Difference In Terms Of Progression-free Survival Research Articles

The clinical impact of serous tubal intraepithelial carcinoma on outcomes of patients with high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum.

To investigate whether the presence of serous tubal intraepithelial carcinoma (STIC) is associated with clinical outcomes in a nonselected (unknown BRCA status) cohort of patients with a high-grade serous carcinoma (HGSC) of the ovary, fallopian tube, and peritoneum. A prospective case-series with planned data collection. The study was conducted in a total of 131 patients, who underwent primary cytoreductive surgery between 2007 and 2012. Histological examination of the fallopian tubes included the "sectioning and extensively examining the fimbriated end" protocol. The diagnosis of STIC was based on the combination of morphology and immunohistochemistry. The patients were divided into two groups according to the absence or presence of STIC and compared clinicopathologically. Analyses were performed using PASW 18 (SPSS/IBM, Chicago, IL, USA) software. The primary outcome was progression-free survival (PFS), and the secondary outcome was overall survival (OS). STIC was identified in 20.6% of patients. Median follow-up time was 49.5 months for the STIC-positive group and 38.0 months for the STIC-negative group. Study groups were comparable in terms of clinicopathological characteristics with the exception that patients with STIC had less lymph node involvement (55.0% vs. 65.4%, P = 0.001), and more diagnosis of primary tubal carcinoma (29.6% vs. 3.8%, P = 0.001) compared to those without STIC. No statistically significant differences in terms of PFS (P = 0.462) and OS (P = 0.501) were observed between the groups. The absolute identification of the origin of tumor cell does not seem to significantly affect the clinical course of the patients with HGSC.

Total tumor burden as predictive tool of response and survival of patients with metastatic melanoma treated with nivolumab.

e21022 Background: Nivolumab (NIVO) has shown increased results either in objective response rate (ORR), progression free survival (PFS) and overall survival (OS), which have completely changed the treatment of patients with metastatic melanoma (MM). Tools to guide selection of patients are absent Methods: This is a retrospective, observational, single-center study. The TBT was calculated considering the sum of the largest diameter of all measurable lesions and the smallest diameter of lymph nodes affected Results: 54 patients with histologiacally confirmed mm were included in the protocol (OCT/14-may/16). Patients had a median age of 61 years (22-86 years), 58% were male, and 73% of tumor were located in the skin. 42% had ECOG 1, 72% had M1c, and 36% had LDH over the upper limit of normality (ULN). 34% had the mutation of the BRAF (half of them treated with IBRAF). About 75% had no prior benefit with anti-CTLA4 and 21% of the population had brain metastases. The median follow-up was 11.1 months and the median NIVO doses was 10 cycles. The ORR was 30.2% and the clinical benefit rate was 54.7%. The median PFS was 6.89 months (95% CI 1.12 to 12.6 months) and OS was not reached. TBT being < or > the median impact on OS with HR 4.5 (95% CI 1.22 to 16.9; p = 0.024). Once again, there was a statistically significant difference in terms of PFS and OS when related to pooled TBT ≤ or > 200 mm. The PFSm was 9.4 months (95% CI NR) for TBT ≤ 200 and 2.6 months ( 95% CI 1.9 to 3.2 months) to TBT > 200, with a HR: 2.64 (95% CI 1.03 to 6.74; p = 0.042). OSm regarding TBT ≤ 200 was not reached and was 2.6 months (95% CI 2.0 to 3.2 months) to TBT > 200, with RH:8.9 (95% CI 2.56 to 30.9; p = 0.001). According to the Fisher's exact test analysis, there is a significant association between LDH > ULN and pooled TBT > 200, with p = 0.023. Also, a relation between grouped TBT ( ≤ 200 or > 200) and the type of response seemed to be significant, with p = 0.021. Conclusions: The results of our study are very consistent with current medical literature. In our study, high TBT was associated with less response rates and both less OS and PFS rates.

Total tumor burden as predictive tool of response and survival of patients with metastatic melanoma treated with nivolumab.

48 Background: Nivolumab (NIVO) has shown increased results either in objective response rate (ORR), progression free survival (PFS) and overall survival (OS), which have completely changed the treatment of patients with metastatic melanoma (MM). Tools to guide selection of patients are absent. Methods: This is a retrospective, observational, single-center study. The TBT was calculated considering the sum of the largest diameter of all measurable lesions and the smallest diameter of lymph nodes affected. Results: 54 patients with histologiacally confirmed MM were included in the protocol (OCT/14-may/16). Patients had a median age of 61 years (22-86 years), 58% were male, and 73% of tumor were located in the skin. 42% had ECOG 1, 72% had M1c, and 36% had LDH over the upper limit of normality (ULN). 34% had the mutation of the BRAF (half of them treated with IBRAF). About 75% had no prior benefit with anti-CTLA4 and 21% of the population had brain metastases. The median follow-up was 11.1 months and the median NIVO doses was 10 cycles. The ORR was 30.2% and the clinical benefit rate was 54.7%. The median PFS was 6.89 months (95% CI 1.12 to 12.6 months) and OS was not reached. TBT being < or > the median impact on OS with HR 4.5 (95% CI 1.22 to 16.9; p = 0.024). Once again, there was a statistically significant difference in terms of PFS and OS when related to pooled TBT ≤ or > 200 mm. The PFSm was 9.4 months (95% CI NR) for TBT ≤ 200 and 2.6 months ( 95% CI 1.9 to 3.2 months) to TBT > 200, with a HR: 2.64 (95% CI 1.03 to 6.74; p = 0.042). OSm regarding TBT ≤ 200 was not reached and was 2.6 months (95% CI 2.0 to 3.2 months) to TBT > 200, with RH:8.9 (95% CI 2.56 to 30.9; p = 0.001). According to the Fisher's exact test analysis, there is a significant association between LDH > ULN and pooled TBT > 200, with p = 0.023. Also, a relation between grouped TBT ( ≤ 200 or > 200) and the type of response seemed to be significant, with p = 0.021. Conclusions: The results of our study are very consistent with current medical literature. In our study, high TBT was associated with less response rates and both less OS and PFS rates.

Efficacy of fluoropyrimidine-based chemotherapy in patients with advanced biliary cancer after failure of gemcitabine plus cisplatin: Retrospective analysis of 321 patients.

425 Background: In advanced biliary tract cancer (BTC), the role of 2nd line chemotherapy after failure of 1st line gemcitabine plus cisplatin (GEMCIS) has not been established. Fluoropyrimidine(FP)-based regimens are widely used as 2nd line treatment in clinical practice. We retrospectively analyzed the efficacy of 2nd line FP-based chemotherapy in patients(pts) with advanced BTC after failure of GEMCIS. Methods: Histologically confirmed advanced BTC pts who received 1st line GEMCIS at Asan Medical Center between December 2010 and June 2016 were identified. Among 748 pts treated with GEMCIS, 331 patients (44%) subsequently received 2nd line chemotherapy and FP-based regimens were used in 321 pts (97%). Results: The median age was 60 years (range, 27-82) and 57% of pts were male. Intrahepatic cholangiocarcinoma(IH-CCC) (44%) was the most common type, and followed by extrahepatic cholangiocarcinoma (32%). Most pts (n = 289, 89%) had metastatic/recurrent disease at the time of 1st line treatment. FP alone and FP plus platinum combination were used in 255 pts (79%) and 66 pts (21%), respectively. In pts with measurable disease, response rate (RR) was 3% (8/301) and disease control rate was 47% (142/301). After a median follow-up of 27.6 months (0.9-70.4 months), the median progression free survival (PFS) and overall survival (OS) were 1.9 months (95% CI, 1.6-2.2) and 6.5 months (95% CI, 5.9-7.0). RR was significantly higher in pts with combination of FP and platinum compared to FP alone (8% vs 1%, p = 0.009). However, there were no statistically significant differences in terms of PFS (p = 0.43) or OS (p = 0.88) between two groups. In the multivariate analysis for OS, IH-CCC, initially metastatic disease and elevated CA 19-9 level at the time of 1st line treatment, and time-to-progression at 1st line GEMCIS > 4 months were independent poor prognostic factors. Conclusions: In this analysis, FP-based regimen showed modest efficacy as 2nd line chemotherapy for advanced BTC patients after failure of 1st line GEMCIS. Combination of FP and platinum was not associated with improved survival outcomes compared to FP monotherapy, despite of higher RR.

The role of pharmacogenetics in the new ESMO colorectal cancer guidelines.

The role of pharmacogenetics in the new ESMO colorectal cancer guidelines.

Gemcitabine-induced thrombocytosis as a potential predictive factor in non-small cell lung cancer: analysis of 318 patients.

In spite of the progress in the treatment of non-small-cell lung cancer (NSCLC), the majority of patients with advanced disease still receive chemotherapy. Gemcitabine alone or combined with a platinum compound is a valid option. Thrombocytosis is a recognized prognostic factor in lung cancer and an adverse event that may occur during gemcitabine infusion. We retrospectively evaluated all patients with NSCLC treated with first-line gemcitabine-based chemotherapy in two Italian hospitals. We assessed the onset of thrombocytosis within the third cycle of therapy and the relation between thrombocytosis and survival. We included 318 patients. Thrombocytosis occurred in 156 patients (49.1%). Median progression-free survival (PFS) was 5.6 months (95% CI, 4.7-6.9 months) in patients who developed thrombocytosis versus 6 months (95% CI, 5.1-7.2 months) in patients without thrombocytosis (p = 0.21). Median overall survival (OS) was 11.2 months (95% CI, 9.8-13.4 months) in patients with thrombocytosis versus 12 months (95% CI, 10.1-14.4 months) in patients without thrombocytosis (p = 0.25). We observed no difference in terms of PFS or OS according to age, sex, stage, chemotherapy (single-agent versus combination chemotherapy) and thrombocytosis. Thrombocytosis is neither a prognostic nor a predictive factor for PFS or OS in patients with advanced NSCLC treated with first-line gemcitabine-based chemotherapy.

Everolimus and sunitinib as first- and second-line treatments of patients with metastatic papillary renal cell carcinoma (pRCC): A retrospective study of the GETUG (Groupe Français d’Etude des Tumeurs Uro-Génitales).

505 Background: pRCC accounts for 15% of all renal cancers. Two French prospective phase II trials demonstrated efficacy of both Sun and Eve in first-line treatment of metastatic disease (RAPTOR (NCT00688753) and SUPAP (NCT00541008)). Most patients (pts) usually receive the alternate drug at progression. We report the first series of drug sequencing in pRCCs. Methods: We updated clinical data of metastatic pts with pathologically documented pRCC, who were treated in firs line or more with Sun or Eve, from 2/06 to 6/15, in 24 GETUG centers. Results: 196 pts (166 men, 30 women), median aged of 61 years, with histological subtypes (HST) I (28 pts), II (122 pts) or unclassified (46 pts), were treated for metastatic pRCC in 1st-line: group 1 Su 50 mg daily 4/6 weeks (n=158 pts) ; group 2 Eve 10 mg daily (n=38 pts). 76 pts were included in the RAPTOR or SUPAP studies. The median follow-up was 59.5 months. We found no difference between the 2 groups in terms of patients’ characteristics, clinical benefit in first-line (CR+PR+SD) (71% vs 72%; p=0.95) or progression-free survival (PFS) (PFS-1: 5.7 vs 4.6 months; p=0.152). Reasons for treatment discontinuation were tumor progression (74% vs 70%) or toxicity (26 vs 30%) (p=0.58). 134 pts received the alternative drug in second-line (group 1: Eve; group 2: Sun) with similar clinical benefit (64% vs 58%; p=0.69) and median PFS (PFS-2: 3.5 vs 3.0 months p=0.98). Overall survival (OS) did not differ between the two groups (16.4 vs 17.6 months; p=0.58). Age, Karnofsky performance status < 80 (KPS-80), HST, platelet (Plts) and absolute neutrophil counts (ANC), hemoglobin and calcium levels, time from diagnosis to metastases (TTM) were studied as prognostic variables. In multivariable analysis, only Plts and KPS-80 had prognostic impact on EFS-1, whereas ANC, KPS-80 and TTM were prognostic for OS. We found a trend in favor of HST I vs non I, with no statistical difference in terms of PFS or OS. Conclusions: In this large retrospective series of metastatic pRCC pts, Sun and Eve had good compliance and similar efficacy in terms of first-, second-line PFS and overall survival.

Efficacy and prognostic factors of induction therapy combined with autologous stem cell transplantation in 201 patients with multiple myeloma

目的探讨诱导治疗序贯自体外周血造血干细胞移植（APBSCT）后多发性骨髓瘤（MM）患者预后的影响因素。方法回顾性分析1998年1月至2015年5月接受诱导治疗序贯APBSCT的201例MM患者临床资料。对预后影响因素进行分析。结果①201例患者中位疾病无进展生存（PFS）期为22.87（17.48~28.26）个月，中位总生存（OS）期为69.63（63.57~75.69）个月，5年PFS率、OS率分别为17%、49%。②APBSCT后达完全缓解（CR）组（112例）与未达CR组（89例）的中位PFS期分别为32.93（21.03~44.83）、18.13（14.46~21.80）个月（P<0.001），中位OS期分别为96.77（71.79~121.75）、54.70（49.53~59.87）个月（P=0.004）。③诱导治疗方案含硼替佐米或沙利度胺组（123例）与不含硼替佐米或沙利度胺组（21例）的中位PFS期分别为31.67(24.36~38.98)、15.20(10.11~20.29)个月（P=0.013），中位OS期分别为76.30（55.44~97.15）、52.03（33.76~70.30）个月（P=0.014）。④国际分期系统（ISS）Ⅰ、Ⅱ、Ⅲ期组中位OS期分别为99.47 (59.58~139.36)、66.77（52.17~81.37）、53.97（28.71~79.23）个月（P<0.001），Ⅱ、Ⅲ期患者发生死亡的风险分别为Ⅰ期患者的2.16、3.40倍。⑤IgD型（22例）、IgG型（101例）MM患者中位PFS期分别为11.17（10.27~13.13）、35.43(22.69~48.17)个月（P=0.007），中位OS期分别为30.83(0.24~61.42)、70.70（53.52~87.88）个月（P=0.039），IgD型患者发生疾病进展的风险是IgG型患者的2.47倍。⑥接受一线诱导（132例）和更换诱导治疗方案（69例）患者的中位PFS期分别为25.43（16.09~34.77）、20.27(15.04~25.50)个月（P=0.042），后者发生疾病进展的风险较前者高1.48倍，两组中位OS期差异无统计学意义（P=0.415）。⑦Cox多因素回归分析显示，移植后达CR和ISS分期是影响OS的独立预后因素，IgD型、移植后达CR是影响PFS的独立预后因素。结论移植后达CR、ISS分期是影响MM患者OS的独立预后因素。移植后达CR、IgD型也是影响PFS的独立预后因素。

Simplified in-House Deep Sequencing Method of Inmunoglobulin Genes for Minimal Residual Dissease Quantification and Risk Stratification in Multiple Myeloma

▪BACKGROUND: The first step to the cure of Multiple myeloma (MM) is achieving a clinical complete response (CR). However, a majority of patients relapse in part due to the persistence of low levels of pathological plasma cells after treatment (minimal residual disease (MRD)). In previous work, we have shown that Next generation sequencing (NGS) of immunoglobulin (IG) rearranged genes is an effective technology to identify and quantify pathological clonal cells in MM, and also it is a good predictor of patient prognosis. However, this technology is a proprietary multiplex PCR, uses a reference plasmid, it is performed at the centralized laboratories, and it is not broadly available.AIMS: To present a new in-house simplified method for quantification of IG gene clonal rearrangements by NGS. To test the suitability of the method for MRD detection in MM patients compared with 8-color high sensitivity Flow Cytometry (8c-MFC) data on a prospective way. To determine its capability as a predictor of patient prognosis.METHOD: We use deep sequencing to prospectively analyzed DNA from bone marrow samples of 58 patients (58 diagnostic samples and 80 follow-up samples) of patients included the GEM10 clinical trial. The method employs the primers developed by BIOMED-2 for IGH and IGK, and a set of specific mathematical and bioinformatics tools. First, we identified the clonal rearrangement(s) (clonotype) in the diagnostic sample by fragment analysis and NGS. Second, we searched the NGS sequences from follow-up samples to detect and quantitate (MRD) the presence of the clonotype identified in the diagnostic sample. Overall Survival (OS) and Progression free Survival (PFS) were estimated by Kaplan-Meier survival analysis. The survival curves generated were compared with the log-rank test for trend.RESULTS: The sensitivity of the method is 10-5 for 150.000 cells. Reproducibility is >90%. The Spearman correlation coefficient between NGS and 8c-MFC data for diagnosis and follow-up samples was R=0.6903, p<0.0001. When we applied the criteria of 10-5 for NGS, discordant results were as follow: 121 cases were positive by both methods, 2 cases were positive (>10-5) by 8c-MFC but negative (<10-5) by NGS; 7 samples were negative (<10-5) by 8c-MFC but positive (>10-5) by NGS; and 7 cases were negative by both methods. Next we analyzed de correlation of OS and PFS with MRD levels determined by NGS and by 8c-MFC. For NGS data, median PFS (FigA) was 34 months for patients with values of MRD>10-5 vs not reached for patients with values of MRD<10-5 (hazard ratio [HR] = 3.69, P =0 .0109). Also, for 8c-MFC data, the patients with values of MRD<10-5 had longer PFS than those with values of MRD>10-5 (34 months versus 47; HR = 3.69, P =0 .0109). Median OS (FigB) was also significantly longer in MRD<10-5 (NGS) patients (not yet reached), compared to MRD>10-5 (NGS) patients (41 months, HR = 3.6, P =0.0495). For 8c-MFC we did not get a significant association (41 vs 50 months, HR=1.979, p=0.228). It should be noted that this comparison was made with the standard 8c-MFC and it is probable that the sensitivity will be inferior to that of the Next generation flow. There were no significant differences in terms of PFS between the data obtained by our in-house method, 8c-FCM and previous data obtained with LymphoSight technology.CONCLUSIONS: Our data confirms that analysis of MRD levels determined by deep sequencing is capable of predict survival outcomes in myeloma patients. NGS sequencing of Ig genes is an effective technology to identify and quantify pathological clonal cells in MM. This approach is a methodological and economical alternative to MFC and other methods for MRD follow-up. [Display omitted] DisclosuresPaiva:Janssen: Consultancy; Celgene: Consultancy; BD Bioscience: Consultancy; Sanofi: Consultancy; Binding Site: Consultancy; Onyx: Consultancy; Millenium: Consultancy; EngMab AG: Research Funding. Ocio:Pharmamar: Consultancy, Research Funding; MSD: Research Funding; Novartis: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Array BioPharma: Consultancy, Research Funding; Jassen: Honoraria. Mateos:Celgene: Consultancy, Honoraria; Takeda: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Onyx: Consultancy. San Miguel:Novartis: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Bristol-Myers Squibb: Honoraria; Millennium: Honoraria; Onyx: Honoraria; Sanofi-Aventis: Honoraria.

Radiation Therapy Overcomes Adverse Prognostic Role of Cyclooxygenase-2 Expression on Reed-Sternberg Cells in Early Hodgkin Lymphoma

To analyze the role of radiation therapy (RT) on the adverse prognostic influence of cyclooxygenase-2 (COX-2) expression on Reed-Sternberg (RS) cells, in the setting of early Hodgkin lymphoma (HL) treated with ABVD (adriamycin, vinblastine, bleomycin, dacarbazine). In the present study we retrospectively investigated the prognostic value of COX-2 expression in a large (n=143), uniformly treated early HL population from the Spanish Network of HL using tissue microarrays. Univariate and multivariate analyses were done, including the most recognized clinical variables and the potential role of administration of adjuvant RT. Median age was 31 years; the expression of COX-2 defined a subgroup with significantly worse prognosis. Considering COX-2(+) patients, those who received RT had significantly better 5-year progression-free survival (PFS) (80% vs 54% if no RT; P=.008). In contrast, COX-2(-) patients only had a modest, nonsignificant benefit from RT in terms of 5-year PFS (90% vs 79%; P=.13). When we compared the outcome of patients receiving RT considering the expression of COX-2 on RS cells, we found a nonsignificant 10% difference in terms of PFS between COX-2(+) and COX-2(-) patients (P=.09), whereas the difference between the 2 groups was important (25%) in patients not receiving RT (P=.04). Cyclooxygenase-2 RS cell expression is an adverse independent prognostic factor in early HL. Radiation therapy overcomes the worse prognosis associated with COX-2 expression on RS cells, acting in a chemotherapy-independent way. Cyclooxygenase-2 RS cell expression may be useful for determining patient candidates with early HL to receive consolidation with RT.

Lenalidomide and Dexamethasone Alone Is Equivalent To Lenalidomide and Dexamethasone With Autologous Stem Cell Transplant In Newly Diagnosed Multiple Myeloma: Interim Study Results Of a Randomized Trial

The current standard of care for patients with newly diagnosed multiple myeloma (MM) aged less than 65 years is high-dose chemotherapy combined with autologous stem cell transplantation (ASCT) based on improved progression free survival (PFS) and overall survival (OS) compared with conventional chemotherapy. The introduction of novel agents, for example lenalidomide and bortezomib over the last decade, has substantially improved MM outcomes providing similar response rates to ASCT. As a consequence, the role of upfront ASCT has become more controversial. Therefore, this randomized clinical trial aims to determine the role of upfront ASCT in patients with newly diagnosed MM patients receiving lenalidomide and low-dose dexamethasone as induction therapy.Patients enrolled into the study were aged ≥18 years with newly diagnosed MM, transplant eligible, and meeting CRAB criteria. Patients were randomized to receive 4 cycles of lenalidomide (25 mg days 1–21) plus low-dose dexamethasone (40 mg days 1, 8, 15, 22) followed by ASCT conditioned with 200 mg/m2 melphalan (Arm A; LD+ASCT) or 8 cycles of lenalidomide plus low-dose dexamethasone (Arm B; LD alone). Both groups received lenalidomide maintenance therapy 10-15 mg for up to 2 years. Patients in both treatment arms received stem cell collection after 4 cycles of lenalidomide plus dexamethasone if at least a partial response was achieved. Patients with stable disease or progressive disease (PD) went off study. The primary objective was to compare the best response between patients treated with lenalidomide plus dexamethasone followed by ASCT and patients treated with lenalidomide plus dexamethasone alone. Secondary objectives were to compare the duration of response (DOR), PFS, and OS between the two treatment arms and to evaluate the secondary malignancies in both arms.Fifty patients with newly diagnosed MM were randomized between February 2008 and May 2013, and 47 patients were eligible for evaluation in this interim analysis; 25 patients randomized to Arm A (LD+ASCT) and 22 patients randomized to Arm B (LD alone). Overall, patients had a median age of 61.6 years (range 48–75), 60% were male, 34% ISS Stage I, 49% ISS Stage II, 17% ISS Stage III. The data were analyzed according to the IMWG response criteria (Blood. 2011 May 5;117(18):4691-5). In an intention-to-treat analysis, there was a trend towards improved overall response rate (ORR) in patients receiving LD+ASCT (96%) compared with patients receiving LD alone (77%; p=0.08) (Table 1). After a median follow-up of 36.8 months (range 1.1–62.7), the median DOR was 13.9 months (95% confidence interval [CI] 4.0–34.1) in the LD+ASCT group compared with 21.2 months (95% CI 11.0–22.9) in the LD group. Overall, 18 patients have PD (10 patients in the LD+ASCT arm and 8 patients in LD arm), and 8 patients have died (4 patents in the LD+ASCT arm and 4 patients in the LD arm). Median PFS for LD+ASCT versus LD was 17.0 months (95% CI 15.5–not estimable) versus 25.2 months (95% CI 9.0–not estimable; p=0.94). Median OS for LD+ASCT versus LD was 57.6 months (95% CI 48.0–not estimable) versus not reached (p=0.94). Two patients in the LD alone arm developed a secondary malignancy, including 1 patient with myelodysplastic syndrome (MDS) 13 months after the start of therapy.This interim analysis of an ongoing randomized clinical study comparing lenalidomide plus low-dose dexamethasone induction with and without upfront ASCT in patients with newly diagnosed MM suggests that addition of ASCT resulted in a trend towards improved ORR. This did not result in a significant difference in terms of PFS or OS between the two treatment arms. In contrast there was a trend of better DOR in the LD alone arm. The data show that LD alone can achieve similar results as LD+ASCT, however careful interpretation is required due to the low patient number and relatively short follow-up. The incidence of secondary malignancy was low, including the development of 1 MDS. Disclosures:Schecter:Celgene: Honoraria, Speakers Bureau. Mapara:Celgene: Research Funding, RO1 Other. Lentzsch:Celgene: Research Funding.Table 1Best response and survivalBest response, n (%)Arm A (LD+ASCT) (n=25)Arm B (LD alone) (n=22)Stringent complete response1 (4.0)1 (4.6)Complete response4 (16.0)5 (22.7)Very good partial response8 (32.0)6 (27.3)Partial response11 (44.0)5 (22.7)Stable disease1 (4.0)5 (22.7)Progressive disease00Overall response rate24 (96.0)17 (77.3)

Abstract A77: Randomized phase II study comparing paclitaxel/carboplatin intercalated with gefitinib to paclitaxel/carboplatin alone for chemotherapy-naive non-small cell lung cancer patients either with history of smoking or with wild-type EGFR.

Abstract Background: There are preclinical and clinical reports of schedule-dependent synergism or antagonism when combining cytotoxic chemotherapy and EGFR inhibitor therapy in non-small cell lung cancer (NSCLC). While antagonism was associated with EGFR inhibitor-induced G1-phase blockade protecting tumor cells from chemotherapy cytotoxicity, appropriate scheduling of EGFR inhibitor with chemotherapy might produce additive or synergistic tumor growth inhibition. This randomized phase 2 study compared the efficacy of paclitaxel-carboplatin (PC) intercalated with gefitinib (G) versus PC alone, as a first-line treatment in a selected population of advanced NSCLC patients either with history of smoking or with wild-type EGFR. Methods: Eligible patients were chemotherapy-naive advanced NSCLC patients with good ECOG PS of 0 or 1. Non-smoking patients with adenocarcinoma or patients with activating EGFR mutation were excluded because they could benefit from gefitinib alone. Eligible patients were randomized to either one of the treatments; PCG arm, P 175 mg/m2 and C AUC 5 intravenously on day 1 intercalated with G 250 mg orally on days 2 through 15 every 3 weeks for four cycles followed by G 250 mg orally until progressive disease; or PC arm, P 175 mg/m2 and C AUC 5 on day 1 every 3 weeks for four cycles only without maintenance therapy. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression free survival (PFS), overall survival (OS) and toxicity profile. Results: A total of 90 patients (male 85.6%; median age, 59; adenocarcinoma 63%; smoker 90%; and wild-type EGFR 24%, unknown EGFR status 76%) participated into the study. The ORR was 40.9% (95% CI 27.3-56.8%) and 37.0% (95% CI 23.8-51.2%) for the two arms (p=0.701). There was also no difference in terms of PFS (the median PFS; PCG arm, 4.1 mo vs. PC arm 4.1 mo, HR=0.941 [95%CI: 0.61-1.45], p=0.781) and OS (the median OS; PCG arm 9.3 mo vs. PC arm10.5 mo, HR=0.95 [95% CI: 0.58-1.54], p=0.827). Safety analyses showed a similar incidence of drug-related grade 3/4 toxicity in PCG arm (20.9%) compared with in PC arm (23.3%). G1/2 rash and diarrhea was more frequent in PCG arm (58% vs.9% and 14% vs. 7%, respectively). Conclusion: Paclitaxel-carboplatin chemotherapy intercalated with gefitinib did not improved ORR, PFS, and OS compared to PC chemotherapy alone in this selected population of advanced NSCLC patients either with history of smoking or with wild-type EGFR. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A77. Citation Format: Dae Ho Lee, Jeong Eun Kim, Yoon Ji Choi, Chang Min Choi, Jung-Shin Lee, Sang-We Kim. Randomized phase II study comparing paclitaxel/carboplatin intercalated with gefitinib to paclitaxel/carboplatin alone for chemotherapy-naive non-small cell lung cancer patients either with history of smoking or with wild-type EGFR. [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 A77.

Paclitaxel/carboplatin (PC) intercalated with gefitinib or paclitaxel/carboplatin (PC) for advanced non-small cell lung cancer (NSCLC) in selected population who were smoker or wild-type EGFR: Randomized phase II study.

e19079 Background: The introduction of EGFR inhibitors to standard chemotherapy is an attractive approach to improved outcome. However, the tumor cells which were driven to G0/G1 phase by gefitinib may not sensitive to cytotoxic chemotherapy which is active to G2M arrested tumor cells. This randomized phase II study compared the efficacy of PC intercalated with gefitinib versus PC, as first-line treatment in a clinically selected population of advanced NSCLC patients. Methods: Eligible patients were chemotherapy-naïve advanced NSCLC patients with good ECOG PS of 0 or 1. Non-smoking patients with adenocarcinoma or patients with activating EGFR mutation were excluded because they could benefit from gefitinib alone. They were randomized to either one of the treatments; standard chemotherapy alone (control arm, 46 pts) of paclitaxel (175 mg/m2) and carboplatin (AUC 5) on day 1; or the same chemotherapy plus gefitinib 250 mg/day on day 2 through 15 (study arm, 44 pts). The treatment was repeated every 3 weeks for maximum 4 cycles without maintenance. The primary endpoint included the response rate (RR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 90 patients (male 85.6%, median age 59, adenocarcinoma 63.3%, smoker 90.0%, wild-type EGFR 24.4%, unknown EGFR status 75.6%) were included. There was no difference in terms of RR (the study arm, 40.9% [95% CI 27.3-56.8%] vs. the control arm, 37.0% [95% CI 23.8-51.2%], p=0.701). There was also not difference in terms of PFS (the median PFS; 4.13 vs. 4.13, HR=0.941 [95% CI 0.61-1.45], p=0.781) and OS (the median OS; 9.33 vs. 10.53, HR=0.95 [95% CI 0.58-1.54], p=0.827). Safety analyses showed a similar incidence of drug-related grade 3/4 toxicity in study group (20.9%) compared with control group (23.3%), while mild rash (58% vs. 9%) and diarrhea (14% vs. 7%) were more common in the study arm. Conclusions: PC chemotherapy intercalated with gefitinib did not improved RR, PFS, and OS compared to PC chemotherapy alone in clinically selected population of advanced NSCLC patients who were smoker or wild-type EGFR. Clinical trial information: NCT01196234.

Proof of concept of correlation between progression-free survival (PFS) and overall survival (OS) in treatment-naive patients with advanced renal-cell carcinoma (mRCC): Final results of a randomized phase II study comparing sorafenib plus interleukin-2 (IL-2) versus sorafenib alone: The ROSORC trial.

e15589 Background: The outcome analyses of the randomized phase 2 ROSORC trial, did not show any difference in terms of PFS between mRCC patients undergoing first-line treatment with sorafenib plus IL-2 versus sorafenib monotherapy (7.3 versus 6.9 months in favour of the combination arm; p= 0.109). (Procopio et al BJC 2011). Overall survival analyses are here reported. Methods: In this open-label phase 2 prospective study, 128 treatment-naïve patients with mRCC were randomized to receive either sorafenib 400 mg twice daily plus subcutaneous IL-2 4.5 MIU five times a week for 6 weeks every eight weeks (Arm A), or sorafenib alone (Arm B). The primary endpoint was PFS, while the secondary endpoint was OS. Survival analyses were evaluated by Kaplan-Meier plots and compared by two-sided log-rank test. Results: After a median follow up of 58 months (interquartile range 28-63), the median OS was 38 and 33 months in arm A and B respectively (p= 0.667). The 5-year OS was 26.3 % (95% CI: 15.9-43.5) and 23.1% (95 % CI: 13.2-40.5) in the combination and single agent arm, respectively. Overall we observed 85 deaths and among them, 42 occurred in the Arm B. Overall, 49 (74 %) and 48 (77 %) patients in the Arm A and B, respectively, received at least one targeted therapy (TT) after disease progression, including sunitinib, everolimus, axitinib or temsirolimus. Most common adverse events (AEs) included fatigue, hand-foot syndrome, hypertension and diarrhea and were mild in grade (Grade 1-2). Grade 3-4 AEs were documented in 38 % and 25 % of patients receiving combination and single agent treatment, respectively. Conclusions: While the PFS observed was in keeping with previous literature data regarding sorafenib, either as a single agent or in combination, the OS dramatically improved results reported so far in prospective randomized trials. This outcome suggests lack of correlation between PFS and OS and a synergistic effect of sequential TTs following sorafenib failure. Clinical trial information: NCT00609401.

Retrospective cohort study on the safety and efficacy of panitumumab (Pmab) for patients with metastatic colorectal cancer (mCRC): The HGCSG1002 study—Analysis of clinical early predictor for the efficacy.

593 Background: Inhibition of the EGFR pathway has become a key part in the treatment of colorectal cancer. There were few studies for clinical early predictive markers. To investigate the early magnesium (Mg2+), calcium (Ca2+), albumin (Alb), CEA and CA 19-9 plasma level reductions as a predictor for clinical outcome in terms of progression free survival (PFS) and overall survival (OS). Methods: 200 patients (pts) with mCRC treated by Pmab contained chemotherapy were retrospectively registered from 20 centers in Japan (HGCSG 1002 study). Of these, the pts that were refractory to or intolerant for 5-FU/ irinotecan/ oxaliplatin, and were never administered anti-EGFR-antibody, were included in this analysis. Mg2+, Ca2+, Alb, CEA and CA19-9 plasma levels were obtained from medical records. The differences in terms of PFS and OS according to the presence of Mg2+, Ca2+, Alb, CEA and CA19-9 reductions were evaluated by the log-rank test. Results: Of 67 pts were able to evaluate for this analysis. Pts’ characteristics were as follows: male/female 38/29, median age 64 (range 45-81), ECOG PS (0/1/2- ) 45/17/5. Response rate and disease control rate were 16.4% and 65.7%, PFS and OS were 4.3 m and 12.4 m, respectively. There were no correlations between Ca/Alb plasma level reductions and PFS/OS. Mg2+ reduction of at least 50% respect to the basal value during the course of treatment was significantly correlated with improved OS and PFS (OS, P=0.03; PFS, P=0.01), but the early reduction (until the 4th week or the 8th week after start of chemotherapy) was not correlated with OS and PFS. An early CEA serum level reduction of at least 40% until the 8th week was significantly correlated with improved OS and PFS (OS, P=0.04; PFS, P=0.07), moreover of at least 30% until the 4th week was correlated to longer PFS (P=0.053). Similar results were seen in CA19-9. Conclusions: An early CEA plasma level reduction of at least 30% or 40% was suggested to be a predictor for PFS in Pmab containing chemotherapy for mCRC pts. Although Mg2+ serum level reduction was correlated to clinical outcome, but could not show that is an early predictor for PFS and OS in our study.

1308P - Pkm2 Expression May Predict Chemosensitivity to Cisplatin-Based Chemotherapy in Metastatic Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Background Tumor cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase (PKM2). Overexpression of PKM2 has been correlated with cisplatin resistance in cell lines and xenograft models. We evaluated the predictive significance of PKM2 in patients with stage IV NSCLC. Methods PKM2 mRNA expression was analysed by RT-qPCR in microdissected FFPE primary tumors from 305 NSCLC patients (148 as training set and 157 as experimental set) treated with front-line cisplatin-based chemotherapy and 85 patients treated with a non-platinum doublet (as validation set). Results The patients' characteristics were all typical for metastatic NSCLC (median age 61 years, 86% males, 64% adenocarcinomas and 28% squamous cell carcinomas, ECOG PS 0-1: 83%). PKM2 was successfully amplified in all specimens. Progression Free Survival (PFS) was significantly lower in patients with overexpression of PKM2 (4.9 vs. 6.4 months for high and low expression, respectively, p = 0.028) in the training set and the results were confirmed in the experimental set (3.7 vs. 5.9 months, p = 0.006). Similarly, median overall survival (mOS) was significantly decreased in patients with upregulation of PKM2 in both sets: 10.1 vs 17.0 months in the training set (p = 0.01) and 8.3 vs 16.8 months in the experimental sets (p = 0.003), for high and low expression, respectively. In contrast, there was no statistical difference in terms of PFS (5.6 vs. 5.9 months, p = 0.431) and mOS (9.8 vs. 10.1 months, p = 0.512) between low and high PKM2 expression in the validation group. Multivariate analysis revealed that PKM2 high mRNA expression could be emerged as an independent factor associated with decreased PFS (training set: HR = 1.6, p = 0.02; experimental set: HR = 2.1, p = 0.013) and mOS (training set: HR = 1.9, p = 0.02; experimental set: HR = 2.6, p = 0.001), but not in the validation set (PFS: HR = 1.1, p = 0.627; mOS: HR = 0.96, p = 0.495). Conclusions These results indicate that the PKM2 mRNA expression may be used as a predictive factor for sensitivity to cisplatin-based chemotherapy. Disclosure All authors have declared no conflicts of interest.

Maintenance therapies of thalidomine and interferon-α in multiple myeloma

To explore the efficacies and toxicities in multiple myeloma (MM) patients on the maintenance therapies of thalidomide and interferon-α so as to seek the optimal chemotherapeutic regimen. A retrospective analysis was conducted for 57 MM patients on the maintenance therapies of thalidomide and interferon-α after introduction and consolidation. And 56 MM patients without maintenance therapy were enrolled as the control group. The values of progression-free survival (PFS) and overall survival (OS) were significantly longer in the maintenance group and this translated into an improved estimated 3-year PFS of 75.4% (71.8%, 83.3%) versus 23.2% in the control group (P < 0.01). The estimated 4-year OS was higher in the maintenance group [89.5% (89.7%, 88.9%) vs 33.9%, P < 0.01]. No statistically significant differences existed among different maintenance groups in terms of PFS and OS. The administration of maintenance therapy extended both PFS and OS for MM patients of various M-proteins (P < 0.05). However, in the thalidomide group, PFS and OS were extended only in MM of immunoglobulin G (IgG) and immunoglobulin A (IgA) but not in light-chain patients. Furthermore, the MM patients of Durie-Salmon (DS) stages II and III and international staging system (ISS) stages II and III extended PFS and OS through maintenance (P < 0.05). While in those of ISS stage I, the differences were insignificant in terms of PFS and OS between two groups. The results were similar between the thalidomide and control groups. The patients achieving a partial remission (PR) or higher response level benefited from the maintenance therapy in terms of PFS and OS (P < 0.05). In the thalidomide group, the patients with below PR prolonged OS (P = 0.031) but did not achieve a longer PFS (P = 0.091). Both PFS and OS were extended through maintenance therapy after either stem cell transplantation or consolidation chemotherapies (P < 0.05). There was no significant difference in terms of PFS and OS between MM patients without maintenance therapy after transplantation and those without transplantation. The adverse effects of thalidomide, milder than those of interferon-α, could be tolerated in most patients. The incidence and severity of adverse effects showed no significant difference between the combination maintenance and single agent therapies. The maintenance therapies of thalidomide and interferon-α could improve the profiles of PFS and OS in MM patients. And there was no significant difference between them in terms of PFS and OS. However, the maintenance therapy of thalidomide is a better option due to its convenient application, milder adverse effects, reasonable cost and better efficacies in MM patients not achieving PR or receiving induction therapy without bortezomib or without transplantation.

EGFR Gene Copy Number and Response to Lapatinib/Capecitabine in HER2 Positive Metastatic Breast Cancer Patients Pretreated with Trastuzumab.

Abstract Background: Lapatinib (L) is a potent and selective dual inhibitor of EGFR and HER2. In HER2 positive metastatic breast cancer (MBC) pretreated with trastuzumab-based therapies, the association of L + Capecitabine (C) showed superior response rate (RR) and progression free survival (PFS) over C alone. We analyzed the correlation between EGFR gene copy number and clinical outcome in a population undergoing treatment with L 1250 mg daily plus C 2000 mg/m2 days 1-14 every 21. Materials and methods: EGFR gene copy number was assessed by FISH analysis in paraffin-embedded tissue blocks from 30 HER2 positive patients who had failed at least one trastuzumab-based therapy in the metastatic setting. EGFR gene status was scored as: the mean value of EGFR gene copy number (GCN) per nucleus, the mean ratio between EGFR and Chromosome 7 and the percentage of cells displaying more than 5 EGFR GCN. A receiver operating characteristic (ROC) analysis was set up to define the cut-off of mean EGFR GCN. A value greater than 3.36 was able to discriminate responders versus non-responders. The primary end point of the study was identification of the EGFR FISH score that best predicts RR Results: Twenty-five patients were evaluable for EGFR FISH analysis. No sample displayed a homogeneous amplification of the EGFR gene by ratio (EGFR gene/CEP 7 ≥2). Patients characteristics were as follows: median age 52.4 (range 32-70), visceral disease in 20 patients (80%), brain metastases in 11 patients; median number of previous trastuzumab-based therapies was 2 (1-4). Twelve patients achieved a partial response for a RR of 48% (95% CI: 28.8-64.5). At a median follow up of, PFS was 7 months (95%CI: 5-8). Median overall survival has not been reached at the time of analysis. Mean EGFR GCN was &amp;gt; 3.36 in 10/25 patients. These patients showed a significantly higher RR (n=8/10; 80%) as compared to those with mean EGFR GCN ≤3.36 (n= 4/15; 27%), (p=0.009). No significant difference in terms of PFS was seen. Conclusion: high EGFR GCN might predict for an increased likelihood of responding to L. This is the first report associating increased EGFR GCN with sensitivity to L. These results warrant further investigation on a larger sample of patients. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3095.

Efficacy and Toxicity of Pemetrexed as a Third-line Treatment for Non-small Cell Lung Cancer

Pemetrexed has been approved for second-line treatment in non-small cell lung cancer (NSCLC). However, the role of third-line pemetrexed therapy in NSCLC has not yet been generally accepted. We attempted to validate third-line pemetrexed therapy and evaluate predictive factors for pemetrexed therapy for NSCLC. Medical records of NSCLC patients who received pemetrexed therapy that progressed after systemic therapy were reviewed retrospectively. We stratified patients according to clinicopathologic characteristics to find predictive factors for pemetrexed therapy. A total of 100 patients were eligible for analysis, and overall progression-free survival (PFS) was 3.03 months. The objective response rate was 12%, and the toxicity profile was favorable. Pemetrexed was used as a second-line treatment in 30% of patients, and as third- or further-line treatment in 70%. Comparing the efficacy of pemetrexed in these two settings (second-line versus third- or further-line), there was no significant difference in terms of PFS (3.07 versus 2.83 months, P = 0.86). When we evaluated predictive factors by multivariate analysis, performance status significantly influenced PFS. Pemetrexed is a suitable third-line treatment option with good efficacy and tolerable toxicity profile for NSCLC.

Limited Feasibility of Double Transplant Program: A Multicenter Study on 151 Multiple Myeloma Patients Aged≤65 Years.

High dose therapy represents the gold standard therapy for newly diagnosed multiple myeloma (MM) patients (pts), with no definite agreement about the adoption of single or double transplant. From January 2000 to December 2004, 151 consecutive MM pts aged ≤65 years in stage II, III or I in progression according to Durie-Salmon were enrolled in a multicenter no randomised high dose program including a tandem transplant (Tx1; Tx2). The protocol was designed as follows: 2 pulse-VAD as induction, 2 DCEP to mobilise peripheral blood stem cells (PBSC), double auto-transplant 3-6 months apart each conditioned with high-dose Melphalan at the dose of 200 mg/m2. Patients characteristics at the enrolment: males 76 (51%), females 75 (49%), median age 55 (range: 35–65), stage I in progression 26 (17%), stage II 25 (16%), stage III 100 (67%). Response rates after each phase for the evaluable patients are reported in the table belowVAD (151 pts)DCEP (146 pts)Tx1 (119 pts)Tx2 (63 pts)CR (%)491829VGPR (%)28354860PR (%)4430259SD (%)181020Progr (%)61670Patients not addressed to transplant for mobilization failure were only 5%. Most of the patients (75%) collected ≥ 4x106CD34+cells/Kg after each DCEP-cycle which were considered adequate to rescue hemopoiesis after each transplant. The whole protocol was well-tolerated. In particular, no therapy related mortality was associated to pulse-VAD, or DCEP, and no difference between Tx1 and Tx2 as far the transplant related mortality was registered (1.5% after each transplant). Second transplant was not performed in 48 pts for the following reasons: 8 pts (7%) did not collect enough PBSC, 8 pts (7%) have had severe toxicity with the first transplant; 8 pts (7%) underwent allo-TMO; 7 pts (6%) had progressive disease and 15 pts (12%) refused Tx2. Finally only 76 pts (50% of the enrolled pts) completed the program with the second transplant. Analysing data on an intention-to-treat basis, median follow-up was 30 months, median Progression Free Survival (PFS) was 31 months, median overall survival (OS) was not reached. The median Event Free Survival (calculated from the completion of Tx1 to progression or any other event) was 20 months. No difference in terms of PFS and EFS was found comparing pts who finally received only Tx1, with those who completed the protocol (p=0.9; p=0.5). The EFS was not statistically different for patients receiving one or two transplant even when the analysis was performed according to the type of response achieved after Tx1. In conclusion, despite higher percentage of good quality responses (CR+VGPR) can be obtained with 2 transplants with respect to 1 (66% vs 89%) without additional toxicity, no difference in terms of PFS or EFS were observed between the patients who underwent 1 or 2 transplants. Thus, keeping into account the more complex management of patients in a tandem transplant program, it might be more advantageous to perform as initial therapeutic approach, high-dose protocol including only 1 transplant procedure.