Trials In Metastatic Breast Cancer Research Articles

Overall survival (OS) in metastatic breast cancer (MBC): Are we using the right endpoint in the right way?

142 Background: OS has been historically considered the most important clinical endpoint in MBC trials; however survival could be influenced by treatment after progression in an era of effective subsequent-line agents. Methods: We conducted a search strategy using PubMed for randomized phase 3 trials published in the last 2 decades (1994-2014) evaluating survival outcome in MBC. We investigated the frequency of trials reporting post progression outcome and response/resistance to treatment beyond progression. Results: 110 trials met our eligibility criteria: 69 (63%) evaluated chemotherapy regimens (group A), 27 (25%) evaluated targeted therapy (group B) and 14 (13%) focused on endocrine treatment (group C). The majority of the trials had OS as a primary or secondary endpoint (97% (66/69), 100% (27/27) and 86% (12/14) of the trials in group A, B and C respectively). An OS benefit was demonstrated in approximately 22% of the trials in each group. Post progression survival (PPS) and its effect on OS was reported and discussed in only 1% (1/69), 4% (1/27) and 7% (1/14) of the trials for group A, B and C respectively. Less than 10% of the trials in group A and B reported response data and duration of response after progression on trial therapy. In addition, post progression treatment resistance was only reported in group A in 3% (2/69) of the trials. Furthermore, the number of lines of treatment used post progression was reported in only 14% (10/69), 11% (3/27) and 14% (2/14) of the trials in group A, B and C respectively. Conclusions: A clear paucity of post progression treatment information is noted in the majority of the phase 3 trials for MBC. We do know that OS is directly affected by treatments used after progression. In order to assess the true clinical benefit of a new drug and a complete evaluation of overall survival outcome, a detailed collection of post progression treatment information is required and should be mandated in MBC clinical studies.

A systematic review of gemcitabine and taxanes combination therapy randomized trials for metastatic breast cancer.

PurposeGemcitabine/taxanes-based combination shows anti-tumor activity for the treatment of metastatic breast cancer, but there is a debate regarding the advantages of gemcitabine and taxanes regimens as a first-line or second-line treatment for metastatic breast cancer. Here we conducted a systematic review and meta-analysis to compare the efficacy and toxicity for patients receiving chemotherapy with or without GT-based regimens.MethodsThe randomized controlled trials were performed by searching Pubmed, MEDLINE, EMBASE, and conference proceedings. We identified eight randomized controlled trials and then extracted and combined the data using to calculate hazard ratios (HR). The primary outcomes were progression-free survival (PFS) and time to progression (TTP). The secondary outcomes were overall survival (OS) and acute toxicity. A meta-analysis was performed using Review Manager Version 4.2.ResultsEight eligible trails were identified. These studies involved 2234 patients with metastatic breast cancer, (1122 patients received GT-based combination regimen and 1112 patients received a regimen without the combination). A fixed-effects model meta-analysis showed that ORR and TTP are superior for GT-treated patients ORR (OR = 1.28, 95% CI 1.07-1.53), TTP (HR = 0.80; 95% CI 0.71-0.89). And GT-based combination significantly improved OS in the first-line subgroup (HR = 0.84; 95% CI 0.71-0.99). However, there were significant differences regarding acute hematological toxicity, particularly thrombocytopenia.ConclusionGemcitabine/taxanes-treated patients with metastatic breast cancer showed a significant improvement in the ORR, TTP and OS (first-line background) compared to patients not treated with the combination regimen.

Treatment ofpatients (pts) with HER2- metastatic breast cancer (MBC) with nab-paclitaxel (nab-P) in the clinical practice setting—Results of a US Oncology survey.

e12008 Background: Different dosages/schedules of nab-P (ie, 260 mg/m2 q3w, 100 mg/m2 qw, and 150 mg/m2 qw) have been assessed in phase 2/3 trials of MBC. However, limited information exists on the use of nab-P in the community setting. Here we report on experience with nab-P for the treatment of HER2− MBC and pt characteristics that impact nab-P treatment patterns in the community practice setting. Methods: From 9/6 to 10/21, 2013, US Oncology network physicians completed 30-question, web-based surveys on nab-P utilization, toxicity frequency, management, and duration. Responses were analyzed categorically by pt characteristics and proportional nab-P utilization. High (H) nab-P users were defined as those with ≥ 33% of HER2− pts who received nab-P. Results: 104/428 responded; 84% were from large practices (≥ 16 oncologists) and 56% were H nab-P users. For first- and second-line treatment, 100 mg/m2 qw (51% and 58%) was the most common starting dosage/schedule followed by 125 mg/m2 qw (22% and 14%), while...

PRM73 - Survival modeling for the estimation of transition probabilities in model-based economic evaluations in the absence of individual patient data: A tutorial

Survival modeling techniques are increasingly being used as part of decision modeling for health economic evaluations. As many models are available, it is imperative for interested readers to know about the steps in selecting and using the most suitable ones. The objective of this paper is to propose a tutorial for the application of appropriate survival modeling techniques to estimate transition probabilities, for use in model-based economic evaluations, in the absence of individual patient data (IPD). An illustration of the use of the tutorial is provided based on the final progression-free survival (PFS) analysis of the BOLERO-2 trial in metastatic breast cancer (mBC). An algorithm was adopted from Guyot and colleagues, and was then run in the statistical package R to reconstruct IPD, based on the final PFS analysis of the BOLERO-2 trial. It should be emphasized that the reconstructed IPD represent an approximation of the original data. Afterwards, we fitted parametric models to the reconstructed IPD in the statistical package Stata. Both statistical and graphical tests were conducted to verify the relative and absolute validity of the findings. Finally, the equations for transition probabilities were derived using the general equation for transition probabilities used in model-based economic evaluations, and the parameters were estimated from fitted distributions. The results of the application of the tutorial suggest that the log-logistic model best fits the reconstructed data from the latest published Kaplan–Meier (KM) curves of the BOLERO-2 trial. Results from the regression analyses were confirmed graphically. An equation for transition probabilities was obtained for each arm of the BOLERO-2 trial. In this paper, a tutorial was proposed and used to estimate the transition probabilities for model-based economic evaluation, based on the results of the final PFS analysis of the BOLERO-2 trial in mBC. The results of our study can serve as a basis for any model (Markov) that needs the parameterization of transition probabilities, and only has summary KM plots available.

Abstract P3-13-03: A phase III, open-label, randomized study of eribulin versus capecitabine in patients (pts) with metastatic breast cancer (MBC): Effect of post-progression anti-cancer treatments (PPT) and metastatic progression events on overall survival

Abstract Background A Phase III trial (Study 301; NCT00337103) in MBC comparing eribulin (E) with capecitabine (C) showed a trend for improved overall survival (OS) (hazard ratio [HR] 0.88; 95% CI 0.77, 1.00; P = 0.056) but not progression-free survival (PFS) (HR 1.08; 95% CI 0.93, 1.25; P = 0.30) with E. In order to investigate this apparent discordance, post-hoc analyses assessed the effect of PPT and events defining disease progression on OS. Methods Pts with locally advanced or MBC who had received an anthracycline and a taxane (≤2 prior chemotherapy regimens for advanced disease), were randomized to E (554) or C (548). Co-primary endpoints were OS and PFS. The impact of PPT on OS was assessed by analysis of exploratory PPT subgroups. Analyses of OS sensitivity censoring at time of PPT, and OS adjusted by PPT as a time-dependent covariate in a Cox regression model, were performed. The relationship between OS and progression events (appearance of a “new” lesion or metastasis [NM]; increase in size of pre-existing lesions [IPEL]; or other [death, clinical progression, or censored]) was investigated using Cox regression. Results PPT was received by 70% and 62% of E and C pts, respectively. For E pts, there were no significant OS differences by PPT (Table 1). Excluding 56 pts (22 E, 34 C) who received anti-HER2 therapy as PPT from the intent-to-treat OS analysis, OS was longer with E (HR 0.86; 95% CI 0.76, 0.99; nominal P = 0.03). OS sensitivity analysis censoring at time of PPT was consistent with the overall study results (HR 0.82; 95% CI 0.65, 1.03). Assessment of the overall effect of PPT, adjusting by PPT as a time-dependent covariate in a Cox regression model, showed that OS was longer with E (HR 0.85; 95% CI 0.75, 0.97; nominal P = 0.02). Progression due to NM or IPEL occurred in 271 and 147 of E pts, and 285 and 129 of C pts, respectively. Median OS was similar between arms in pts with IPEL and longer with E vs C in pts with NM (Table 2). Pts who progressed due to NM were at higher risk of death (HR 2.12; 95% CI 1.84, 2.43; nominal P<0.01). Conclusions Treatment with C or any other PPT after progression on E did not account for the trend in OS benefit with E observed in the primary analysis. Pts who progressed with NM had a worse prognosis than those with IPEL. The appearance of NM was highly correlated with OS, and the apparent discordance between PFS and OS seems to be related to these different progression events. Tab 1: OS by PPT after EPPTAll ptsC as 1stOther than C as 1stC at any timeOther than C at any timeNoneN554221169275115164Median OS, months (95% CI)15.9 (15.2, 17.6)18.3 (15.8, 20.9)19.9 (17.6, 24.0)19.6 (17.6, 21.5)18.0 (15.4, 22.7)7.4 (6.2, 9.1) Tab 2: OS by progression event Progression event NMIPELOther ECECECN271285147129136134Median OS, months (95% CI)15.5 (14.2, 17.5)12.9 (11.3, 14.5)17.4 (14.4, 19.7)17.4 (15.3, 20.9)16.7 (14.8, 24.2)15.5 (11.7, 18.3)HR (95% CI)0.81 (0.68, 0.97)1.13 (0.87, 1.46)0.78 (0.59, 1.03)Nominal P -value0.020.350.08Time to NM or death, months (95% CI)5.8 (5.2, 6.5)5.2 (4.3, 5.9)NANAHR (95% CI)0.90 (0.77, 1.05)NANANominal P-value0.17NANA Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-03.

Abstract OT3-1-01: A randomized phase II study of maintenance hormone therapy with or without capecitabine after induction chemotherapy with bevacizumab plus paclitaxel in hormone receptor positive and HER2 negative metastatic breast cancer (KBCSG-TR1214)

Abstract Background: The combination therapy of Bevacizumab (B) and Paclitaxel (P) has demonstrated to prolong progression free survival (PFS) in E2100 study. Because its PFS is very long, developing optimal therapeutic strategy of B+P, including management of toxicity is crucial. At the 1st International Consensus Conference for Advanced Breast Cancer, most experts agreed the maintenance endocrine therapy after effective induction chemotherapy. In KBCSG-TR 1214 study, we planned to examine the following clinical questions. 1. As a maintenance therapy, which is more effective either endocrine therapy alone (E) or endocrine therapy with Capecitabine (E+C)? 2. Can maintenance therapy reduce toxicity of B+P and restore patient's QOL.? 3. How effective is B+P re-challenge after failure of maintenance therapy? Methods: KBCSG-TR 1214 study is multicenter open-labeled randomized phaseII trial for HR-positive and HER2-nagative metastatic breast cancer(MBC) patients. Patients will receive B (10mg/kg q2w) in combination with P (90mg/m2 on day 1, 8, and 15 q4w) as an induction therapy. Patients without progression after 6 cycles of B+P will be randomized to E or E+C. Endocrine therapy will be chosen by their physician (treatment of physician's choice). Patients in E+C will receive endocrine therapy with Capecitabine 1657mg/m2 on day1 to 21 q4w. Stratification factors for randomization are menopausal status, presence of target lesion, number of prior endocrine therapies for MBC, with or without 1st line chemotherapy for MBC. After progression of maintenance therapy (E or E+C), B+P will be started again as a reintroduction therapy. Primary end point is PFS of maintenance therapy. Secondary end points include time to failure of strategy from randomization, efficacy of reintroduction therapy, overall survival and safety of induction therapy. Translational research is also planned. VEGF, angiopoetin-1, and apelin in plasma will be measured at four points (before induction therapy, at the beginning of the maintenance therapy and the re-induction therapy, and at the end of the trial). This study has just begun and planned 120 patients will be enrolled. (UMIN000008662). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-01.

Survival Modeling for the Estimation of Transition Probabilities in Model-Based Economic Evaluations in the Absence of Individual Patient Data: A Tutorial

Survival modeling techniques are increasingly being used as part of decision modeling for health economic evaluations. As many models are available, it is imperative for interested readers to know about the steps in selecting and using the most suitable ones. The objective of this paper is to propose a tutorial for the application of appropriate survival modeling techniques to estimate transition probabilities, for use in model-based economic evaluations, in the absence of individual patient data (IPD). An illustration of the use of the tutorial is provided based on the final progression-free survival (PFS) analysis of the BOLERO-2 trial in metastatic breast cancer (mBC). An algorithm was adopted from Guyot and colleagues, and was then run in the statistical package R to reconstruct IPD, based on the final PFS analysis of the BOLERO-2 trial. It should be emphasized that the reconstructed IPD represent an approximation of the original data. Afterwards, we fitted parametric models to the reconstructed IPD in the statistical package Stata. Both statistical and graphical tests were conducted to verify the relative and absolute validity of the findings. Finally, the equations for transition probabilities were derived using the general equation for transition probabilities used in model-based economic evaluations, and the parameters were estimated from fitted distributions. The results of the application of the tutorial suggest that the log-logistic model best fits the reconstructed data from the latest published Kaplan-Meier (KM) curves of the BOLERO-2 trial. Results from the regression analyses were confirmed graphically. An equation for transition probabilities was obtained for each arm of the BOLERO-2 trial. In this paper, a tutorial was proposed and used to estimate the transition probabilities for model-based economic evaluation, based on the results of the final PFS analysis of the BOLERO-2 trial in mBC. The results of our study can serve as a basis for any model (Markov) that needs the parameterization of transition probabilities, and only has summary KM plots available.

Surrogate endpoints in metastatic breast cancer treated with targeted therapies: an analysis of the first-line phase III trials

Progression-free survival (PFS) has not yet been established as a surrogate endpoint for overall survival (OS) in metastatic breast cancer (MBC). In particular, surrogacy has not been investigated with modern molecular agents. Randomized phase III trials for MBC were identified using a PubMed and EMBASE search. Correlations between PFS/time to progression (TTP), post-progression survival (PPS), response rate (RR) and OS were evaluated through a linear regression analysis. We also evaluated the potential of PFS to serve as a surrogate for OS in first-line trials exploring new drugs. Twenty trials with a total of 32 treatment arms and 10,138 patients were included. Spearman rank correlation coefficients (r s) between median PFS/TTP, RR and PPS with OS were 0.81 (95 % CI 0.58-0.92), 0.61 (95 % CI 0.59-0.63) and 0.73 (95 % CI 0.71-0.74). The correlation coefficient between hazard ratios in PFS/TTP and OS (HRPFS/TTP/HROS) was 0.73 (95 % CI 0.719-0.738; p < 0.00001); the slope of the regression line was 0.56 ± 0.0034, indicating that an agent producing a 10 % risk reduction for PFS will provide a 5.6 ± 0.34 % risk reduction for OS. In particular, the HRPFS/TTP/HROS correlation is stronger in an HER2-positive setting versus HER2-negative (r s = 0.91 vs. 0.67; p for difference <0.0001). These results suggest that improvements in PFS/TTP in MBC strongly correlate with improvements in OS with molecular agents, especially anti-HER2 therapeutics. Further analyses at patient-level data are required to confirm the surrogacy of PFS for OS with new agents.

Abstract C295: Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.

Abstract Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50&amp;lt;1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. PARP inhibition has also been shown to be effective in preclinical models of small cell lung cancer and Ewing sarcoma, possibly related to high PARP expression. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage escalation/expansion study. Expansion included cohorts of pts with BRCA-related cancers, small cell lung cancer (SCLC) and Ewing sarcoma (ES). Results: (As of July 29, 2013) In escalation, 39 pts were enrolled in 9 cohorts from 25 to 1100 µg/d with 1000 µg/d being the MTD related to dose-limiting hematologic toxicity. 38 pts have been enrolled in expansion including 25 patients with BRCA related cancers. For all 77 (63F/14M) pts, median age (range) is 52 (18-81), PS, 0 (0-1) and # of prior therapies 4 (1-13). Eight ES, 7 SCLC and 48 patients with deleterious BRCA mutations and breast (n=18), ovarian (n=28) or pancreatic (n=2) cancer were enrolled. BMN 673 demonstrated good oral bioavailability and a long half-life supporting daily dosing (ASCO 2013 Abstract 2580). One related grade 4 toxicity (thrombocytopenia) occurred. Related grade 3 adverse events have included fatigue, anemia, neutropenia and thrombocytopenia, all in fewer than 15% of patients. Dose-related inhibition of PARP activity in PBMC's was observed. Response, reduction in neutrophils and platelets and the need for blood transfusions and dose reductions appear to correlate with BMN 673 exposure.Overall, the objective response (including CA-125) and clinical benefit response rates are for all BRCA patients are 60.4% and 81%, respectively. Treatment is ongoing in 5 of 7 SCLC patients and 2 of 8 ES patients with no objective responses observed yet. Conclusions: BMN 673 is well tolerated with high objective and clinical benefit response rates in heavily pre-treated ovarian and breast cancer pts with deleterious germline BRCA mutations. A phase 3 trial in metastatic breast cancer is underway. Clinicaltrial.gov ID: NCT01286987 BRCA Breast and Ovarian CancerNBRCA Tumor TypeResponse18BreastCRPRSD &amp;gt; 12 weeksCBR*18Breast1 (6%)9 (50%)∧14 (78%)Response - 25 RECIST evaluable; 27 CA-125 evaluable28Ovarian28OvarianCRPRCA-1251 (4%)10 (40%)19 (70%)2PancreasCRPRSD ≥ 12 weeks2Pancreas0 (0%)0 (0%)2 (100%)**∧3 breast cancer responses are not yet confirmed; *CBR: clinical benefit response; **CA19-9 normalized in 1 patient Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C295. Citation Format: Zev A. Wainberg, Johann S. de Bono, Lida Mina, Jasgit Sachdev, Lauren Averett Byers, Rashmi Chugh, Charlie Zhang, Joshua W. Henshaw, Andrew Dorr, John Glaspy, Ramesh Ramanathan. Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C295.

Absence of pharmacokinetic drug–drug interaction of pertuzumab with trastuzumab and docetaxel

Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.

Impact of routine tumor genotyping on enrollment in targeted therapy trials for metastatic breast cancer (MBC): 4-year review.

145 Background: Major barriers to enrollment in therapeutic clinical trials (&lt;5% in United States) include low response rate in phase I/II trials and low enthusiasm among oncologists. Stratified clinical trial enrollment based on molecular profiling of tumors represents a potential paradigm shift in drug development. Here we assess the clinical utility of tumor genotyping for identification of oncogenic driver mutations and enrollment in therapeutic clinical trials for patients with metastatic breast cancer (MBC). Methods: A robust, high-throughput tumor genotyping assay (Snapshot), was developed at our institution to assess for presence of potentially actionable oncogenic driver mutations (15 genes, 130 mutations) using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. The tumor genotyping assay was ordered by oncologists in clinic for patients with MBC. Relevant clinical information was gathered from chart reviews. Descriptive statistics were used for analysis. Results: From 2009-2012, 347 breast tumors were prospectively genotyped in the study population (median age = 50, range 27-90). The common oncogenic mutations were seen in all breast cancer subtypes. PIK3CA mutation (23.3%) was the most common mutation detected overall, albeit at varying frequency in tumor subtypes: HR+ (29.1%, N= 210), HER-2+ (21.5%, N = 65), TN (8.3%, N = 72). Unanticipated mutations in KRAS, BRAF, IDH, and HER-2 were also discovered. Clinical genotyping helped identify breast origin for carcinomas of unknown primary and revealed changes in mutation profile in metastatic tumors from primary tumors. Enrollment in clinical trials for MBC almost quadrupled from 2005-2008 to 2009-2012, with approximately one-third of patients undergoing tumor genotype testing enrolling in clinical trials, particularly phase-I genotype-directed targeted therapy, such as PI3K inhibitor, Akt inhibitor, and PI3K/MEK inhibitor combination. Conclusions: Routine tumor genotyping can be successfully incorporated into clinical practice to significantly enhance therapeutic clinical trial enrollment and potentially accelerate development of genotype-directed targeted therapies for MBC.

Phase III Trial of Sunitinib in Combination With Capecitabine Versus Capecitabine Monotherapy for the Treatment of Patients With Pretreated Metastatic Breast Cancer

Metastatic breast cancer (MBC) remains an incurable illness in the majority of cases, despite major therapeutic advances. This may be related to the ability of breast tumors to induce neoangiogenesis, even in the face of cytotoxic chemotherapy. Sunitinib, an inhibitor of key molecules involved in neoangiogenesis, has an established role in the treatment of metastatic renal cell and other cancers and demonstrated activity in a phase II trial in MBC. We performed a randomized phase III trial comparing sunitinib plus capecitabine (2,000 mg/m2) with single-agent capecitabine (2,500 mg/m2) in patients with heavily pretreated MBC. Eligibility criteria included MBC, prior therapy with anthracyclines and taxanes, one or two prior chemotherapy regimens for metastatic disease or early relapse after a taxane plus anthracycline adjuvant regimen, and adequate organ function and performance status. The primary end point was progression-free survival, for which the study had 90% power to detect a 50% improvement (from 4 to 6 months). A total of 442 patients were randomly assigned. Progression-free survival was not significantly different between the treatment arms, with medians of 5.5 months (95% CI, 4.5 to 6.0) for the sunitinib plus capecitabine arm and 5.9 months (95% CI, 5.4 to 7.6) for the capecitabine monotherapy arm (hazard ratio, 1.22; 95% CI, 0.95 to 1.58; one-sided P = .941). There were no significant differences in response rate or overall survival. Toxicity, except for hand-foot syndrome, was more severe in the combination arm. The addition of sunitinib to capecitabine does not improve the clinical outcome of patients with MBC pretreated with anthracyclines and taxanes.

Room for improvement in breast cancer clinical trial design: taking advantage of the preoperative setting

Achieving approval of new oncologic drugs in breast cancer (BC) is lengthy and costly. After approval in a randomized Phase III trial in metastatic BC, an agent is then evaluated in stage I-III BC. It can take a decade for drug approval in early-stage BC, given the large sample size and long follow-up to detect improvements in disease-free or overall survival. One way to reduce this time period is conducting preoperative trials. In neoadjuvant BC trials, improvements in pathologic complete response in randomized trials of chemotherapy with and without a new agent can lead to accelerated approval. In exploratory investigational new drug trials, such as Phase 0 trials, new drugs can be evaluated for a limited time prior to traditional dose escalation trials. The US FDA has released guidelines for utilization of preoperative trials. The goal is to administer a new agent to the right subset of BC patients quicker and more effectively.

The importance of adjusting for treatment crossover bias in oncology clinical trials: An analysis of the EGF104900 trial in metastatic breast cancer (mBC).

636 Background: EGF104900 is a phase III trial in mBC that compared lapatinib + trastuzumab (LAPTRZ, n=146) with LAP monotherapy (LAP, n=145). The trial allowed LAP subjects to switch to LAPTRZ on documented disease progression (following ≥4 weeks of LAP). Conventional intent-to-treat (ITT) analysis does not control for potential bias due to treatment crossover. The Rank Preserving Structural Failure Time Model (RPSFTM) estimates event times had patients not switched, and performs re-censoring. The approach preserves randomization and ordering of patients’ observed survival times, assuming that patients switching benefit from the treatment effect seen in those initially randomized to the treatment arm. The method is recognized by NICE, UK, as an appropriate method for adjusting for crossover bias. Methods: 53% of LAP subjects crossed over to LAPTRZ. Analyses were stratified by hormone receptor status and visceral/non-visceral disease. RPSFTM was implemented in Stata (using White’s strbee procedure). Absolute overall survival (OS) was estimated using a parametric survival distribution fitted to the trial data with/without crossover adjustment. The unadjusted ITT Cox hazard ratio (HR) was compared with the crossover adjusted RPSFTM estimate, and the absolute gain in OS evaluated. Results: Median OS in the LAPTRZ and LAP arms was 61 and 41 weeks, respectively (ITT HR 0.74, 95% CI: 0.56, 0.96); RPSFTM crossover-adjusted median OS for LAP was 32 weeks (RPSFTM HR 0.52; 95% CI: 0.29, 0.92). Mean OS for LAPTRZ was estimated under a Weibull distribution as 74 weeks, compared with 57 (ITT) and 44 (RPSFTM) weeks for LAP. Treatment with LAPTRZ was estimated to extend mean OS by 30 weeks controlling for treatment crossover using RPSFTM compared with 17 weeks by ITT. Conclusions: Oncology trials are often subject to treatment crossover. Controlling for potential treatment crossover bias can result in greater estimates of gain in OS compared with ITT analysis. In the context of mBC such differences are of great importance to patients, clinicians, and healthcare payers. Treatment crossover-analyses are therefore also important for estimating cost-effectiveness in oncology.

Impact of routine tumor genotyping on enrollment in targeted therapy trials for metastatic breast cancer (MBC): 4-year review.

533 Background: Major barriers to enrollment in therapeutic clinical trials (&lt;5% in United States) include low response rate in phase 1/2 trials and low enthusiasm among oncologists. Stratified clinical trial enrollment based on molecular profiling of tumors represents a potential paradigm shift in drug development. Here we assess the clinical utility of tumor genotyping for identification of oncogenic driver mutations and enrollment in therapeutic clinical trials for patients with MBC. Methods: A robust, high-throughput tumor genotyping assay (Snapshot), was developed at our institution to assess for presence of potentially actionable oncogenic driver mutations (15 genes, 130 mutations) using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. The tumor genotyping assay was ordered by oncologists in clinic for patients with MBC. Relevant clinical information was gathered from chart reviews. Descriptive statistics were used for analysis. Results: From 2009-2012, 347 breast tumors were prospectively genotyped in the study population (median age = 50, range 27-90). PIK3CA mutation (23.3%) was the most common mutation detected overall, albeit at varying frequency in tumor subtypes: HR+ (29.1%, N= 210), HER-2+ (21.5%, N = 65), TN (8.3%, N = 72). Unanticipated mutations in KRAS, BRAF, IDH, and HER-2 were also discovered. Clinical genotyping helped identify breast origin for carcinomas of unknown primary and revealed changes in mutation profile in metastatic tumors from primary tumors. Enrollment in clinical trials for MBC almost quadrupled from 2005-2008 to 2009-2012, with 35.5% of patients undergoing tumor genotype testing enrolling in trials, particularly phase-1 genotype-directed targeted therapy, such as PI3K inhibitors, Akt inhibitors, and combined PI3K/MEK inhibitors. Conclusions: Routine tumor genotyping can be successfully incorporated into clinical practice to significantly enhance therapeutic clinical trial enrollment and potentially accelerate development of genotype-directed targeted therapies for MBC.

Treatment (tx) patterns and clinical outcomes for patients (pts) with de novo versus recurrent HER2+ metastatic breast cancer (MBC).

523 Background: Use of adjuvant trastuzumab (T) in pts with HER2+ early breast cancer is associated with decreased recurrence. As fewer patients relapse, the proportion of pts with de novo metastatic disease in the first-line (1L) setting will increase, which could have implications for the design/interpretation of results from HER2+ MBC trials. To date, little data exist on potential differences in prognosis and outcomes between pts with recurrent vs de novo HER2+ MBC. Methods: registHER is an observational cohort of pts with HER2+ MBC diagnosed ≤6 mo from enrollment and followed until death, disenrollment, or June 2009 (median follow-up: 27 mo). Demographics and 1L tx patterns (using descriptive analyses), as well as clinical outcomes (median PFS and OS estimated by Kaplan-Meier method) were examined for pts with de novo vs recurrent HER2+ MBC. De novo was defined as disease-free interval (DFI) between initial and metastatic diagnosis ≤90 days; recurrent was defined as DFI &gt;90 days. Cox regression analyses were used to generate hazard ratios (HRs). Results: Pts with de novo HER2+ MBC (327 of 1001 enrolled) were more likely to be younger and non-white; have lymph, bone, and/or liver metastases and &gt;4 sites of metastatic disease; less likely to have lung or CNS metastases; and have received 1L regimens of TCH or AC more frequently vs pts with recurrent disease (who received T + vinorelbine more frequently). PFS and OS were longer in the de novo vs recurrent group (Table). Conclusions: Despite presenting with more advanced-stage disease accompanied by higher tumor burdens, pts with de novo HER2+ MBC had more favorable clinical outcomes vs those with recurrent disease. Differences in disease characteristics and tx patterns resulting in more refractory disease (including acquired resistance from adjuvant tx) may account for these observations. Clinical trial information: NCT00105456. [Table: see text]

Differences in psychosocial factors among diverse women enrolled in a phase III cooperative group metastatic breast cancer trial (CALGB 40502/Alliance).

9581 Background: Previous metastatic breast cancer trials have shown lower overall survival among African American (AA) women. Studies have also shown links between higher comorbidities and lower levels of social support and survival. Whether these factors differ by race and ethnicity is not known. Methods: Breast cancer patients enrolling in a phase III cooperative group metastatic breast cancer trial completed a self-administered survey measuring psychosocial and socio-demographic factors and comorbidities. Results were analyzed by self-identified race/ethnicity and evaluated by other measured variables. Results: 703 out of 799 patients completed the survey (88%). Questions were answered by greater than 95% of participants. The table shows differences broken down by Race/Ethnicity. AA and Hispanic (H) patients were more likely to have trouble paying for medications and have incomes less than 15K per year. AA were less likely to be married, and had lower levels of social support. Differences in income did not mediate these social support differences. Marital status did not mediate lower social support for AA (p=0.79) but did so for whites (p&lt;0.001) Conclusions: Compliance with the questionnaire was quite high. Differences in social support by race were apparent and were mediated by different factors according to race. Future efforts will analyze the impact of these factors on survival and as mediators for potential racial and ethnic differences in survival. [Table: see text]

Progression-free survival (PFS) as surrogate endpoint for overall survival (OS) in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer (MBC): An individual patient data (IPD) analysis.

610 Background: The gold standard endpoint in randomized clinical trials (RCTs) in MBC is OS, which has the disadvantage of requiring extended follow-up and being confounded by subsequent anti-cancer therapies. Although therapeutics have been approved based on PFS, its use as a primary endpoint is controversial. This study, the first IPD meta-analysis of targeted agents in MBC, aimed to collect data from RCTs of HER2-targeted agents in HER2+ MBC, assessing to what extent PFS correlates with, and may be used as, a surrogate for OS. Methods: A search was conducted in April 2011. Eligible RCTs accrued HER2+ MBC patients (pts) in 1992-2008. Collaboration was obtained from industrial partners (Roche, GSK) for industry-led studies. Investigator-assessed PFS was defined as the time from randomization to clinical or radiological progression, or death. A correlation approach was used: at the individual level, to estimate the association between PFS and OS using a bivariate survival model and at the trial level, to estimate the association between treatment effects on PFS and OS. Squared correlation values close to 1.0 would indicate strong surrogacy. Results: The search strategy resulted in 2137 eligible pts in 13 RCTs testing trastuzumab or lapatinib. We collected IPD data from 1963 pts in 9 RCTs. One phase II RCT did not have sufficient follow-up data so that 1839 pts in 8 RCTs were retained (5 evaluating trastuzumab, 3 lapatinib); 6 out of 8 RCTs were first-line. At the individual level, the Spearman rank correlation using Hougaard copula was equal to r=0.66 (95% CI 0.65 to 0.66) corresponding to an r2 of 0.42. At the trial level, the squared correlation between treatment effects on PFS and OS was provided by R2=0.33 (95% CI -0.22 to 0.86) using Hougaard copula and R2=0.53 (95% CI 0.22 to 0.83) using log hazard ratios from Cox models. Conclusions: In RCTs of HER2-targeted agents in HER2+ MBC, PFS is moderately correlated with OS and treatment effects on PFS are modestly correlated with treatment effects on OS, similarly to first-line chemotherapy in MBC (Burzykowski et al JCO 2008). PFS does not completely substitute for OS.

Choice of primary endpoints in first-line phase III trials of HER2-negative or HER2-unknown metastatic breast cancer (MBC).

607 Background: OS is considered the most clinically relevant endpoint in cancer therapy trials, but OS can be confounded by post-trial therapy, particularly in settings with long post-progression survival (PPS). Based on statistical modelling with 50,000 simulated trials, Broglio &amp; Berry [JCNI 2009] suggested the association between improved progression-based endpoints (eg, PFS) and OS is weak in settings with PPS &gt;12 months and can only be shown in very large trials. To test this hypothesis, we analysed efficacy outcomes and choice of primary endpoints in first-line MBC trials. Methods: Data wereanalysed from:randomised, controlled phase III trials comparing systemic chemotherapies and/or targeted agents; enrolling ≥150 pts; published in peer-reviewed journals from 2000–2011. Trials that enrolled only HER2-positive MBC pts or evaluated non-EU approved agents were excluded. Results: Of27 trials, 1 (3.7%) had OS as the primary endpoint, while 18 (66.7%) had progression-based parameters, commonly PFS (9 trials, 33.3%). A significant increase in progression-based parameters was seen in 14 trials (51.9%). All 5 trials (18.5%) showing a significant OS benefit had a PPS &lt;12 months. Mean PPS was considerably longer in trials published in 2006–2011 vs 2000–2005 (14.1 ± 4.0 vs 9.7 ± 2.3 months, respectively), as was mean PFS (8.3 ± 2.2 vs 6.6 ± 1.6 months) and mean OS (25.4 ± 5.6 vs 18.6 ± 3.0 months). A weak correlation was seen between OS and PFS (Pearson’s coefficient r=0.32), but a higher correlation was seen in treatment arms with an OS benefit (r=0.59), as well as in treatment arms with a PPS &lt;12 months (r=0.43) or older studies (r=0.51). Data were insufficient to allow a valid analysis of the effect of further-line therapies or cross-over on OS (16 trials reported further-line therapies; 9 cross-over therapy). Conclusions: In support of the hypothesis by Broglio &amp; Berry, a significant OS advantage was shown exclusively in trials with a PPS &lt;12 months. Due to the weak correlation between PFS and OS, it is difficult to determine the possible surrogacy of PFS for OS. Thus, as an OS benefit might be increasingly difficult to attain, progression-based parameters appear to be valid endpoints in MBC clinical trials.

Benefit of chemotherapy after third line and evaluation of post-progression survival (PPS) in metastatic breast cancer (MBC): A single institution study.

e11517 Background: MBC remains an incurable disease with median survival of 2-3 years despite new drugs. The gain of benefit from third-line chemotherapy (CT3) in MBC is unknown. The validation of PPS as surrogate endpoint and its correlation to OS is under debate. Methods: From 2006-2012 we analyzed retrospectively consecutive 114 pts treated for MBC, 67 with at least 3 lines CT, to show the gain of benefit after CT3 and predictive factors of response to multiple lines of therapy. Moreover, we evaluated PPS for each line and its relation to OS. Results: Median age at M+ diagnosis was 58 years (29-87), median site of disease 2 (1-6), 66.7% visceral, HER-2+ pts 31.1%, median number of anti-Her-2 treatment 2 (1-6); 56.1% received a maintenance treatment (37% M1, 13% M2), median number of treatment 3 (1-8). Median OS for all pts was 47.1 (95%CI: 36.5-57.6). No difference in OS for pts with maintenance treatment vs not, respectively 49.1 vs 45.6 P=0.17. Multivariate Cox analysis showed that OS is related with ER/Pgr status (positive vs negative p=0.03) number of lines ( &gt;3 vs ≤ 3) p&lt; 0.0001 and number of metastatic sites (&gt;2 vs ≤2) p=0.01. We evaluated relation between PFS and OS and PPS and OS until 6th line of therapy with a linear regression model. Conclusions: These results supported the use of chemotherapy after CT3. PFS and PPS are related to OS until 6th line of treatment. PPS as surrogate endpoint of OS is a valid hypothesis to be evaluated in prospective trials of MBC [Table: see text]