n = 150) were made between the 3 tests using the analysis populations as defined in the original protocol of each trial. Main Outcomes and Measures: Nominal significance based on a 2-sided .05-level test was used to evaluate concordance. Case studies featuring different types of nonproportional hazards were used to discuss more robust ways of characterizing treatment benefit instead of sole reliance on hazard ratios. Results: In this systematic review and meta-analysis of 63 studies including 35 902 patients, between the log-rank and MaxCombo, 135 of 150 comparisons (90%) were concordant; MaxCombo achieved nominal significance in 15 of 15 discordant cases, while log-rank did not. Several cases appeared to have clinically meaningful benefits that would not have been detected using log-rank. Between the log-rank and dRMST tests, 137 of 150 comparisons (91%) were concordant; log-rank was nominally significant in 5 of 13 cases, while dRMST was significant in 8 of 13. Among all 3 tests, 127 comparisons (85%) were concordant. Conclusions and Relevance: The findings of this review show that MaxCombo may provide a pragmatic alternative to log-rank when departure from proportional hazards is anticipated. Both tests resulted in the same statistical decision in most comparisons. Discordant studies had modest to meaningful improvements in treatment effect. The dRMST test provided no added sensitivity for detecting treatment differences over log-rank.

Assessing the Influence of Subsequent Immunotherapy on Overall Survival in Patients with Unresectable Stage III Non-Small Cell Lung Cancer from the PACIFIC Study.

BACKGROUND: Historically, the standard of care for patients with unresectable, Stage III non-small cell lung cancer had been concurrent chemoradiotherapy. However, outcomes had been poor, with approximately 15% to 32% of patients alive at 5 years. In the placebo-controlled Phase III A PACIFIC trial, consolidation treatment with durvalumab after concurrent chemoradiotherapy significantly improved overall survival (OS) and progression-free survival in patients with unresectable, Stage III non-small cell lung cancer, establishing this regimen as a new standard of care in this setting. In the PACIFIC trial, crossover between treatment arms (durvalumab or placebo) was not permitted. However, after discontinuation from study treatment, patients from both arms of PACIFIC could switch to subsequent anticancer therapy, including durvalumab and other immunotherapies, which is known to influence standard intention-to-treat analysis of OS, potentially underestimating the effect of an experimental drug. Moreover, the introduction of immunotherapies has demonstrated marked improvements in the postprogression, metastatic non-small cell lung cancer setting. OBJECTIVE: To examine the influence of subsequent immunotherapy on OS in the PACIFIC trial. METHODS: Both a Rank Preserving Structural Failure Time Model (RPSFTM) and modified 2-stage method were used. RPSFTM assumes that a patient's survival time with no immunotherapy (counterfactual survival time) is equal to the observed time influenced by immunotherapy, multiplied by an acceleration factor, plus the time not influenced. The modified 2-stage method estimates the effect of immunotherapy by comparing postsubsequent-treatment-initiation survival times between patients with and without subsequent immunotherapy. In both models, OS was adjusted to reflect a hypothetical scenario in which no patients received subsequent immunotherapy. RPSFTM was also used for scenarios in which subsequent immunotherapy was received by increasing proportions of placebo patients but none of the durvalumab patients. RESULTS: In the intention-to-treat analysis (3-year follow-up), durvalumab improved OS versus placebo (stratified hazard ratio = 0.69; 95% CI, 0.55-0.86). Overall, 10% and 27% of durvalumab and placebo patients, respectively, received subsequent immunotherapy. With subsequent immunotherapy removed from both arms, estimated hazard ratio was 0.66 (95% CI, 0.53-0.84) with RPSFTM and 0.68 (95% CI, 0.54-0.85) with the modified 2-stage method. With subsequent immunotherapy removed from the durvalumab arm only (RPSFTM), estimated hazard ratio increased as the proportion of placebo patients receiving subsequent immunotherapy increased, up to 0.75 (95% CI, 0.60-0.94) maximum (assuming all placebo patients with subsequent treatment received immunotherapy). CONCLUSIONS: Results were consistent with the intention-to-treat analysis, supporting the conclusion that durvalumab after chemoradiotherapy provides substantial OS benefit in patients with Stage III, unresectable non-small cell lung cancer. ClinicalTrials.gov identifier: NCT02125461 (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX).

SAEgnal: A Predictive Assessment Framework for Optimizing Safety Profiles in Immuno-Oncology Combination Trials.

Combination therapies are an emerging drug development strategy in cancer, particularly in the immunooncology (IO) space. Many combination studies do not meet their safety objectives due to serious adverse events (SAEs). Prediction of SAEs based on evidence from single and combination studies would be highly beneficial. To address the emerging challenge of optimizing the safety and efficacy of combination studies, we have assembled a novel oncology clinical trial data set with 329 trials, 685 arms (279 unique treatment arms), including 200 combinations, 79 mono arms, and 59 curated adverse event categories in the setting of non-small cell lung cancer (NSCLC). We integrated the database with an analytical framework: SAEgnal. Using SAEgnal, we have investigated the difference in the risk of 39 adverse event types between combination and monotherapy arms across a subset of 34 combination trials. We observed different risk profiles between combination and monotherapies; interestingly, while the risk of elevated AST/ALT is lower in combination arms (in 1/8 trials, p-value < 0.05), it is higher for bleeding (7/8 trials, p-value < 0.05). We envisage that the SAEgnal framework would enable rapid predictive analytics of SAEs in oncology and accelerate drug development in oncology.

Correlation Between Early Endpoints and Overall Survival in Non-Small-Cell Lung Cancer: A Trial-Level Meta-Analysis.

Early endpoints, such as progression-free survival (PFS), are increasingly used as surrogates for overall survival (OS) to accelerate approval of novel oncology agents. Compiling trial-level data from randomized controlled trials (RCTs) could help to develop a predictive framework to ascertain correlation trends between treatment effects for early and late endpoints. Through trial-level correlation and random-effects meta-regression analysis, we assessed the relationship between hazard ratio (HR) OS and (1) HR PFS and (2) odds ratio (OR) PFS at 4 and 6 months, stratified according to the mechanism of action of the investigational product. Using multiple source databases, we compiled a data set including 81 phase II-IV RCTs (35 drugs and 156 observations) of patients with non-small-cell lung cancer. Low-to-moderate correlations were generally observed between treatment effects for early endpoints (based on PFS) and HR OS across trials of agents with different mechanisms of action. Moderate correlations were seen between treatment effects for HR PFS and HR OS across all trials, and in the programmed cell death-1/programmed cell death ligand-1 and epidermal growth factor receptor trial subsets. Although these results constitute an important step, caution is advised, as there are some limitations to our evaluation, and an additional patient-level analysis would be needed to establish true surrogacy.

Relationship Between Progression-Free Survival, Objective Response Rate, and Overall Survival in Clinical Trials of PD-1/PD-L1 Immune Checkpoint Blockade: A Meta-Analysis.

PD-1/PD-L1 immune checkpoint blockade (ICB) has improved overall survival (OS) in solid tumor trials; however, parallel improvements in Response Evaluation Criteria in Solid Tumors (RECIST)-based surrogate end points, progression-free survival (PFS), and objective response rate (ORR), are not always observed. Here, we assess the surrogacy of PFS/ORR for OS with ICB therapy across advanced/metastatic tumors. In a trial-level analysis (N = 40 randomized trials), PFS, ORR, and OS treatment effects were correlated (Spearman's rho). In a patient-level analysis, data were extracted from available trials of durvalumab; the correlation of PFS and OS was evaluated (Bayesian normal-induced-copula-estimation model) and the ordinal association between objective response and OS hazard ratio (HR) were assessed with concordance index measures. High correlation was observed between PFS HR and OS HR in intention-to-treat (ITT; rho = 0.76) and PD-L1-enriched populations (0.74); modest (or limited) benefit in PFS was associated with meaningful improvement in OS. Moderate correlations were observed between ΔORR and OS HR: ITT, -0.63; PD-L1-enriched, -0.53. At the patient level, a positive association was observed between PFS and OS in non-small cell lung cancer (Kendall's Tau = 0.793; 95% confidence interval, 0.789-0.797), head and neck squamous cell carcinoma (0.794; 0.789-0.798), and bladder cancer (0.872; 0.869-0.875). Objective responders had significantly better OS (concordance index > 0.9) than nonresponders across these tumor types. Modest (or limited) improvement in RECIST-based end points did not rule out meaningful OS benefit, indicating they are imperfect surrogates and do not fully capture ICB clinical benefit. Therefore, caution is advised when basing early discontinuation of novel ICB agents on these end points.

Optimal PD-L1-high cutoff for association with overall survival in patients with urothelial cancer treated with durvalumab monotherapy.

BACKGROUND: Studies have indicated that programmed death ligand 1 (PD-L1) expression may have utility as a predictive biomarker in patients with advanced/metastatic urothelial carcinoma (UC). Different immunohistochemical (IHC) assays are in development to assess PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs). METHODS: In this post hoc analysis of the single-arm, phase 1/2 Study 1108 (NCT01693562), PD-L1 expression was evaluated from tumor samples obtained prior to second-line treatment with durvalumab in patients with advanced/metastatic UC using the VENTANA (SP263) IHC Assay. The primary objective was to determine whether the TC ≥ 25%/IC ≥ 25% algorithm (i.e., cutoff of ≥ 25% TC or ≥ 25% IC with PD-L1 staining at any intensity above background) was optimal for predicting response to durvalumab. PD-L1 expression data were available from 188 patients. RESULTS: After a median follow-up of 15.8 and 14.6 months, higher PD-L1 expression was associated with longer overall survival (OS) and progression-free survival (PFS), respectively, with significant separation in survival curves for PD-L1-high and-low expressing patients for the TC ≥ 25%/IC ≥ 25% cutoff (median OS: 19.8 vs 4.8 months; hazard ratio: 0.46; 90% confidence interval: 0.33, 0.639). OS was also prolonged for PD-L1-high compared with-low patients when samples were categorized using TC/IC combined positive score ≥ 10 and IC≥ 5% cutoffs. In multivariate analysis, IC but not TC PD-L1 expression was significantly associated with OS, PFS, and objective response rate (P < 0.001 for each), although interaction analysis showed similar directionality of benefit for ICs and TCs. CONCLUSIONS: These findings support the utility of a combined TC/IC algorithm for predicting response to durvalumab in patients with UC, with the TC≥ 25%/IC≥ 25% cutoff optimal when used with the VENTANA (SP263) IHC Assay.

Statistical and practical considerations in designing of immuno-oncology trials.

The novel mechanism of action of immunotherapy agents, in treatment of various types of cancer, poses unique challenges during the designing of clinical trials. It is important to account for possibility of a delayed treatment effect and adjust sample size accordingly. This paper provides an analytical approach for computing sample size in the presence of a delayed effect using a piece-wise proportional hazards model. Failing to account for an anticipated treatment delay may result in considerable loss in power. The overall hazard ratio (HR), which now represents the average HR across the entire treatment period, can remain a meaningful measure of average benefit to patients in the trial. We show that, special consideration needs to be given for the designing of interim analyses related to futility, so as not to increase the probability of incorrectly stopping an effective agent. It is shown that the weighted log-rank test, using the Fleming-Harrington class of weights, can be used as supportive analysis to better reflect the impact of a delayed effect and possible long-term benefit in a subset of the overall population.

Patient-reported outcomes and inflammatory biomarkers in patients with locally advanced/metastatic urothelial carcinoma treated with durvalumab in phase 1/2 dose-escalation study 1108.

BACKGROUND: Durvalumab has shown meaningful clinical activity in patients with metastatic urothelial carcinoma (mUC) in Study 1108 (NCT01693562). An important focus in treatment is health-related quality of life (HRQOL). Here, patient-reported outcomes (PROs) from Study 1108 and their relationship with inflammatory biomarkers are explored. METHODS: Disease-related symptoms, functioning, and HRQOL were assessed with the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30). Relationships between PRO improvements and the best changes in the tumor size, albumin level, and neutrophil-lymphocyte ratio (NLR) were assessed with Spearman correlation analysis. RESULTS: The mean FACT-Bl total score improved from 107.5 (standard deviation [SD], 23.0) at the baseline to 115.4 (SD, 22.6) on day 113, with similar increases found for the Trial Outcome Index (TOI) and Bladder Cancer Subscale (BLCS) scores. The mean FACT-Bl total scores improved over time, and the FACT-Bl TOI scores significantly improved by day 113 (P < .05). The mean EORTC QLQ-C30 Global Health Status/Quality of Life score improved from 57.1 (SD, 24.8) at the baseline to 69.0 (SD, 21.4) on day 113; the functional scale and symptom scores (day 113) were higher than the baseline scores (P < .05) for EORTC Social Functioning. The FACT-Bl total, BLCS, and TOI scores improved in 32.6%, 34.9%, and 32.6% of the patients by day 113; 26.3% to 37.8% of the patients exhibited improvements in EORTC QLQ-C30 functional scores. The best tumor shrinkage and posttreatment improvements in serum albumin and NLR correlated with increases in FACT-Bl total, TOI, and BLCS scores and in EORTC Physical Functioning and Role Functioning scores (P < .05). CONCLUSIONS: Durvalumab was associated with improvements in disease-related symptoms, functioning, and HRQOL in patients with mUC. Improvements in systemic inflammation may contribute to PRO improvements in these patients.

Prognostic Significance of Liver Metastasis in Durvalumab-Treated Lung Cancer Patients.

INTRODUCTION: Two clinical studies (Study 1108 and ATLANTIC) were analyzed to evaluate the prognostic value of baseline liver metastases (LMs) in advanced/metastatic non-small-cell lung cancer patients treated with durvalumab 10 mg/kg every 2 weeks. PATIENTS AND METHODS: A multivariate Cox proportional hazards analysis was conducted; covariates included performance status, tumor stage, histology, sex, age, smoking status, and programmed cell death ligand 1 (PD-L1) status. RESULTS: In all, 569 patients were included. LMs were present in 31.6% (96/304) of Study 1108 patients and 17.9% (47/263) of ATLANTIC patients. Median overall survival (OS) was shorter in patients with LMs than in those without in both studies. In both studies, LMs were an independent negative prognostic factor for OS and progression-free survival. Objective response rates were also significantly lower. PD-L1 independently predicted benefit across all patients. CONCLUSION: Liver metastases were associated with worse outcomes irrespective of PD-L1 status, but PD-L1 status predicted benefit from durvalumab irrespective of LMs.

Estimating Lifetime Benefits Associated with Immuno-Oncology Therapies: Challenges and Approaches for Overall Survival Extrapolations.

BACKGROUND: Standard parametric survival models are commonly used to estimate long-term survival in oncology health technology assessments; however, they can inadequately represent the complex pattern of hazard functions or underlying mechanism of action (MoA) of immuno-oncology (IO) treatments. OBJECTIVE: The aim of this study was to explore methods for extrapolating overall survival (OS) and provide insights on model selection in the context of the underlying MoA of IO treatments. METHODS: Standard parametric, flexible parametric, cure, parametric mixture and landmark models were applied to data from ATLANTIC (NCT02087423; data cut-off [DCO] 3 June 2016). The goodness of fit of each model was compared using the observed survival and hazard functions, together with the plausibility of corresponding model extrapolation beyond the trial period. Extrapolations were compared with updated data from ATLANTIC (DCO 7 November 2017) for validation. RESULTS: A close fit to the observed OS was seen with all models; however, projections beyond the trial period differed. Estimated mean OS differed substantially across models. The cure models provided the best fit for the new DCO. CONCLUSIONS: Standard parametric models fitted to the initial ATLANTIC DCO generally underestimated longer-term OS, compared with the later DCO. Cure, parametric mixture and response-based landmark models predicted that larger proportions of patients with metastatic non-small cell lung cancer receiving IO treatments may experience long-term survival, which was more in keeping with the observed data. Further research using more mature OS data for IO treatments is needed.

Population Modeling of Tumor Kinetics and Overall Survival to Identify Prognostic and Predictive Biomarkers of Efficacy for Durvalumab in Patients With Urothelial Carcinoma.

Durvalumab is an anti-PD-L1 monoclonal antibody approved for patients with locally advanced or metastatic urothelial carcinoma (UC) that has progressed after platinum-containing chemotherapy. A population tumor kinetic model, coupled with dropout and survival models, was developed to describe longitudinal tumor size data and predict overall survival in UC patients treated with durvalumab (NCT01693562) and to identify prognostic and predictive biomarkers of clinical outcomes. Model-based covariate analysis identified liver metastasis as the most influential factor for tumor growth and immune-cell PD-L1 expression and baseline tumor burden as predictive factors for tumor killing. Tumor or immune-cell PD-L1 expression, liver metastasis, baseline hemoglobin, and albumin levels were identified as significant covariates for overall survival. These model simulations provided further insights into the impact of PD-L1 cutoff values on treatment outcomes. The modeling framework can be a useful tool to guide patient selection and enrichment strategies for immunotherapies across various cancer indications.

Population Pharmacokinetics of Durvalumab in Cancer Patients and Association With Longitudinal Biomarkers of Disease Status.

The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, an anti-PD-L1 antibody, and quantify the impact of baseline and time-varying patient/disease characteristics on PK. Pooled data from two studies (1,409 patients providing 7,407 PK samples) were analyzed with nonlinear mixed effects modeling. Durvalumab PK was best described by a two-compartment model with both linear and nonlinear clearances. Three candidate models were evaluated: a time-invariant clearance (CL) model, an empirical time-varying CL model, and a semimechanistic time-varying CL model incorporating longitudinal covariates related to disease status (tumor shrinkage and albumin). The data supported a slight decrease in durvalumab clearance with time and suggested that it may be associated with a decrease in nonspecific protein catabolic rate among cancer patients who benefit from therapy. No covariates were clinically relevant, indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following weight-based and flat-dosing regimens.

Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer.

OBJECTIVE: The purpose of this multicenter, open label, randomized phase III study was to determine whether ixabepilone resulted in improved overall survival (OS) compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel) in women with locally advanced, recurrent, or metastatic endometrial cancer with at least one failed prior platinum-based chemotherapeutic regimen. METHODS: Patients were randomized 1:1 to ixabepilone (40mg/m(2)), or either paclitaxel (175mg/m(2)) or doxorubicin (60mg/m(2)), every 21days. Patients that had previously received an anthracycline were randomized to ixabepilone or paclitaxel; all other patients were randomized to ixabepilone or doxorubicin. An interim analysis of futility for OS was planned. RESULTS: At the time of database lock, 496 patients were randomized to receive ixabepilone (n=248) or control (n=248); nine patients in the control arm were not treated. The interim analysis of futility for OS (219 events) favored the control chemotherapy arm (hazard ratio=1.3 [95% confidence interval: 1.0-1.7], stratified log rank test P=0.0397), indicating that the study would not meet its primary objective. The study was discontinued based on the interim OS results. The frequency of adverse events was comparable between the treatment arms. CONCLUSIONS: The study did not meet its primary objective of improving OS in the ixabepilone arm compared to the control chemotherapy arm. A favorable risk/benefit ratio was not observed for ixabepilone versus control at the time of the interim analysis. The safety results were consistent with the known safety profiles of ixabepilone and control.

Relationship between treatment effects on progression-free survival and overall survival in multiple myeloma: a systematic review and meta-analysis of published clinical trial data.

BACKGROUND: Demonstrating improved overall survival (OS) with new multiple myeloma (MM) treatments is becoming difficult because of extended survival, so progression-free survival (PFS) is commonly used as a surrogate endpoint for OS. We evaluated PFS as a potential surrogate for OS by examining whether observed treatment effects on PFS are positively associated with treatment effects on OS in MM. METHODS: A systematic literature review identified 21 randomized control trials reporting hazard ratios (HRs) for treatment effects on PFS and OS. Pearson's r estimated the relationship between HRs (HRPFS and HROS), and between log-transformed HRs (log(HRPFS) and log(HROS)). R(2) values were estimated from linear regression models of the HR and the log(HR) relationships. Sensitivity and subgroup analyses examined the robustness of the HR findings. RESULTS: Positive correlations were found between HRPFS and HROS (r = 0.82; p < 0.0001) and between log(HRPFS) and log(HROS) (r = 0.80; p < 0.0001). Linear regression models produced R(2) values of 0.67 and 0.63 when regressing HROS on HRPFS, and log(HROS) on log(HRPFS), respectively. Sensitivity analyses supported the HR findings. CONCLUSION: This analysis provides evidence for a positive association between treatment effects on PFS and OS. Studies involving patient level data are necessary to confirm whether PFS is a valid surrogate for OS in MM.

A retrospective analysis of cross-reacting cetuximab IgE antibody and its association with severe infusion reactions.

Severe infusion reactions (SIRs) at rates of 5% or less are known side effects of biological agents, including mAbs such as cetuximab. There are currently no prospectively validated risk factors to aid physicians in identifying patients who may be at risk of experiencing an SIR following administration of any of these drugs. A retrospective analysis of 545 banked serum or plasma samples from cancer patients participating in clinical trials of cetuximab was designed to evaluate whether the presence of pretreatment IgE antibodies against cetuximab, as determined by a commercially available assay system, is associated with SIRs during the initial cetuximab infusion. Patients with a positive test indicating the presence of pretreatment antibodies had a higher risk of experiencing an SIR; however, at the prespecified cutoff utilized in this analysis, the test has a relatively low-positive predictive value (0.577 [0.369-0.766]) and a negative predictive value of 0.961 (0.912-0.987) in an unselected patient population. Data collected in this large retrospective validation study support prior observations of an association between the presence of pretreatment IgE antibodies cross-reactive with cetuximab and SIRs. Further analysis of the test's ability to predict patients at risk of an SIR would be required before this assay could be used reliably in this patient population.

Ixabepilone alone or with cetuximab as first-line treatment for advanced/metastatic triple-negative breast cancer.

BACKGROUND: Despite high initial sensitivity to chemotherapy, TNBC is associated with a poor prognosis, highlighting the need for novel therapeutic strategies. The aim of this multicenter, randomized, open-label phase II trial was to assess the efficacy of ixabepilone as monotherapy, and the combination of ixabepilone with cetuximab, as first-line treatment in patients with triple-negative locally advanced nonresectable and/or metastatic breast cancer. PATIENTS AND METHODS: Women were randomly assigned to receive either ixabepilone (40 mg/m(2)) every 21 days (n = 40), or ixabepilone (40 mg/m(2)) every 21 days with cetuximab (400 mg/m(2) loading dose, followed by 250 mg/m(2)) once weekly (n = 39). The primary end point of the trial was to estimate the response rates of ixabepilone monotherapy and ixabepilone with cetuximab combination therapy. RESULTS: Of 79 randomized patients, 77 were treated. Based on an intent-to-treat analysis, an objective response rate of 30% (95% confidence interval [CI], 16.6-46.5) was observed in the monotherapy arm, and 35.9% (95% CI, 21.2-52.8) in the combination arm. Median progression-free survival was 4.1 months in both treatment groups. Safety findings were consistent with the known individual toxicity profiles of ixabepilone and cetuximab. Skin and subcutaneous tissue disorders were more common with combination therapy, as were discontinuations because of adverse events. CONCLUSION: Ixabepilone monotherapy and the ixabepilone and cetuximab combination demonstrated similar levels of clinical activity in first-line treatment of advanced TNBC, with a predictable safety profile. Further investigation of novel therapies for TNBC is required to improve patient outcomes.

Phase II randomized trial of weekly and every-3-week ixabepilone in metastatic breast cancer patients.

This multicenter, open-label, randomized phase II trial compared the efficacy and tolerability of weekly ixabepilone versus the standard 3 weekly dosing regimen. Patients with human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC) were randomly assigned to receive either ixabepilone 16 mg/m(2) as a 1-h intravenous (IV) infusion weekly on days 1, 8, and 15 of a 28-day cycle (1 week off therapy; n = 85), or 40 mg/m(2) as a 3-h IV infusion on day 1 of a 21-day cycle (n = 91), until disease progression or unacceptable toxicity. Randomization was stratified by (i) measurable versus nonmeasurable (evaluable) disease, (ii) ≤two versus >two prior chemotherapy regimens for MBC, and (iii) hormone receptor (HR)-positive versus HR-negative breast cancer. The primary endpoint was rate of progression-free survival (PFS) at 6 months. Of 176 randomized patients, 171 were treated. The 6-month PFS rate was significantly higher in patients treated with ixabepilone every 3 weeks (42.7, 95 % confidence interval [CI] 31.5-53.5) compared with those who received ixabepilone weekly (28.6, 95 % CI 18.9-38.9; log-rank P = 0.03). Every-3-week dosing significantly prolonged median PFS versus weekly dosing (5.3 vs. 2.9 months; log-rank P = 0.05). The every-3-week regimen was associated with higher rates of grade 3/4 toxicities, particularly neutropenia (38.2 vs. 6.1 %) and a higher rate of patient withdrawal due to adverse events. These results suggest that every-3-week ixabepilone is more effective than weekly treatment in MBC, albeit with more toxicity.