Ratio For Progression-free Survival Research Articles

Economic evaluation of sequencing strategies in HER2-positive metastatic breast cancer in Mexico: a contrast between public and private payer perspectives.

Breast cancer is the most common malignancy among women in Mexico. A large proportion of Mexican patients present with advanced disease, and 25% have HER2-positive tumors. We performed a cost-effectiveness analysis of different sequencing strategies of HER2-targeted agents in Mexico according to various payer perspectives. A Markov model was constructed to evaluate the cost-effectivenessof four different HER2-targeted treatment sequences among patients with HER2-positive metastatic breast cancer treated in Mexico according to three public and one private payer perspectives. Patients were followed weekly over their remaining life expectancies within the model. Health states considered were progression-free survival (PFS) 1st-3rd lines, and death. Transition probabilities between states were based on published trials. Cost data were obtained from official publications from Mexican healthcare institutions. The evaluated outcomes were PFS, OS, costs, QALYs, and incremental cost effectiveness ratio (ICER). In the public payer perspective, sequences containing pertuzumab or T-DM1 were not cost-effective when compared with a sequence including the combination of trastuzumab/docetaxel as first line without subsequent T-DM1 or pertuzumab, even when utilizing alternate definitions for willingness to pay thresholds. In the private payer perspective, a sequence containing T-DM1 but not pertuzumab proved cost-effective at a lower clinical effectiveness. In Mexico, the use of at least three lines of trastuzumab in combination with other therapies, but not with pertuzumab or TDM-1, represents the most cost-effective option for patients covered by the public healthcare system, and this sequence should be made available for all patients.

Ixazomib: A Review in Relapsed and/or Refractory Multiple Myeloma.

The oral proteasome inhibitor ixazomib (Ninlaro®) is approved in the USA, EU and Japan in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. In adults with relapsed and/or refractory MM who had received one to three prior therapies, progression-free survival (PFS) was significantly prolonged in patients who received the ixazomib- versus placebo-based triple therapy in the pivotal, global TOURMALINE-MM1 trial and its regional expansion (China continuation study). A significantly longer time to progression and favourable hazard ratios for PFS were observed across all prespecified subgroups, including patients with high cytogenetic risk. Overall response was achieved in a significantly higher proportion of patients receiving ixazomib- than placebo-based treatment. Ixazomib had a manageable tolerability profile in patients with MM. Ixazomib is the first orally-administered proteasome inhibitor approved for patients with MM, and in combination with lenalidomide and dexamethasone represents an important new option for use in patients with relapsed and/or refractory MM who have previously received at least one prior therapy.

THE PROGNOSTIC VALUE OF FLIPI IN THE ERA OF RITUXIMAB

Introduction: Follicular Lymphoma International Prognostic Index (FLIPI) was developed in the pre-rituximab era to predict the outcome of follicular lymphoma (FL) patients. With the introduction of rituximab (R) into treatment, the predictive value of FLIPI needed reassessment. We performed a retrospective study to evaluate the prognostic value of FLIPI in the era of rituximab. Methods: One hundred and eleven FL patients (pts) with evaluable FLIPI, needing therapy, were included in the study. They induction regimen was R-CHOP in 106 pts (95.5%) and R-CVP in 6 pts. With Cox model, we evaluated hazard ratios (HR) for overall survival (OS) and progression free survival (PFS) for intermediate risk versus low-risk FLIPI group and high-risk versus low-risk group. Results: Among 111 pts, 43% were over 60 years old, and 85% had stage III–IV disease. According to FLIPI score, 34 pts (30.6%) were categorized as low-risk, 35 pts (31.5%) as intermediate-risk and 42 pts (37.9%) as high-risk pts. At a median follow-up of 4.5 years, the 5-year PFS and OS for all 111 pts were 54% and 82%, respectively. The 5-year PFS for low-, intermediate- and high-risk FLIPI pts was 53%, 64% and 49% (p = 0.148) and the 5-year OS 87%, 91% and 67%, respectively. The difference in OS was significant (p = 0.002). HR for OS was 2.93 for the high-risk FLIPI group compared to the low risk group (95% CI 1.14–7.53, p = 0.025) and HR for PFS was 1.58 for the high-risk FLIPI group compared to the low-risk group (CI 0.71–3.54, p = 0.261). There were no differences in any outcome between the low and the intermediate-risk groups (Table1). Table 1: Hazard ratios for OS and PFS by FLIPI prognostic groups in R-chemo pts (N = 111). OS HR (95% CI), p PFS HR (95% CI), p 0.61 (0.17–1.16) p = 0.442 0.75 (0.29–1.90) p = 0.546 2.93 (1.14–7.53) p = 0.025 1.58 (0.71–3.54) p = 0.261 Conclusions: FLIPI retained its prognostic value in terms of OS in the era of rituximab. High-risk FLIPI patients receiving induction R-chemo had a significantly worse survival compared to the low-risk patients. However, we did not confirm the adverse impact of high FLIPI in terms of PFS in this group of pts. It seems that rituximab in induction therapy eliminated the unfavorable influence of high FLIPI and thus diminished its prognostic significance for disease progression. Keywords: follicular lymphoma (FL); prognostic indices; rituximab.

Evaluation of PFS ratio in patients with cancer enrolled in early-phase clinical trials: A single center, retrospective analysis.

e14025 Background: Progression-free survival ratio (PFSr) has been proposed as a direct evaluation of treatment benefit in advanced cancer patients, based on the hypothesis that the natural history of cancer is accelerating and therefore successive lines of treatments become less efficient over time. Consequently, PFS at line +2 (PFS2) is expected to be shorter than PFS at line +1 (PFS1), whereas a PFS2/PFS1 ratio > 1.3 might reflect treatment benefit. However, this hypothesis has been poorly documented, especially in the context of early phase trials where determining treatment benefit is becoming key. We therefore proposed to evaluate PFSr in a large cohort of cancer patients enrolled in early phase clinical trials at Gustave Roussy Drug Development Department. Methods: Patients enrolled in at least two phase 1 studies for advanced solid tumors or lymphomas were retrospectively identified. Demographical, clinical and therapeutic data were collected. Time to progression (PFS) was measured from treatment initiation to progression, using radiological evaluations. Patients who had gone off-trial for reasons other than progression were censored. PFSr was defined as the ratio of the PFS under line 2 divided by the PFS under line 1 and might be censored in presence of censored PFS2. Ratio distribution in this population was estimated using Kaplan Meier. Calibration of the ratio was proposed for hypothesis testing. The influence of therapeutic class and combination versus monotherapy was studied via non parametric Gehan-Wilcoxon tests or Mick tests. Results: 212 patients enrolled between 2009 and 2016 in at least two phase 1 clinical trials were included, corresponding to 113 different clinical trials. PFSr distribution was described and correlated with demographical, clinical and therapeutic data. The relevance of the usual 1.3 PFSr cut-off to determine treatment benefit was evaluated. Final analysis results will be presented at the time of the congress. Conclusions: This study, one of the first to establish PFSr in a large cohort of patients treated in early phase clinical trials, provides guidelines for using PFSr to assess the impact of treatment sequences in advanced cancer patients.

Clinical outcomes after whole genome sequencing in patients with metastatic non-small cell lung cancer.

e20563 Background: The Personalized OncoGenomics (POG) program at the BC Cancer Agency integrates whole genome (DNA) and RNA sequencing into practice for metastatic malignancies. We examine patients with metastatic NSCLC and report the prevalence of actionable targets, treatments, and outcomes. Methods: Between 2012-2016, 217 patients had a tumor biopsy and blood sample with comprehensive DNA (80X; 40X normal) and RNA sequencing followed by in-depth bioinformatics to identify potential cancer “drivers” and/or actionable/treatable targets. In NSCLC cases, we compared the progression-free survival (PFS) of “POG-informed therapies” with the PFS of the last regimen prior to POG (PFS ratio). Results: In 29 NSCLC cases, median age was 60.2 years (range 39.4-72.6), 11 were male (38%), and histologies were: adenocarcinoma (93%); squamous cell carcinoma (7%). Potential molecular targets (i.e. cancer “drivers”) were identified in 26 (90%), and 21 (72%) had actionable targets. 13 received POG-informed therapies, of which 3 had no therapy before POG. Of 10 patients with POG-informed therapy, median PFS ratio was 0.94 (IQR 0.2-3.4). 3 (30%) had a PFS ratio ≥1.3, and 3 (30%) had a PFS ratio ≥0.8 and <1.3. Conclusions: In this NSCLC cohort, 30% demonstrated longer PFS with POG-informed therapies. Larger studies will help clarify the role of whole genome analysis in clinical practice. [Table: see text]

Molecular profiling-guided therapy in gastroesophageal carcinoma: A single-institution experience.

e15582 Background: Gastroesophageal carcinoma (GEC) including carcinoma of stomach (GC), gastroesophageal junction (GEJ), and esophagus (EC) is the 2nd leading cause of cancer death worldwide. Chemotherapy and HER2-targeted therapy (trastuzumab) have shown limited efficacy. We aim to assess the impact of molecular profile (MP)-guided therapy (MPgt) by correlating expression of select biomarkers in GEC patients (pts) with survival. Methods: 27 GEC (11 GC, 9 GEJ, 7 EC) submitted to Caris Life Sciences for molecular profiling between 2011 and 2016 were analyzed and correlated with pt survival. The impact of MPgt was assessed by calculating the ratio of progression-free survival (PFS) on MPgt to PFS on the preceding empiric therapy. MPgt was deemed beneficial if PFS ratio ≥1.3. Results: In-situ hybridization indicated amplification of HER2 (15.4%) and c-MET (7.4%). Immunohistochemistry revealed increased expression of TOPO1 (57.7%), TOP2A (38.5%), HER2 (15.4%) and c-MET (6.9%), as well as decreased expression of TS (69.2%), ERCC1 (42.3%), and PGP (15.4%). These data suggest sensitivity to topoisomerase inhibitors, anthracyclines, trastuzumab, MET-targeted therapy, fluoropyrimidine, platinums, and taxanes, respectively. Expression of these markers was heterogeneous among pts, and a trend toward improved PFS was noted in pts with low/absent ERCC1 expression on platinum-based therapy ( P= 0.06). Of the 13 pts who had sufficient data to assess the benefit of MPgt, 5 (38%) achieved a PFS ratio ≥1.3. One pt with metastatic HER2-amplified EC who had initially demonstrated clinical benefit from trastuzumab-containing chemotherapy, developed a new HER2 and c-MET co-amplified lung metastasis. Conclusions: While MPgt was beneficial in 38% of pts, tumor-associated plasticity, clonal evolution, and adaptive resistance may have limited efficacy. The emergence of HER2 and c-MET co-amplified clones is a potential resistance mechanism in HER2-amplified GEC, and highlights combined inhibition of receptor tyrosine kinases as a therapeutic strategy. Further studies with expanded data sets will be needed to test the hypothesis that actionable targets can be used independently to predict treatment response in GEC pts.

First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study.

7500 Background: BRIGHT, a phase 3, open-label, noninferiority study comparing efficacy and safety of bendamustine plus rituximab (BR) vs rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP) in treatment-naive patients (pts) with indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL), showed that the complete response rate for first-line BR was statistically noninferior to R-CHOP/R-CVP ( Blood 2014). Pts were monitored for ≥5 years (yr) to assess the overall effect of BR or R-CHOP/R-CVP in a controlled clinical setting. This analysis reports the time-to-event variables of the 5-yr follow-up (FU) study. Methods: Pts with iNHL or MCL randomized to 6-8 cycles of BR or R-CHOP/R-CVP underwent complete assessments at end of treatment, then were monitored regularly. Progression-free survival (PFS), event-free survival (EFS), duration of response (DOR) and overall survival (OS) were compared using a stratified log-rank test. Results: Of 447 randomized pts, 224 received BR, 104 R-CHOP, and 119 R-CVP; 419 entered the FU. The median FU time was 65.0 and 64.1 months for BR and R-CHOP/R-CVP, respectively. The 5-yr PFS rate was 65.5% (95% CI 58.5-71.6) and 55.8% (48.4-62.5), and OS was 81.7% (75.7-86.3) and 85% (79.3-89.3) for BR and R-CHOP/R-CVP, respectively. The hazard ratio (95% CI) for PFS was 0.61 (0.45-0.85; P= .0025), EFS 0.63 (0.46-0.84; P= .0020), DOR 0.66 (0.47-0.92; P= .0134), and OS 1.15 (0.72-1.84; P= .5461) comparing BR vs R-CHOP/R-CVP. Similar results were found in iNHL [PFS 0.70 (0.49-1.01; P= .0582)] and MCL [PFS 0.40 (0.21-0.75; P= .0035)], with the strongest effect in MCL. Use of R maintenance was similar, 43% in BR and 45% in R-CHOP/R-CVP. B was included as second-line in 27 (36%) of the 75 pts requiring therapy who originally received R-CHOP/R-CVP. Comparable safety profiles with expected adverse events were observed in the FU study in BR vs R-CHOP/R-CVP. Conclusions: The long-term FU of the BRIGHT study has confirmed that PFS, EFS, and DOR were significantly better for BR, and OS was not statistically different between BR and R-CHOP/R-CVP. The safety profile was as previously reported. Clinical trial information: NCT00877006.

Molecular profiling-selected treatment in metastatic gastric and oesophageal cancer: Real-life clinical experience.

e15537 Background: We evaluated real-life clinical experience with molecular profiling (MP)-guided therapy in metastatic gastric and oesophageal cancer in Israel Methods: This multicenter retrospective cohort study included patients with metastatic gastric or oesophageal cancer who were treated in the participating institutions and underwent MP (Caris Molecular Intelligence). Treatment was considered as having benefit if the ratio between the longest progression-free survival (PFS) post MP and the last PFS pre MP was ≥1.3. The null hypothesis was that ≤15% of patients gain such benefit. Results: The analysis included 46 patients (61% males; median age, 58 years; 57% with poorly-differentiated tumours). At least one actionable (i.e., predictive of response to a specific therapy) biomarker was identified per patient. Immunohistochemistry was performed on all samples and identified 1-8 (median: 3) biomarkers per patient (most commonly: low TS, high TOPO1, high TOP2A). Twenty-eight patients received therapy post MP (1-4 lines). In the 1st-line post MP, 5 patients (18%) achieved partial response and 5 (18%) stable disease; the median (range) PFS was 4.3 (0.4-38.5) months. Twenty-four patients were evaluable for PFS ratio analysis; in 7 (29.2%), the ratio was ≥1.3. In one-sided exact binomial test vs. the null hypothesis, P = 0.019; therefore, the null hypothesis was rejected. Conclusions: Our findings demonstrated that implementing MP is feasible and that MP could provide clinical benefit for a considerable proportion (~30%) of patients with metastatic gastric or oesophageal cancer.

KRAS G12C mutation as a poor prognostic marker of pemetrexed treatment in non-small cell lung cancer.

Background/AimsThe predictive and prognostic value of KRAS mutation and its type of mutations in non-small cell lung cancer (NSCLC) are controversial. This clinical study was designed to investigate the predictive value of KRAS mutations and its mutation types to pemetrexed and gemcitabine based treatment.MethodsAdvanced NSCLC patients tested for KRAS mutation (n = 334) were retrospectively reviewed and 252 patients with wild type epidermal growth factor receptor and no anaplastic lymphoma kinase fusion were enrolled for the analysis. KRAS mutations were observed in 45 subjects with mutation type as followed: G12C (n = 13), G12D (n = 12), G12V (n = 12), other (n = 8). Response rate (RR), progression-free survival (PFS), and overall survival (OS) of pemetrexed singlet and gemcitabine based chemotherapy were analysis.ResultsAge, sex, performance status were well balanced between subjects with or without KRAS mutations. No difference was observed in RR. Hazard ratio (HR) of PFS for pemetrexed treated subjects with G12C mutation compared to subjects with KRAS wild type was 1.96 (95% confidential interval [CI], 1.01 to 3.79; p = 0.045), but other mutations failed to show clinical significance. By analysis done by PFS, compared to the subjects with transition mutation, HR was 1.48 (95% CI, 0.64 to 3.40; p = 0.360) for subjects with transversion mutation on pemetrexed treatment and 0.41 (95% CI, 0.19 to 0.87; p = 0.020) for subjects treated with gemcitabine based chemotherapy. No difference was observed in OS.ConclusionsIn this study, different drug sensitivity was observed according to the type of KRAS mutation. NSCLC subpopulations with different KRAS mutation type should be considered as different subgroups and optimal chemotherapy regimens should be searched in further confirmative studies.

End points and statistical considerations in immuno-oncology trials: impact on multiple myeloma.

Unlike conventional cancer treatment, immuno-oncology therapies are commonly associated with delayed clinical benefit and durable responses, as seen with immuno-oncology therapies for multiple myeloma (MM). Therefore, a longer-term approach to immuno-oncology data assessment is required. Appropriate study designs, end points and statistical methods are essential for evaluating immuno-oncology therapies to assess treatment outcomes, and may better accommodate immuno-oncology clinical trial data. In addition to conventional end points including median progression-free survival (PFS) and overall survival (OS), end points such as hazard ratios for PFS and OS over time, PFS and OS landmark analyses beyond the median, and immune-response end points might provide better indications of the efficacy of immuno-oncology therapies. Long-term data with these agents will allow better prediction of outcomes in MM.

Surrogate End Points for Overall Survival in Metastatic, Locally Advanced, or Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis of 24 Randomized Controlled Trials

Overall survival (OS) has traditionally been the primary end point in studies evaluating the clinical benefit of first-line chemotherapy in metastatic, locally advanced, or unresectable pancreatic cancer (MLAUPC). Given the prolonged follow-up assessment required to obtain OS and its potential to be confounded by second-line treatments, this study sought to determine whether progression-free survival (PFS), response rate (RR), or disease control rate (DCR) can serve as a reliable surrogate for OS. A systematic review and meta-analysis was performed including all phase 3 clinical trials for MLAUPC, with gemcitabine as the control arm of the trial. The hazard ratios (HRs) for OS and PFS and odds ratios (ORs) for RR and DCR were recorded. A weighted Pearson correlation coefficient was estimated for the association between OS and the other outcomes. The primary analysis used a random effects weighting model, whereas the secondary analyses used a fixed effects- or sample size-weighted approach. For the study, 24 randomized controlled trials were identified. The Pearson correlation coefficient between OS and PFS was 0.86 (95% confidence interval [CI] 0.67-0.94; p<0.001). Sensitivity analysis of the studies with little to no crossover further showed a correlation coefficient of 0.91 (95% CI 0.76-0.97; p<0.001). The correlation coefficient between OS and RR was 0.45 (95% CI 0.07-0.72; p=0.02) and between OS and DCR was 0.74 (95% CI 0.38-0.90; p<0.001). First-line chemotherapy trials for MLAUPC show a robust correlation between OS and PFS, affirming its role as a surrogate of OS.

ADCtotal ratio and D ratio derived from intravoxel incoherent motion early after TACE are independent predictors for survival in hepatocellular carcinoma

To explore the threshold of intravoxel incoherent motion (IVIM) parameters, apparent diffusion coefficient [ADCtotal and ADC(0,500) ] ratios 24-48 hours after transarterial chemoembolization (TACE) to assess early response in patients with unresectable hepatocellular carcinoma (HCC) and to compare the association between diffusion-weighted imaging with the intravoxel incoherent motion (IVIM-DWI) and mRECIST with survival. Institutional Review Board approval and informed consent were obtained for this prospective study. There were 30 patients undergoing 1.5T magnetic resonance imaging (MRI) with IVIM-DWI of 12 b values (0, 10, 20, 30, 40, 50, 70, 100, 200, 300, 500, 800 s/mm2 ) 1 week before and 24-48 hours after TACE. Response was assessed with the change of true diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (PF), ADCtotal , and ADC(0,500) values relative to baseline and with mRECIST. Receiver operating characteristic (ROC) curve analysis was used to explore the threshold of these parameters ratios. Kaplan-Meier, log-rank tests, and the Cox hazard model were used to correlate the response variables with progression-free survival (PFS) and to assess the incidence and potential clinical risk factors for PFS. Mann-Whitney U-test was used to compare the difference in parameters between different groups with progression within and beyond median PFS prior to TACE. Median PFS was 99 days, within which 16 patients progressed. The threshold of ADCtotal ratio, D ratio, and ADC(0,500) ratio were 13.1% (P = 0.001), 7.0% (P = 0.011), and 3.6% (P = 0.018) with sensitivity and specificity of 78.6% and 87.5%, 85.7% and 62.5%, 78.6% and 75%, respectively. The predictive utility of ADCtotal ratio, D ratio, and ADC(0,500) ratio for PFS were 0.848, 0.772, and 0.754, respectively. Survival analyses showed ADCtotal ratio, D ratio, ADC(0,500) ratio, liver cirrhosis, and mRECIST had a significant effect on PFS (P < 0.05). ADCtotal ratio and D ratio were independent predictors for 99-day PFS (P = 0.025, P = 0.036). There were no significant differences in pretreatment IVIM-DWI parameters between PFS > 99-day group and PFS ≤ 99-day group with P values of 0.547 for D, 0.394 for D*, 0.575 for PF, 0.901 for ADC(0,500) , and 0.506 for ADCtotal , respectively. The ADCtotal ratio and D ratio 24-48 hours after TACE were independent predictors for response to TACE for HCC, and showed stronger association with PFS than mRECIST. 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:820-830.

Randomized phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer: cross-over analysis from the SHIVA trial

Several studies used the ratio of progression-free survival (PFS) on genotype-matched treatment to PFS on genotype-unmatched treatment to assess the efficacy of therapy guided by patients' tumor molecular profiling. We evaluated the PFS ratio from patients who cross-over in the SHIVA trial. The primary end point of the SHIVA trial was to compare PFS on molecularly targeted agents (MTAs) based on tumor molecular profiling and treatment at physician's choice (TPC) in patients with any kind of cancer who had failed standard-of-care therapy. The experimental treatment included only marketed MTAs given outside their indications according to a pre-specified treatment algorithm. Patients were allowed to cross-over at disease progression in both arms. Response was evaluated according to RECIST 1.1 at randomization and at cross-over. We evaluated the ratio of PFS on MTA (PFSMTA) to PFS on TPC (PFSTPC) in patients who crossed-over. Among 741 patients enrolled in the SHIVA trial, 197 were randomized, and 95 crossed-over, including 70 patients from the TPC to the MTA arm and 25 patients from the MTA to the TPC arm. Two patients crossed-over in the TPC arm without disease progression. The PFSMTA/PFSTPC ratio exceeded 1.3 in 37% of patients who crossed-over from the TPC to the MTA arm. The PFSMTA/PFSTPC ratio exceeded 1.3 in 61% of patients who crossed-over from the MTA arm to the TPC arm. The cross-over analysis of the SHIVA trial identified 37% of patients who crossed-over from TPC to MTA with a PFSMTA/PFSTPC ratio exceeding 1.3.

Abstract P5-15-09: Evaluation of growth modulation index as a marker of benefit for consecutive lines of treatment for metastatic breast cancer

Abstract Background: Sequencing of single-agent chemotherapy (CT) is the current standard of treatment for endocrine-resistant metastatic breast cancer (MBC). However, shrinking benefit for consecutive lines of CT and lack of data from randomized trials may question the real value of advanced lines of treatment. Growth modulation index (GMI), the ratio of progression free survival (PFS) with PFS of previous line, has been reported as a marker of treatment benefit when equal to or above 1.3. This value is similar to the clinical benefit threshold proposed by ESMO and ASCO for non-curative CT. The aim of this work was to determine GMI change across the successive lines of CT for MBC. Methods: We retrospectively analyzed all MBC patients currently on treatment at our center. GMI was determined for each CT line and for each patient and a cut-off value of 1.3 was chosen as a marker of treatment benefit. Chi-squared test and Spearman's Rho were used for proportion comparison and correlations. Kaplan-Meier curves and log-rank test were performed for survival analysis. Results: 128 ABC patients were included; median age: 57; ECOG 0-1: 92.2%; visceral disease: 46%; bone-only disease: 46.9%; TNBC: 5.5%, HER2+: 23.5%, ER+HER2-: 71.1%; 50% more than 2 lines of CT. GMI and PFS values are shown in Table 1. GMI values were significantly associated with PFS values in all lines (p&amp;lt;0.001 for 2nd, 4th and 5th lines; p&amp;lt;0.01 for 3rd and 6th). GMI was neither significantly different between CT lines nor significantly correlated with GMI of previous line. No consistent association of GMI values with age, performance status, tumor subtype or visceral disease were found. Table 1. GMI and PFS values for each line of CTCT linenGMI Median (range)GMI ≥ 1.3PFS Median (95%CI)2nd630.88 (0.03-27)36.5%10.4 months (7.2-13.2)3rd390.62 (0.05-7.5)23.1%4.9 months (4.1-5.7)4th280.83 (0.05-12.6)21.4%5.3 months (1.1-9.4)5th200.68 (0.05-9.1)30.0%4.7 months (1.5-7.9)6th140.80 (0.25-22.8)42.9%4.5 months (2.0-7.1) Conclusions: GMI does not significantly change along successive CT lines for MBC. Our results, showing a constant rate of 20-40% of patients with GMI≥1.3 up to the sixth line of CT, suggest a benefit within the range of magnitude established by ASCO and ESMO framework for cancer care value. Although potential biases of this work warrant further evaluation with a cohort design, GMI, together with toxicity data and absolute gains of PFS, may be used as an additional tool to establish the real value of late lines of CT for MBC. Citation Format: Ayala de la Peña F, Ivars Rubio A, de la Morena Barrio P, Fernández Sánchez A, Luengo Gil G, García Martínez E, García Garre E, Marín Zafra G, Vicente V. Evaluation of growth modulation index as a marker of benefit for consecutive lines of treatment for metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-09.

Impact of Dose-Difference in Comparator Arms Among Clinical Trials on Treatment Effect Size in a Network Meta-Analysis: A Case of First-Line Therapies in Chronic Lymphocytic Leukemia (CLL)

Introduction:Network meta-analyses (NMA) are used commonly to allow formal comparisons between drugs that were not compared head-to-head in a clinical trial through a common comparator. Two main assumptions are made to allow such methodology: a) the study samples are drawn from similar populations and b) the common comparator in the trials represents the same intervention. Clinical trials for first-line treatment of chronic lymphocytic leukemia (CLL) offer an opportunity to perform NMA through a common comparator chlorambucil (CHL). In cases where the common comparators differ, the results of the NMA may be impacted; for example, the dose for CHL for most trials was 0.5 to 0.8 mg/kg of body weight given orally on days 1 and 15 of each 28-day cycle (total dose = 70 to 112 mg; denoted as CHL-low arm) in CLL-11 for obinutuzumab (OBI)-CHL and rituximab (RTX)-CHL, in RESONATE for ibrutinib (IBR), and in Knauf 2012 for bendamustine (BEN). The dose for CHL for COMPLEMENT-1 trial for ofatumumab (OFA)-CHL was 10 mg/m2 per day given orally on days 1-7 of each 28 day cycle (total dose = 132 mg; denoted as CHL-high arm). We sought to evaluate the impact of the dose difference, CHL0.5 vs. CHL10 on efficacy outcomes in CLL patients receiving these treatments.Methods:A systematic literature review was conducted in PubMed, Embase, and Cochrane library for the time period of 2010-2016 and in conference proceedings of American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO), and the European Hematology Association (EHA) for 2014-2016. Search was limited to clinical trials conducted on humans and published in English language. Randomized clinical trials (RCTs) evaluating first-line CLL therapies were included. Bayesian NMA of efficacy outcomes, including progression-free survival (PFS), complete response (CR), and overall response rate (ORR) were conducted without accounting for CHL dose-difference (base-case analyses) and with accounting for CHL dose-difference (secondary analyses) using SAS® (v9.3). For the base case analyses, the CHL-high and CHL-low comparator arms were assumed to have similar effects and treated as the same intervention. For secondary analyses, the two doses of CHL were evaluated as different interventions and trials where fludarabine treatment arms were a common comparator was included.Results:Of the 77 studies screened, four RCTs (n = 1,624) were included in the NMA. In the base-case NMA where CHL dose-difference is not accounted, hazard ratios (HRs) for PFS with OFA-CHL in comparison to OBI-CHL and RTX-CHL were both non-significant (95% CI: 0.01, >100), the odds ratios (95% CI) for ORR with OFA-CHL in comparison to OBI-CHL and RTX-CHL were both non-significant, and the odds ratios for CR with OFA-CHL in comparison to OBI-CHL and RTX-CHL were 0.07 (0.01-0.90) and 0.29 (0.01-6.03) respectively. In the secondary NMA where CHL dose difference is taken into account, HRs for PFS and odds ratios for ORR with OFA-CHL in comparison to OBI-CHL and RTX-CHL were both also non-significant, and the odds ratios for CR were 0.03 (0.01- >100) and 0.01 (0.01- >100) respectively.Conclusion:The differences in estimations and their respective confidence intervals demonstrate the importance of employing appropriate methodology and clinical considerations in NMA. In this case, conclusions arising from the results of two scenarios differed based on accounting for any clinically significant dose differences in "a potential common comparator." When CHL dose was not accounted for, OBI-CHL appeared to be superior to OFA-CHL in CR. After accounting for the dose-difference, OBI-CHL, OFA-CHL and RTX-CHL were similar to each other. Accurate estimation of treatment effects is important as these results are used to inform health policies and treatment guidelines through regulatory or HTA bodies and professional clinical bodies respectively. These data are also used to inform health economic models and budget impact models. Inaccurate results are propagated to future evidence synthesis efforts that further misinform policies and guidelines. DisclosuresMwamburi:Novartis Pharmaceuticals: Consultancy. Bal:Novartis Pharmaceuticals: Employment. Cascella:Novartis Oncology: Employment. Shah:Novartis Pharmaceuticals: Consultancy. Nanavaty:Novartis Pharmaceuticals: Consultancy. Gala:Novartis Pharmaceuticals: Consultancy.

Comparative Effectiveness of Daratumumab Monotherapy Versus a Real-World Historical Control from the Czech Republic in Heavily Pretreated and Highly Refractory Multiple Myeloma Patients

BACKGROUND: The European Commission has granted conditional approval to daratumumab (DARA) as monotherapy in adult patients (pts) with relapsed or refractory multiple myeloma (MM) whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) and who have demonstrated disease progression on the last therapy. DARA was approved under an accelerated assessment based on single-arm phase 2 studies. Outcomes in these heavily pretreated pts in a real-world (RW) setting can provide evidence on the relative treatment efficacy of DARA versus physician's choice (PC).AIMS: To perform an adjusted comparison of overall survival (OS) and progression-free survival (PFS) for DARA monotherapy versus PC, as observed in a RW historical cohort of heavily pretreated and highly refractory MM pts from the Czech Republic using pt-level data.METHODS: Using RW longitudinal pt chart data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group, pts with ≥2 prior lines of therapy previously exposed to both a PI and an IMiD were identified. Pt-level data from the RMG were pooled from pivotal DARA monotherapy studies (pts treated with DARA 16 mg/kg). Pts in the RMG could contribute information to the analysis for multiple lines of therapy, with baseline defined as the date of initiation of the actual treatment line. For the definition of PFS, missing data for the date of disease progression for pts in the RMG who initiated subsequent therapy were replaced by the conservative proxy of the date of initiation of the next treatment. OS and PFS were analysed using a Kaplan-Meier analysis. To adjust for confounding variables, a multivariate Cox proportional hazards regression was developed that included age, gender, beta-2 microglobulin levels (β2M : <3.5/3.5-5.5/>5.5 g/L), albumin levels (<3.5/≥3.5 g/L), line of therapy (3-13), prior exposure to pomalidomide/carfilzomib, refractory status (none/double/triple/quadruple), andincidence of thrombocytopenia (defined as platelet counts <150.000 per µL) as covariates. Predicted PFS and OS curves for the RMG cohort were derived from the multivariate model.RESULTS: From the RMG database, we identified 971 treatment lines in 463 pts previously exposed to both a PI and an IMID (n=206 in third line, n=256 in fourth line, n=203 in fifth line, n=307 in ≥sixth line). The dates of treatment initiation for the RMG pts ranged from March 2006 to March 2015. The most frequent treatment regimens were lenalidomide (33.4%), chemotherapy (18.1%), bortezomib (13.6%), thalidomide (8.0%), and bortezomib+thalidomide (5.3%). The number of pts treated with carfilzomib (2.5%) and pomalidomide (2.4%) was limited. DARA-treated pts (N=148) differed from the RMG cohort in median age (64 vs 62 years), median prior lines of therapy (5 vs 4), prior exposure to carfilzomib (41.2% vs 0.3%) and pomalidomide (55.4% vs 0.6%), thrombocytopenia incidence (46.9% vs 18.0%), and ≥triple refractory status (64.2% vs 5.3%). Median observed PFS and OS for DARA versus PC were 4.0 and 5.6 months, respectively, for PFS and 20.1 and 11.9 months, respectively, for OS. Older age, male sex, low albumin levels, high β2M levels, thrombocytopenia incidence, and double/triple/quadruple refractory status were all independent, statistically significant risk factors for mortality. Albumin levels, β2M levels, thrombocytopenia incidence, and refractory status were also predictive of PFS. The adjusted hazard ratio (95% confidence interval) for OS and PFS for DARA versus PC was 0.35 (0.22-0.56) and 0.79 (0.56-1.12), respectively. Figure 1 represents the predicted survival curves for the RMG cohort that were derived from the multivariate model, comparing observed PFS/OS versus predicted with DARA treatment.CONCLUSIONS:This adjusted treatment comparison suggests a significant improvement in OS and a numerical improvement in PFS for DARA compared to RW historical control data in heavily pretreated/highly refractory MM pts. The lower PFS benefit estimate for DARA compared to OS may be partly explained by limitations in the availability and comparability of data regarding progressive disease in the RMG cohort compared to clinical trial data. Adjusted comparisons between trial data and historical cohorts can provide useful insights to clinicians and reimbursement decision makers on relative treatment efficacies in the absence of head-to-head comparison studies for DARA monotherapy. [Display omitted] DisclosuresHájek:Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Spicka:BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Gatopoulou:Janssen Health Economics & Market Access EMEA: Employment. Vesela:Janssen Cilag s.r.o., Czech Republic: Employment. Diels:Johnson & Johnson: Employment, Equity Ownership. Besson:Janssen: Employment. Ito:Janssen: Employment, Equity Ownership.

Autologous Stem Cell Transplantation for Patients with Early Progression of Follicular Lymphoma- Retrospective Analysis of 2 Randomized Trials of the German Low Grade Lymphoma Study Group (GLSG)

Background: Follicular lymphoma (FL) is a highly heterogeneous disease. Patients with early progression of disease (POD) have a remarkably poor outcome. Approximately 20% of patients with symptomatic, advanced stage FL experience POD within 24 months of first-line treatment (POD24) and have a 5-year overall survival (OS) of <50%, compared to >85% for patients without POD24 (Casulo et al, JCO 2015; Jurinovic et al, Blood 2016). The optimal salvage treatment for these high-risk patients is unclear. We aimed to assess the role of autologous stem cell transplantation (ASCT) applied as 2nd-line treatment for patients with POD24 who -in principle- qualified for dose-intensified regimens.Methods: Patients with advanced stage FL from 2 successive randomized trials of the German Low Grade Lymphoma Study Group (GLSG1996 [MCP versus CHOP] and GLSG2000 [CHOP versus R-CHOP], followed by randomization for ASCT consolidation versus interferon maintenance, respectively) were eligible for retrospective analysis of 2nd-line treatment if they had progressive, relapsed or refractory FL (ie, less than a partial response), were <65 years, required treatment according to our established criteria, and had not received prior ASCT. Three patients who received an allogeneic transplant (alloTx) as 2nd-line treatment were excluded from this analysis. POD24 was defined as progressive, relapsed or refractory disease within 24 months after 1st-line treatment. Progression-free survival (PFS) and OS were calculated from initiation of 2nd-line treatment (2nd-line PFS and 2nd line-OS, respectively).Results: The evaluable 162 patients were enriched for POD24 (113/162 [70%]). POD24 patients were more likely to receive ASCT as 2nd-line treatment (52/113 [46%] versus 11/49 [22%], p=0.008), whereas rituximab was more commonly added to 2nd-line regimens in patients without POD24 (48% versus 69%, p=0.018). With a median follow-up of 9.4 years, POD24 patients had a significantly shorter 5-year 2nd-line PFS and OS with 35% versus 53% (p=0.04) and 60% versus 83% (p=0.02), respectively, compared to patients without POD24.Within the POD24 group, 52 patients (46%) received ASCT, 54 (48%) received rituximab-containing regimens, 25 (22%) received both ASCT and rituximab as part of their 2nd-line treatment. Patients in the ASCT arm were younger (median age 47 versus 51 years, p=0.018) and more frequently male (73% versus 51%, p=0.026). The distribution of high-risk FLIPI (39% versus 46%, p=0.60), ECOG performance status >1 (10% versus 21%, p=0.15) and the addition of rituximab (48% versus 48%, p=1.0) was not significantly different between the ASCT and no-ASCT groups.In univariate analysis, ASCT for POD24 patients was associated with significantly higher 5-year 2nd-line PFS and OS rates of 51% versus 19% and 77% versus 46% (CI=[35;60]), respectively (Figure). The hazard ratios (HR) for 2nd-line PFS and OS were 0.36 (CI=[0.22;0.59], p<0.0001) and 0.50 (CI=[0.30;0.83], p=0.006).Multivariate analysis demonstrated that ASCT had a stronger impact on favorable treatment outcome compared to the addition of rituximab: the HRs of ASCT for 2nd-line PFS and 2nd-line OS were 0.37 (CI=[0.21;0.63], p=0.0003) and 0.34 (CI=[0.21;0.56], p<0.0001), whereas the HRs of rituximab were 0.63 (CI=[0.39;1.00], p=0.05) and 0.64 (CI=[0.39;1.08], p=0.09), respectively.Finally, to account for the selection bias associated with retrospective studies, we considered patients as ASCT if there had been an attempt to collect an autograft. This included an additional 13 patients from the no-ASCT group and another patient who ultimately received an alloTx as 2nd-line treatment. In this intention-to-treat-like analysis the benefit of ASCT remained statistically significant with a HR=0.48 for 2nd line PFS (CI=[0.30;0.77], p=0.002) and a HR=0.50 for 2nd-line OS (CI=[0.30;0.83], p=0.006).Conclusion: This retrospective analysis suggests that ASCT is an effective 2nd-line treatment option for patients with high-risk FL as defined by the early progression of disease (POD24) who qualify for dose-intensified protocols, and should be evaluated in prospective clinical trials. It remains to be determined if ASCT is also an effective 1st-line treatment strategy for selected patients identified to be high-risk by pre-treatment risk classifiers, such as the recently established clinicogenetic risk-model m7-FLIPI. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lenalidomide Maintenance after Front Line Therapy Substantially Prolongs Progression Free Survival in High Risk CLL: Interim Results of a Phase 3 Study (CLL M1 study of the German CLL Study Group)

Lenalidomide Maintenance after Front Line Therapy Substantially Prolongs Progression Free Survival in High Risk CLL: Interim Results of a Phase 3 Study (CLL M1 study of the German CLL Study Group)

Evaluation of Progression-Free Survival (PFS) As a Surrogate Endpoint for Overall Survival (OS) in First-Line Therapy for Diffuse Large B-Cell Lymphoma (DLBCL): Findings from the Surrogate Endpoint in Aggressive Lymphoma (SEAL) Analysis of Individual Patient Data from 7507 Patients

Evaluation of Progression-Free Survival (PFS) As a Surrogate Endpoint for Overall Survival (OS) in First-Line Therapy for Diffuse Large B-Cell Lymphoma (DLBCL): Findings from the Surrogate Endpoint in Aggressive Lymphoma (SEAL) Analysis of Individual Patient Data from 7507 Patients

Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: a New York Cancer Consortium trial.

The proteasome inhibitor bortezomib enhances the effect of the selective estrogen receptor (ER) downregulator (SERD) fulvestrant by causing accumulation of cytoplasmic ER aggregates in preclinical models. The purpose of this trial was to determine whether bortezomib enhanced the effectiveness of fulvestrant. One hundred eighteen postmenopausal women with ER-positive metastatic breast cancer resistant to aromatase inhibitors (AIs) were randomized to fulvestrant alone (Arm A—500 mg intramuscular (i.m.) day −14, 1, 15 in cycle 1, and day 1 of additional cycles) or in combination with bortezomib (Arm B—1.6 mg/m2 intravenous (i.v.) on days 1, 8, 15 of each cycle). The study was powered to show an improvement in median progression-free survival (PFS) from 5.4 to 9.0 months and compare PFS rates at 6 and 12 months (α=0.10, β=0.10). Patients with progression on fulvestrant could cross over to the combination (arm C). Although there was no difference in median PFS (2.7 months in both arms), the hazard ratio for PFS in Arm B versus Arm A (referent) was 0.73 (95% confidence interval (CI)=0.49, 1.09, P=0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 α level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (P=0.03, 1-sided χ2-test; 95% CI for difference (14.5%)=−0.06, 29.1%). Of 27 patients on arm A who crossed over to the combination (arm C), 5 (18%) were progression-free for at least 24 weeks. Bortezomib likely enhances the effectiveness of fulvestrant in AI-resistant, ER-positive metastatic breast cancer by reducing acquired resistance, supporting additional evaluation of proteasome inhibitors in combination with SERDs.