Longer PFS Research Articles

Pembrolizumab: cutaneous AEs associated with longer PFS

Pembrolizumab: cutaneous AEs associated with longer PFS

A phase II trial with anti-Lewis-Y monoclonal antibody (hu3S193) for the treatment of platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma

ObjectivesThe primary objective was to evaluate the clinical efficacy of hu3S193, a humanized monoclonal antibody against the Lewis-Y antigen, in patients with platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma. Secondary objectives were safety and pharmacokinetics. In addition, we sought to determine the potential interaction of clinical benefit and patient characteristics. MethodsThis two-stage, multicenter, single arm, phase II trial enrolled eligible patients to receive hu3S193 weekly at a dose of 20mg/m2 intravenously for 8weeks (1cycle) to a maximum of 3cycles. Efficacy was measured as clinical benefit rate (objective response or stable disease for at least 24weeks). Results26 of 31 patients were eligible for efficacy analysis. No complete/partial responses were observed. Six patients had stable disease for 24+weeks [clinical benefit rate 23% (95% CI=9.77%–46.71%)]. Median PFS was 8.4weeks (95% CI=6.0 to 16.1). Median PFS differed between patients with no ascites and no visceral disease and patients with ascites and/or visceral disease [16.1 vs. 8.1weeks (p=0.0058)]. The most commonly reported treatment-related adverse events were fatigue (19.3%) and nausea (16.2%). Allergic reactions occurred in 6 patients (5 with Grade 1/2; 1 with Grade 3). ConclusionsHu3S193 lacked sufficient activity in the first stage of the study to open enrollment to the second stage. However, based on the longer PFS in patients with no ascites and no visceral disease, consolidation strategies in platinum sensitive disease are currently being tested.

Abstract P6-14-07: High miR-19a serum levels correlate with favorable prognosis in patients with metastatic HER2+ inflammatory breast cancer and may result from an effective antibody-dependent cell-mediated cytotoxicity induced by trastuzumab

Abstract Background: IBC is a rare but highly aggressive form of locally advanced breast cancer (5-year OS rate: 40.5% IBC vs 85% non-IBC patients) accounting for 10% of all breast cancer deaths. To date, no unique molecular diagnostic or prognostic biomarker has been identified for IBC. Increasing evidence supports the potential value of miRNA as prognostic and predictive serum biomarker in cancer. We found that IBC cells expressed high levels of miR-19a and patients with metastatic IBC HER2+ (MIBC HER2+) and high miR-19a serum levels had better prognosis than patients with MIBC HER2+ and low miR-19a serum levels. As one of the mechanisms of action of trastuzumab is the induction of antibody-dependent cell-mediated cytotoxicity (ADCC), we hypothesized that the increased miR-19a serum levels in MIBC HER2+ patients with favorable clinical outcome could result from an effective ADCC and be used as biomarker to monitor the response to trastuzumab. Methods: Total RNA was isolated using the Total RNA Purification Kit (Invitrogen, Norgen Biotek). MiR-19a levels in tumor tissue, serum, cell lines and supernatants were evaluated by qRT-PCR (Applied Biosystems). ADCC was evaluated by Annexin V-FITC Apoptosis Detection Kit I (BD Pharmingen). Results: Microarray was performed in IBC (n=23) and non-IBC (n=24) tumors and normal tissue (n=12). Microarray showed higher miR-19a expression in IBC compared with non-IBC (p=0.028) and normal tissue (p=0.0002). The two IBC cell lines SUM149 (triple receptor-negative) and KPL-4 (HER2-amplified) expressed higher levels of miR-19a compared with the non-IBC cell lines MDA-231 (triple receptor-negative), SKBR3 (HER2-amplified), and MCF-7 (HER2-non-amplified) (p<0.001, p<0.001, p<0.001 and p<0.05, p<0.05, p<0.01 respectively). To assess whether miR-19a could be released from IBC cells upon NK cell-mediated ADCC, we performed a NK cytotoxicity test using the NK-resistant KPL-4 cells and the NK-sensitive SKBR3 and the NK-sensitive MCF-7 cells as control. Co-incubation with trastuzumab induced increased MCF-7, SKBR3 and KPL-4 cell death (2.1-fold, 2.4-fold and 3.5-fold respectively) and accordingly increased miR-19a levels in their supernatants (MCF-7: 3-fold, p=0.017; SKBR3: 6-fold, p=0.005 and KPL-4: 8-fold, p=0.0001). The pattern of miR-19a levels in the supernatants correlated with that expressed at cellular levels (MCF-7<SKBR3<KPL-4). We measured miR-19a serum levels in patients with MIBC HER2+ (n=27) and metastatic nonIBC HER2+ (n=24). Patients with MIBC HER2+ and high miR-19a level had longer PFS (10.3 vs 3.2 months, p=0.022) and OS (median not reached vs 11.2 months, p=0.003) than patients with low miR-19a levels. Patients with metastatic nonIBC HER2+ and high miR-19a levels had longer OS (32.9 vs 13.3 months; p=0.015) than patients with low miR-19a levels (32.9 vs 13.3 months; p=0.015). Conclusion: High miR-19a serum levels are associated with favorable prognosis in patients with MIBC HER2+ and could result from an effective NK cell-mediated ADCC. MiR-19a may represent a novel serum biomarker to monitor the response to trastuzumab therapy and predict clinical outcome in patients with MIBC HER2+. Citation Format: Simone Anfossi, Antonio Giordano, Lei Huo, Ricardo H Alvarez, Vicente Valero, Gabriel N Hortobagyi, Wendy A Woodward, Naoto T Ueno, George A Calin, James M Reuben. High miR-19a serum levels correlate with favorable prognosis in patients with metastatic HER2+ inflammatory breast cancer and may result from an effective antibody-dependent cell-mediated cytotoxicity induced by trastuzumab [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-14-07.

Abstract P4-01-19: The combined detection of CTC and serum HER2 ECD predict PFS for HER2-positive advanced breast cancer patients

Abstract Background: Circulating tumor cell (CTC) and serum HER2 ECD can all reflect an aggressive tumor behavior. We performed this prospective, monocenter, double-blinded study to investigate the potential clinical significance of combined detection of CTC and serum HER2 ECD for advanced breast cancer patients with histological HER2-positivity. Methods: A total of 88 eligible patients were enrolled in the present study from April 2012 to October 2013. We used Cell search system and ADVIA Centaur System to detect CTC and serum HER2 ECD respectively. Patients received systemic treatment according to national and international guidelines. Results: Twenty nine (33%) patients had ≥5 CTC, seventy three (83%) patients had serum HER2 ECD values of at least 15ng/ml, twenty seven (30.7%) patients had both elevated CTC and ECD values and fourteen (15.9%) patients had both normal CTC and ECD values. Patients with both normal CTC and serum HER2 ECD values exhibited a significantly longer median PFS than patients with both elevated values (9.0 months versus 2.8 months, p=0.023) and exhibited a trend toward longer PFS compared with patients with elevated CTC or ECD values (9.0 months versus 4.2 months, p=0.065), patients with both or one elevated values showed similar median PFS (2.8 months versus 4.2 months, p=0.211) (Figure1). Conclusions: The combined detection of CTC and serum HER2 ECD showed prognostic significance for HER-2 positive advanced breast cancer patients, patients with both normal values exhibited longer median PFS than others. Citation Format: Zefei Jiang, Jinmei Zhou, Tao Wang, Yi Liu, Lei Li, Huiqiang Zhang, Shaohua Zhang, Li Bian, Santai Song. The combined detection of CTC and serum HER2 ECD predict PFS for HER2-positive advanced breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-19.

CD34+ selected versus unselected autologous stem cell transplantation in patients with advanced-stage mantle cell and diffuse large B-cell lymphoma

Novel strategies aiming to increase survival rates in patients with advanced-stage mantle cell lymphoma (MCL) and relapsing diffuse large B-cell lymphoma (DLBCL) are a clinical need. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) has improved progression-free (PFS) and overall survival (OS) in MCL and relapsed DLBCL. However, the role of CD34+ cell selection before ASCT in MCL and DLBCL is unclear. We retrospectively analyzed the outcome of 62 consecutive patients with advanced-stage MCL or relapsed DLBCL undergoing ASCT with (n=31) or without (n=31) prior CD34+ selection. All patients had stage III or IV disease, with 47% having DLBCL and 53% MCL. The median duration for neutrophil and platelet recovery was 12 and 16 days in CD34+ selected patients, and 11 (P<.001) and 14 days (P=.012) in the group without selection, respectively. No differences in toxicities were observed. The 5-year PFS for CD34+ selected versus not selected patients was 67% and 39% (P=.016), and the 5-year OS was 86% and 54% (P=.007). Our data suggest that using CD34+ selected autografts for ASCT in advanced stage MCL and DLBCL is associated with longer PFS and OS without increased toxicity.

Exploring the effect of medication features in renal cell carcinoma: A patient preference study.

463 Background: Limited information exists about patient preference (PP) for renal cell carcinoma (RCC) medication profiles, especially related to uncertainty in outcomes, potential correlation between toxicity and efficacy, and dosing schedules. Methods: RCC patients in the United States and Canada completed an online survey with questions that examined PP for medication profiles by varying efficacy (progression free survival [PFS]), tolerability (fatigue, hand-foot syndrome, hypertension, diarrhea) and dosing schedules (with or without 2 week break). A discrete-choice experiment (DCE) survey tested the impact of information on correlation between PFS and toxicity on medication choice, with half of the sample randomly assigned to receive the information. Separate exploratory questions assessed patient tradeoff between higher toxicity during treatment vs. the chance of longer PFS (2+ years) and type of dosing schedules, respectively. Results: The interim survey results included 343 RCC patients (172 metastatic (mRCC), 96 currently on treatment). In the exploratory questions, 50% of mRCC patients and 51% of patients receiving treatment selected the option with higher toxicity and a 5% higher chance of longer PFS. Patients who received information on a potential correlation between tolerability and PFS were more likely to say they would tolerate worse toxicity for a 5% higher chance of longer PFS than those who did not receive the information (49% vs. 31%). A majority of RCC patients preferred a treatment with a 2-week break in the dosing schedule compared to continuous treatment (59% vs. 25%). When told side effects were worse during the treatment period for the medication with the break vs. the continuous treatment (moderate vs. mild), 42% of RCC patient, 50% of mRCC patients, and 55% patients on treatment still preferred a break. Additional DCE analysis is underway and will provide more results on patient preferences for medication profiles, including the importance of information received. Conclusions: Patients have heterogeneous preferences over medicine features and outcomes. Physicians need to provide patients with comprehensive information about medication features and efficacy to provide a personalized and optimal approach to treatment.

Exposure-response (E-R) relationship of ramucirumab (RAM) from two global, randomized, double-blind, phase 3 studies of patients (Pts) with advanced second-line gastric cancer.

121 Background: We evaluated the E-R relationship of RAM in pts with advanced gastric cancer from the REGARD and RAINBOW trials. Methods: Pts received RAM (8 mg/kg) or placebo (PL) q2w in REGARD; or RAM (8 mg/kg) or PL q2w + paclitaxel (PAC) 80 mg/m2 on days 1, 8, and 15 (28-day cycle) in RAINBOW. Sparse pharmacokinetic (PK) samples were collected; a population PK analysis was conducted. A model-predicted minimum concentration after first RAM dose (Cmin,1) was used for correlation with efficacy and safety variables. Kaplan-Meier, Cox regression, and logistic regression analyses evaluated E-R relationships. Results: Analyses included 72 RAM and 35 PL pts from REGARD and 321 RAM+PAC and 335 PL+PAC pts from RAINBOW. Conclusions: Ram was safe and effective at 8 mg/kg q2w. Population PK suggests higher RAM exposures were associated with longer PFS and OS, better hazard ratios, and increased toxicity. Further studies to validate the PK model and evaluate RAM dosing are warranted. [Table: see text]

Polymorphism of the chemokine CXCR4 to predict treatment benefit of first-line bevacizumab-based chemotherapy in patients with metastatic colorectal cancer.

635 Background: The chemokine receptor CXCR4 and its ligand CXCL12 promote angiogenesis and the migration of tumor cells into the metastatic sites in many cancers. CXCR4 expression on tumor cells is upregulated by hypoxia and angiogenic factors, such as vascular endothelial growth factor. Therefore, we analyzed the association between CXCR4/CXCL12 polymorphisms and prognosis in metastatic colorectal cancer (mCRC) patients underwent bevacizumab-based chemotherapy. Methods: This study included 144 Japanese patients (pts) for evaluation set and 424 patients from two clinical trials (204 of TRIBE arm A and 220 of PROVETTA) for validation set, with mCRC treated with bevacizumab-based chemotherapy as first line. A total of 144 Japanese pts with (male/female; 81/63, median age 61 years, median follow-up 4.2 years) and 424 pts (male/female; 252/172, median age 62 years; median follow-up time; 2.8 years) were enrolled in a pharmacogenomics translational study. Genomic DNA was extracted from the pts’ blood or tissue. One CXCR4 single nucleotide polymorphisms (SNP) (rs2228014) and two CXCL12 SNPs (rs1801157, rs3740085) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with the clinical outcome. Results: In univariate analysis, CXCR4 rs2228014 showed a significant difference in PFS [(G/G 15.3 months, any A allele 13.7 months, HR (95% CI) 1.64 (1.01-2.68), p=0.036)]. After multivariate analysis, CXCR4 rs2228014 remained to be a significant for PFS [HR (95% CI) 1.67 (1.01-2.78), p =0.046]. However, this polymorphism was not associated with tumor response and survival. In the validation cohort, pts with GG genotype had significantly longer PFS compared to those with any A allele (10.5 vs 9.6 months, HR (95% CI) 1.40 (1.02-1.93), p =0.035). CXCL12 polymorphisms were not associated with the clinical outcome. Conclusions: This study shows for the first time that CXCR4 rs2228014 may serve as a predictive marker in patients with mCRC treated with bevacizumab-based chemotherapy.

Racial Disparity in Patients with Multiple Myeloma Are Blunted in the Era Novel Therapies

Background: Multiple myeloma is the most common hematological malignancy among african americans (AA). Prior studies have shown conflicting results for outcomes based upon ethnicity following autologous stem cell transplantation (ASCT). However, much of this data is older, and predates the use of novel agents such as bortezomib (V), lenalidomide (R) and thalidomide (T).Methodology: We performed a retrospective analysis of 292 patients (147 AA and 145 Caucasian) treated with novel agents (proteasome inhibitors or immune modulators) and ASCT from 2006 to 2012 at the Winship Cancer Institute of Emory University to evaluate the impact of ethnicity on outcomes.Results: Baseline characteristics such as stage (International Staging System, ISS), presence of lytic lesions or plasmacytomas, immunoglobulin subtype, and cytogenetic risk category at presentation, were comparable between AA and white patients. Among AA, 112 (76.19%) patients received bortezomib containing regimens (VRD: 34.8%, VTD: 22.3%, VDTPACE:11%, VDD:10%, VD:19% and others bortezomib regimens 8%), 54 (36.7%) patients received lenalidomide (VRD: 34.8% or RD: 11.6%) and 72 (49%) patients received thalidomide (VTD: 22.3% or TD: 11.6%). In white patients 113 (77.93%) received bortezomib containing regimens (VRD: 33.1%, VTD: 17.2%, VDTPACE:9.6%, VDD: 1.4% and VD:11.7% and other bortezomib regimens 1.3%), 69 (47.6%) patients received lenalidomide containing regimens (VRD:33.1% and RD:11%) and 62 (42.8%) patients received thalidomide containing regimens (VTD: 17.2% or TD: 15%). A higher percentage of patients in the white cohort carried the antecedent diagnosis of monoclonal gammopathy in white patients (AA:0 vs white: 4.8%, p=0.007), and as expected, AA patients presented at a younger age when compared with whites (mean age of 55 vs 59 years, respectively, p<0.001). The overall response rate (ORR) of induction in the entire population was 86%, with an >VGPR of 58.8%. No difference was identified in pre-transplant ORR and >VGPR between AA (87.9% and 25.9%, respectively) and white patients (81.54% and 22.4%, respectively, p>0.1). Similarly, the ORR and >VGPR 100 days after transplantation was comparable between both ethnic groups (AA: OR:90.74% and >VGPR:74.07% vs white OR:90.65% and >VGPR: 77.57%, p>0.1). The depth of response after ASCT improved similarly in both groups (AA: 57.3% vs white: 67.7%, p=0.1). When the overall survival and progression free survival where evaluated, we found no significant differences between both cohorts. Factors associated with longer PFS in the population studied include AA race and the introduction of lenalidomide in the induction regimen. In AA patients univariate analysis identified early stage at presentation, indolent disease (prolong time from diagnosis to transplant), optimal pre-transplant response, and pre-transplant use of lenalidomide (HR:0.38 (0.18-0.8), p=0.01) as factors that potentially prolong PFS. Multivariate analysis identified the use of lenalidomide, as part of the pretransplant regimen, to reduce the risk of relapse (HR:0.38 (0.18-0.8), p=0.01) compared to bortezomib use (HR: 5.3 (2.11-11.98), p<0.001). In white patients, univariate and multivariate analysis identified that IgG and kappa light chain MM and indolent disease were factors associated with longer PFS, while history of plasma cell leukemia was related to shorter PFS.In conclusion, our results showed that novel agents have improved the response rate of both ethnic populations. From our preliminary analysis, it appears the PFS is longer among AA patients, suggesting a potential difference in MM biology of this patient population. DisclosuresLonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Outcomes for Myeloma in the Era of Lenalidomide Maintenance Are Not Different Among Ethnic Groups Following Autologous Transplant

Background: Multiple myeloma (MM) is the most common hematological malignancy among African Americans (AA). The introduction of postransplant maintenance has had a significant improvement in progression free and overall survival for myeloma patients as demonstrated in large phase III clinical trials. However, the impact of race on the outcome of patients receiving maintenance treatment remains unknown.Methodology: We conducted a retrospective analysis of 299 consecutive patients transplanted for MM from 2005 to 2013 at the Winship Cancer Institute of Emory University. Survival analyses were estimated by Kaplan-Meier methods and univariate and multivariate analysis were performed using a cox proportional hazard model.Results: Baseline characteristics such as stage (International Staging System, ISS), presence of lytic lesions or plasmocytomas, immunoglobulin subtype, and cytogenetic risk category at presentation, were comparable between AA and white patients. Among AA, 57.1% received triple therapy with an immune modulator and a proteasome inhibitor (IMID+PI, lenalidomide (R) or thalidomide (T) and bortezomib (V) and dexamethasone), 49% received doublets (RD, TD or VD) and 29% received other bortezomib based regimens. In white patients 50.3% were treated with IMID+PI, 37% with doublets, 13.6% with received other bortezomib based regimens. Both populations had comparable ORR and >VGPR at day 100 (AA: ORR:90.74% and >VGPR:74.07% vs White ORR:90.65% and >VGPR: 77.57%, p>0.1). Of the 299 patients, 128 patients underwent maintenance treatment with lenalidomide (AA: 61 and White:67 patients) while 171 did not receive lenalidmode as they transplanted prior approval of lenalidomide maintenance. Maintenance treatments improved progression free survival in both ethnic cohorts. AA patients receiving maintenance therapy have not yet reached their median PFS with a median follow up of 8 years (60%), while median PFS was 4.8 years among those who did not receive maintenance (p=0.4). Similarly, in white patients, the PFS improved from 2.8 years without maintenance to 5.4 years with maintenance (p=0.01). Furthermore race did not affect PFS in both maintenance treated cohorts. Within the cohort of patients that did not receive maintenance therapy, we observed a trend of improvement in overall survival in AA patients ( p=0.06), which could suggest difference in the risk of the disease. However, no differences in staging or cytogenetics were identified between both ethnic groups at diagnosis that could explain this difference. Factors associated with longer PFS in univariate and multivariate analysis included AA race and immunoglobulin subtype (IgG and kappa light chain MM). In AA multivariate analysis identified the presence of lytic lesions as a factors associated with shorter PFS. In white patients, factors such as plasma cell leukemia at diagnosis were associated with worst PFS.In conclusion, race did not impact the improvement in PFS associated with post-transplant maintenance therapy. To our knowledge this preliminary analysis provides the first assessment of the influence of race in MM outcomes post-transplant during the lenalidomide maintenance era DisclosuresLonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Triple-negative breast cancer patients treated at MD Anderson Cancer Center in phase I trials: improved outcomes with combination chemotherapy and targeted agents.

Patients with metastatic triple-negative breast cancer (TNBC) have poor treatment outcomes. We reviewed the electronic records of consecutive patients with metastatic TNBC treated in phase I clinic at MD Anderson Cancer Center (Houston, TX) between Augu st 2005 and May 2012. One hundred and six patients received at least 1 phase I trial. Twelve of 98 evaluable patients (12%) had either complete response (CR; n = 1), partial response (PR; n = 7), or stable disease ≥ 6 months (SD; n = 4). Patients treated on matched therapy (n = 16) compared with those on nonmatched therapy (n = 90) had improved SD ≥ 6 months/PR/CR (33% vs. 8%; P = 0.018) and longer progression-free survival (PFS; median, 6.4 vs. 1.9 months; P = 0.001). Eleven of 57 evaluable patients (19%) treated with combination chemotherapy and targeted therapy had SD ≥ 6 months/PR/CR versus 1 of 41 evaluable patients (2%) treated on other phase I trials (P = 0.013), and longer PFS (3.0 vs. 1.6 months; P < 0.0001). Patients with molecular alterations in the PI3K/AKT/mTOR pathway treated on matched therapy (n = 16) had improved PFS compared with those with and without molecular alterations treated on nonmatched therapy (n = 27; 6.4 vs. 3.2 months; P = 0.036). On multivariate analysis, improved PFS was associated with treatment with combined chemotherapy and targeted agents (P = 0.0002), ≤ 2 metastatic sites (P = 0.003), therapy with PI3K/AKT/mTOR inhibitors for those with cognate pathway abnormalities (P = 0.018), and treatment with antiangiogenic agents (P = 0.023). In summary, combinations of chemotherapy and angiogenesis and/or PI3K/AKT/mTOR inhibitors demonstrated improved outcomes in patients with metastatic TNBC.

NI-32 * ENHANCING TUMOR RESPONSE USING QUANTITATIVE VOLUMETRY FROM T1 SUBTRACTION MAPS IN MALIGNANT GLIOMA TREATED WITH DENDRITIC CELL VACCINATION

PURPOSE: To ascertain the radiologic response and serial volumetric changes in patients with glioblastoma multiforme (GBM) treated with dendritic cell (DC) vaccine using contrast enhanced (CE) T1-weighted subtraction maps. METHODS: MR images were acquired for fourteen patients with newly diagnosed or recurrent GBM. Genetic analyses and intratumoral histopathology were performed on all but one patient. Changes in CE tumor volumes were assessed with CE T1-weighted subtraction maps generated via voxel-wise subtraction of Gaussian-normalized signal intensities T1-weighted and CE T1-weighted images. Response criterion was determined as 25% reduction in the T1 subtraction CE tumor volume with respect to pre-vaccination baseline. Response stratification was tested as a predictor of PFS using log-rank univariate analysis. RESULTS: Four patients responded to the treatment within the first three months of treatment. Ten patients did not respond within the same period of time. One patient exhibited a growth pattern consistent with pseudo-progression between 100 and 300 days after vaccination. A significant difference in tumor growth rate (P = 0.0064) months between responders and non-responders was found within the first three months via linear regression. A preference for unfavorable response in MGMT unmethylated, EGFR amplified, and EGFRVIII mutated tumors, and favorable response in IDH1 mutant tumors was observed. A significantly longer PFS was found both from the opening date of the trial for each patient (Log-rank, P = 0.0149) and from the date of first vaccination (Log-rank, P = 0.0440) for responders versus non-responders. CONCLUSION: The clinical utility of T1 subtraction maps for tumor visualization and burden evaluation was shown. Response outcomes to DC vaccine therapy become apparent within the first three months of following treatment. Mischaracterization of pseudo-progression in the context of DC vaccine therapy for malignant glioma may not be a major concern. Genetic analyses and histopathological considerations may be a component in assessing treatment response to immunotherapy in malignant gliomas.

Tumor MET expression profile predicts the outcome of non-small cell lung cancer patients receiving epidermal growth factor receptor tyrosine kinase inhibitors.

This study assesses whether MET expression in tumor tissue is associated with an increased sensitivity to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients. This retrospective study included 69 NSCLC participants with available tumor tissue and data on treatment response and survival. MET and hepatocyte growth factor expression in tumor tissue were evaluated by immunohistochemistry. Positive tMET expression correlated with a shorter progression-free survival (PFS; P = 0.003) and overall survival (OS; P = 0.05). Positive pY1234/1235 expression was significantly associated with a longer PFS (P = 0.031) and OS (P = 0.012). In multivariable analyses, tMET and pY1234/1235 expression were independent factors for PFS and OS, respectively. (tMET, PFS; P = 0.02, OS; P = 0.0007 and pY1234/1234, PFS; P = 0.01, OS; P = 0.004). This study suggests that total and phosphorylated MET expression in tumor tissue is potentially useful for the selection of NSCLC patients who are likely to benefit from EGFR-TKIs, irrespective of their EGFR status.

Stomatitis incidence and its relationship with efficacy: A meta-analysis of everolimus clinical studies.

151 Background: The most common adverse event (AE) with everolimus (EVE) is stomatitis. This meta-analysis evaluated the incidence, severity, and possible impact of stomatitis on efficacy in patients (pts) with cancer or tuberous sclerosis complex (TSC) who received EVE. Methods: Stomatitis events from 7 randomized, double-blind, phase 3 EVE studies included: RECORD-1 (RCC), RADIANT-2 (NET), RADIANT-3 (pNET), BOLERO-2 (HR+/HER2- breast cancer [BC]), BOLERO-3 (HER2+BC), and EXIST-1 and -2 (TSC). Time to first stomatitis occurrence and recurrence were analyzed using Kaplan-Meier (KM) methods. Stratified Cox regression analysis adjusted for baseline prognostic factors and corrected for confounding effect of duration of exposure was used to analyze association between stomatitis occurrence (≤ 8 wks of EVE start) and PFS in pts with cancer and response rate in pts with TSC. Results: This evaluation included EVE-treated pts with cancer (n = 1,455) and TSC (n = 157). Pts with cancer had stomatitis incidence of 66.9%, which occurred early, median 0.82 mo (95% CI, 0.7-1.0; 2-mo KM estimate 60.8%). 8.6% were grade 3/4 events. 1.7% of pts discontinued due to stomatitis. Stomatitis recurred in 40% of pts and appeared gradually. In pts with TSC similar results were observed. In EVE-treated pts, development of stomatitis was associated with longer PFS (corrected HR [95% CI]) in BOLERO-2 (0.78 [0.62-1.00]) and RADIANT-3 (0.70 [0.48-1.01]), and similar trend was observed in RECORD-1 (0.90 [0.66-1.22]) and RADIANT-2 (0.87 [0.61-1.22]), but not in BOLERO-3. In TSC, probably due to few pts, relationship between stomatitis and response was not conclusive. In all trials, pts on EVE had longer PFS vs placebo irrespective of stomatitis incidence. Conclusions: Stomatitis is observed frequently in initial wks of EVE therapy. Most AEs were grade 1/2 and manageable, rarely led to pt discontinuation. Stomatitis recurred in &lt; 50% of pts. EVE-treated pts with cancer who had stomatitis achieved stable benefit similar to overall population, suggesting that continuing EVE is helpful. The importance of prophylactic measures in reducing EVE-induced stomatitis incidence and improving its management is being determined by ongoing studies.

Egfr-Tyrosine Kinase Inhibitor (Tki) Rechallenge with Bevacizumab in Egfr-Mutant Non-Small Cell Lung Cancer (Nsclc)

ABSTRACT Aim: Several reports demonstrated efficacies of EGFR-TKI rechallenge in EGFR-mutant NSCLC, but the efficacies were only moderate (response rate [RR], 0-10% disease control rate [DCR], 20-30%, and progression-free survival [PFS], 2-3 months). Some preclinical studies suggested synergistic effects of bevacizumab and EGFR-TKI in TKI-resistant models. The aim of our study was to evaluate the efficacy and safety of EGFR-TKI rechallenge with bevacizumab after acquired resistance to TKI in EGFR-mutant NSCLC. Methods: Between January 2010 and January 2014, twenty-one NSCLC patients, previously treated with EGFR-TKIs, received EGFR-TKI rechallenge in combination with bevacizumab. We retrospectively evaluated the RR, DCR, PFS, overall survival (OS), and safety. Re-biopsy was performed in all cases to examine T790M resistant mutation status. The efficacy was compared between T790M-positive and –negative populations. Results: The eligible 21 patients were all EGFR mutant. Previous EGFR-TKI treatments were 8 gefitinib, 11 erlotinib, and 2 afatinib. 11 patients had EGFR-TKIs rechallenge with bevacizumab successively without interval, and 10 patients received same after 1-4 intervening systemic regimens. EGFR-TKIs for rechallenge in combination with bevacizumab were 2 gefitinib and 19 erlotinib. Two (9.5%) had partial response, 12 (90%) had stable disease. The RR and DCR were 9.5% and 95%, respectively. The median PFS was 3.6 months (95% confidence interval (CI); 2.5-14.9 months), and the median OS was 13.5 months (95% CI; 9.7-21 months). On re-biopsy, 6 patients had T790M with the initial sensitive mutation. The RR, DCR, median PFS and median OS for T790M positive vs negative were 0% vs 13% (p = 0.23), 100% vs 93% (p = 0.40), 3.6 months vs 4.1 months (p = 0.78), and 15.1 months vs 13.5 months (p = 0.656), respectively. Severe adverse events (≧grade 3) were as follows: grade 3 hypertension in one (4.8%) and grade 3 anemia in one patient (4.8%). Conclusions: EGFR-TKI rechallenge with bevacizumab demonstrated higher DCR and modestly longer PFS, compared with EGFR-TKI monotherapy rechallenge. Its activity did not differ according to T790M status. EGFR-TKI rechallenge with bevacizumab can be a therapeutic option for EGFR-mutant NSCLC with acquired resistance regardless of resistant mechanisms. Disclosure: All authors have declared no conflicts of interest.

Efficacy and safety of lenalidomide in relapse/refractory multiple myeloma--real life experience of a tertiary cancer center.

Lenalidomide was approved for the treatment of relapsed and refractory multiple myeloma (rrMM) based on MM009 and MM010 clinical trials. However, its effectiveness and safety profile in real clinical practice should be further assessed. We retrospectively evaluated 90 consecutive patients treated in our center with lenalidomide and dexamethasone (LenDex) between 2007 and 2012. The overall response rate to this treatment was 68% and the median duration of response was 13.6months. Patients treated in first relapse and those treated with LenDex longer than 1year achieved the best responses. Cytogenetics was associated with PFS and best response to treatment was the only variable associated with longer PFS and OS in univariate and multivariate analyses. Our analysis confirmed that LenDex is effective in rrMM patient, well tolerated, and applicable to the majority of patients outside clinical trials; patients achieving a complete response, even in the context of relapse, have a longer survival; quality of response is better when lenalidomide is used in second line than later on and it is a good surrogate marker for OS. Accordingly, CR should be aimed in the rrMM setting, especially in fit patients. Previous treatment with thalidomide should not hamper the option for lenalidomide therapy.

Different efficacy of EGFR tyrosine kinase inhibitors and prognosis in patients with subtypes of EGFR-mutated advanced non-small cell lung cancer: a meta-analysis.

Background Nearly 85 % of lung-cancer-specific epidermal growth factor receptor (EGFR) sensitive mutations comprise a substitution at position 858 (21L858R) and deletion mutants in exon 19 (19del). The aim of this study was to assess the role of EGFR mutation subtypes in predicting the efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs) and the prognosis of patients with advanced non-small cell lung cancer (NSCLC).Method We systematically searched for eligible articles investigating the association between EGFR mutation subtypes and the efficacy of EGFR TKIs and the prognosis of patients with NSCLC. The summary risk ratio (RR) and mean difference (MD) were calculated using meta-analysis. In addition, we used variance analysis for the progression-free survival data (PFS) and used the rank sum test for the overall survival data.ResultsWe identified 22 eligible trials involving 1,082 patients. The objective response rate of the 19del mutation group was significantly higher than the 21L858R mutation group (RR 1.23; 95 % CI 1.12–1.36; P < 0.0001). The PFS (MD 3.55; 95 % CI 0.90–6.20; P = 0.009; MD 2.57; 95 % CI 0.51–4.62; P = 0.01) and overall survival (OS) (MD 10.52; 95 % CI 5.10–15.93; P = 0.0001) of the 19del mutation group were significantly longer than the 21L858R mutation group; the same results were observed in the variance analysis and rank sum test.ConclusionThe 19del mutation may be a more efficient clinical marker for predicting the response of patients with NSCLC to EGFR TKIs. Furthermore, patients with the 19del mutation have both a longer PFS and OS. The 19del mutation is also the prognostic factor for patients with NSCLC.

Predictive and prognostic significance of early positron emission tomography/computed tomography (PET/CT) in advanced transitional cell carcinoma.

341 Background: A risk-adapted treatment for TCC may guide new trial designs for early-recognized unresponsive patients (pts). We aimed to prospectively identify early fluorodeoxyglucose (FDG)-PET/CT as a predictor of response and outcome. Methods: Pts with newly-diagnosed advanced/metastatic TCC receiving first-line chemotherapy underwent CT and FDG-PET/CT at baseline, a restaging with PET/CT after 2 cycles only (PET2), and a CT (± FDG-PET/CT) at the end of treatment and during follow up. The endpoints were PET2 metabolic response, RECIST response, progression-free (PFS) and overall survival (OS). Univariable (UVA) and multivariable (MVA) Cox models were fitted. Prespecified variables were presence of visceral metastases, nodal or soft tissue disease, and PET2 response. Results: In the time-frame 05/2010-10/2012, 31 pts with ECOG-PS 0 received a modified MVAC regimen according to Institutional protocol, every 3 weeks. After 2 cycles of MVAC, 6 patients (19.3%) had a complete (CR) and 17 (54.8%) a partial metabolic response (PR) (74% total responders; 95% CI, 55.4-88.1%), 4 had stable disease (SD), 4 progressed. Metabolic response (CR + PR) was associated with final CT response (p=0.007 at Fisher exact test). Metabolic CR was followed by a RECIST CR in all but one cases and metabolic progression at PET2 corresponded to a RECIST PD in all four patients and they all switched to second line chemotherapy. Median follow up was 18 months (IQR: 10-47). Those with metabolic response had a median (95% CI) PFS of 8 (7-11) months compared to 3 (2-5) months of patients without response (p=0.024). PET2 responders had a significant benefit in 8-month PFS (p&lt;0.001) and 15-month OS (p=0.016 at Klein test). A significant association was observed between PET2 response and longer PFS in both UVA and MVA (p=0.027 and p=0.023, respectively). Results are limited by small numbers. Conclusions: PET2 response might confer an independent prognostic impact on PFS and OS. Results warrant a validation series, a comparison with the impact of early RECIST response as well as a detailed cost-efficacy analysis prior to devise a new strategy of first-line treatment.

PK-Directed Intravenous Busulfan in Combination with High-Dose Melphalan and Bortezomib As Conditioning Regimen for Patients with Multiple Myeloma

Introduction High dose therapy followed by autologous hematopoietic stem cell transplantation (ASCT) has an established role in the treatment of patients with multiple myeloma (MM). The most commonly used conditioning regimen in this setting is high-dose melphalan (200mg/m2; Mel200), which has been shown to result in improved progression free (PFS) and overall survival (OS). Achievement of a complete response (CR) following ASCT is an indicator for freedom from relapse, as well as PFS and OS. The CR rate observed after Mel200 followed by ASCT is between 10-35%. There is evidence that the combination of busulfan (Bu) and melphalan (Mel) results in longer PFS and OS compared to Mel alone. Additionally, the use of bortezomib (Btz) during conditioning with either high dose Mel alone or the combination of Mel and intravenous (i.v.) Bu has shown to be both safe and to have promising efficacy. The objective of our trial is to assess whether the combination of PK-directed Bu, Mel and Btz (BuMelBtz) during conditioning for a first ASCT in MM patients is both safe and efficacious. Methods Patients aged 18-72 with multiple myeloma, who had 1) measurable disease, 2) received less than one year of prior myeloma-directed therapy, 3) adequate organ function and performance status, and 4) an indication for ASCT were eligible. Exclusion criteria were >/= grade 2 neuropathy, prior stem cell transplant, uncontrolled intercurrent illnesses or comorbidities, unresolved >/= grade 2 toxicities from prior therapies, and prior malignancies except non-melanoma skin cancer. Treatment consisted of PK-directed i.v. Bu (4 daily 3-hour infusions from day (D) -6 to -3 to target a total AUC of 20,000 μMxmin), i.v. Mel 140mg/m2 on D-2, and i.v. Btz 1.4mg/m2 on D-6, -4, +1 and +4. The individual daily doses for Bu on D-6 and D-5 were determined by PK measures following a test dose (0.8mg/kg) 5-9 days prior to first Bu treatment dose; the last 2 doses (day -4 and -3) could be adjusted following another PK measure after the first full treatment dose on D -6. Stem cells were infused on D0. Subsequent consolidative or maintenance therapy was left to investigator choice. Primary outcome was CR rate assessed on D +100 post ASCT as per IMWG criteria. Secondary outcomes were overall response rate (ORR), toxicities, PFS and OS. The trial is registered at clinicaltrials.gov ([NCT01605032][1]). Results To date, 13 patients have been treated. The median age was 63 years (range 44-70), 62% (n=8) were male, 23% had ISS stage 3 (3/13), no patient had high risk cytogenetic features. The median number of regimens prior to ASCT was 1 (range 1-3) and included bortezomib in 92% (n=12). Prior to BuMelBtz the best treatment response had been stable disease (SD) in 3 patients, partial response (PR) in 8; only 1 patient each had achieved a very good partial response (VGPR) or CR. Following BuMelBtz/ASCT, median days to ANC >/=0.5 x 109/L and platelet count >/=30 x 109/L were 11 (range 10-13) and 17 (11-29), respectively. The most common non-hematological toxicities were alopecia (100%), oral mucositis (62% G3), dysphagia (85% G3, but no patient required TPN or enteral feeding), as well as electrolyte abnormalities (62% G3/4). Other common toxicities were nausea (92%, all G1/2), diarrhea (84% G1/2, 8% G3), while 77% of patients developed fully reversible transaminitis (15% G3). Less common G3 toxicities included delirium (8%), colitis (8%), skin infection (zoster, 8%), other infections (23%), and delirium (8%). One patient developed GI symptoms suggestive of acute GVHD on a gastric biopsy 8 weeks after ASCT. No patient developed sinusoidal obstruction syndrome of the liver. At 100 days post BuMelBtz/ASCT, response assessment was available for 8 patients: 1 achieved a stringent CR (12.5%), 4 VGPR (50%), and 3 PR (37.5%), resulting in a 100% ORR. One patient improved from a VGPR to a stringent CR during follow up. After a median follow up of 5 months (range 1-15) all patients are alive and no patient has relapsed. The trial is ongoing. Conclusion PK directed i.v. Bu in combination with Mel and Btz (BuMelBtz) is an effective and safe conditioning regimen for patients with multiple myeloma. Further evaluation is warranted. Disclosures: Barta: Otsuka: Research Funding; Onyx: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria. Off Label Use: IV Busulfan for the treatment of multiple myeloma. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01605032&atom=%2Fbloodjournal%2F122%2F21%2F5513.atom

High‐level ERBB2 gene amplification is associated with a particularly short time‐to‐metastasis, but results in a high rate of complete response once trastuzumab‐based therapy is offered in the metastatic setting

Despite patient selection based on ERBB2 overexpression, not all patients benefit from trastuzumab therapy. We have investigated whether a ERBB2 gene dosage effect might provoke increased biological aggressiveness and altered trastuzumab sensitivity. Absolute ERBB2 copy numbers ("CN") and ERBB2/centromer 17 ratios ("R") were measured by FISH analysis in tumors of 127 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer. CN and R were both significantly associated with shorter time to first metastasis (TTM) (CN: OR: 1.099, 95% CI: 1.042-1.159; R: OR: 1.211, 95% CI: 1.080-1.357) and longer PFS (CN: OR: 0.917, 95% CI: 0.867-0.969; R: OR: 0.840, 95% CI: 0.743-0.949) in a continuous variable Cox's regression model. Tumors with ERBB2/centromer 17 ratios of <2.2 had a significantly shorter TTM (p = 0.002) and significantly longer PFS (p = 0.003) than tumors with low-level (R: 2.2-6) and high-level amplification (R: >6). Interestingly, when ERBB2 copy numbers were analyzed, a significantly shorter TTM (p = 0.001) and longer PFS (p = 0.026) were observed in the group with high-level amplified CN (CN: >13), while no difference was observed between non- and low-level amplified CN. R, but not CN, was an independent predictor of complete (CR; OR: 1.685; 95% CI: 1.122-2.532) and partial (PR; OR: 1.704; 95% CI: 1.136-2.556) response in logistic regression analysis. CR (p = 0.016) rates were significantly higher in the high-level amplification group (R > 6), but no difference existed in response rates between non- and low-level amplified tumors in Chi-square tests. High-level ERBB2 amplification is associated with shorter TTM, but improved response to trastuzumab in metastatic breast cancer.