OS Analysis Research Articles

Immunoscore Signatures in Surgical Specimens and Tumor-Infiltrating Lymphocytes in Pretreatment Biopsy Predict Treatment Efficacy and Survival in Esophageal Cancer.

Tumor-infiltrating lymphocytes (TILs) have long been recognized as playing an important role in tumor immune microenvironment. Lately, the Immunoscore (IS) has been proposed as a new method of quantifying the number of TILs in association with patient survival in several cancer types. In 300 preoperatively untreated esophageal cancer (EC) patients who underwent curative resection at two different institutes, immunohistochemical staining using CD3 and CD8 antibodies was performed to evaluate IS, as objectively scored by auto-counted TILs in the tumor core and invasive margin. In addition, in pre-neoadjuvant chemotherapy (pre-NAC) endoscopic biopsies of a different cohort of 146 EC patients who received NAC, CD3, and CD8 were immunostained to evaluate TIL density. In all cases, the IS-high (score 3-4) group tended to have better survival [5-year overall survival (OS) of the IS-high vs low group: 77.6 vs 65.8%, P = 0.0722] than the IS-low (score 1-2) group. This trend was more remarkable in cStage II-IV patients (70.2 vs 54.5%, P = 0.0208) and multivariate analysis of OS further identified IS (hazard ratio 2.07, P = 0.0043) to be an independent prognostic variable. In preNAC biopsies, NAC-responders had higher densities than non-responders of both CD3 + ( P = 0.0106) and CD8 + cells ( P = 0.0729) and, particularly CD3 + cell density was found to be an independent prognostic factor (hazard ratio 1.75, P = 0.0169). The IS signature in surgical specimens and TIL density in preNAC- biopsies could be predictive markers of clinical outcomes in EC patients.

Real-World Experience of Axicabtagene Ciloleucel and Tisagenlecleucel for Relapsed or Refractory Aggressive B-cell Lymphomas: A Single-Institution Experience

BackgroundCD19-directed chimeric antigen T-cell receptor (CAR-T) therapies have revolutionized the treatment of patients with relapsed/refractory (R/R) aggressive B-cell lymphomas (aBCL). The results of the landmark ZUMA-1 and JULIET trials have been reproducible in real-world settings across multiple institutions, and patients with double (DHL) or triple (THL) hit lymphomas have demonstrated non-inferior outcomes compared to non-DHL/THL counterparts. Materials and MethodsThis retrospective cohort study included 53 patients with R/R aBCL who received CAR-T from October 2017 to June 2020 at the University of California, Los Angeles. Patient characteristics, lymphoma-related variables and outcomes of interest were summarized using descriptive statistics and compared between groups by Fisher's exact test. Kaplan-Meier methods were used for analysis of OS, progression free survival (PFS), and duration of response (DOR). Univariate and multivariate cox regression analysis were performed to evaluate for significant prognostic variables. ResultsWith a median follow-up of 15.2 months, this cohort demonstrated overall response rate and complete response rate of 72% and 64% (n = 34), respectively. The median DOR, PFS and OS were not reached, 7.9 and 17.7 months, respectively. By univariate analysis, DHL/THL status was the only clinical feature significantly associated with relapse post-CAR-T (OR 5.9, P = .015). ConclusionsOur single-institution, real-world cohort of R/R aBCL patients demonstrated similar efficacy outcomes to those of the ZUMA-1 and JULIET trials and published real-world studies. Our findings suggest DHL/THL patients may benefit from novel CAR-T constructs, maintenance strategies with immunomodulatory agents or allogeneic-HCT.

Effect of Postoperative Radiotherapy after Primary Tumor Resection in De Novo Stage IV Breast Cancer: A Multicenter Retrospective Study (KROG 19-02).

PurposeThis study aimed to investigate the impact of postoperative radiotherapy (PORT) in de novo metastatic breast cancer (dnMBC) patients undergoing planned primary tumor resection (PTR) and to identify the subgroup of patients who would most benefit from PORT.Materials and MethodsThis study enrolled 426 patients with dnMBC administered PTR alone or with PORT. The primary and secondary outcomes were overall and progression-free survival (OS and PFS), respectively.ResultsThe median follow-up time was 53.7 months (range, 3.1 to 194.4). The 5-year OS and PFS rates were 73.2% and 32.0%, respectively. For OS, clinical T3/4 category, triple-negative breast cancer (TNBC), postoperative chemotherapy alone were significantly poor prognostic factors, and administration of PORT failed to show its significance. Regarding PFS, PORT was a favorable prognostic factor (hazard ratio, 0.64; 95% confidence interval, 0.50 to 0.82; p < 0.001), in addition to T1/2 category, ≤ 5 metastases, and non-TNBC. According to the multivariate analyses of OS in the PORT group, we divided the patients into three groups (group 1, T1/2 and non-TNBC [n=193]; group 2, T3/4 and non-TNBC [n=171]; and group 3, TNBC [n=49]), and evaluated the effect of PORT. Although PORT had no significance for OS in all subgroups, it was a significant factor for good prognosis regarding PFS in groups 1 and 2, not in group 3.ConclusionPORT was associated with a significantly better PFS in patients with dnMBC who underwent PTR. Patients with clinical T1/2 category and non-TNBC benefited most from PORT, while those with TNBC showed little benefit.

P-191 Prognostic factors of colorectal cancer liver metastasectomy

In selected patients with metastatic colorectal cancer (MCRC), resection of liver metastases may offer the possibility of cure. The aim of this study was to evaluate possible preoperative prognostic factors for survival in patients with MCRC undergoing liver metastasectomy in order to select the ideal patient for this procedure. Retrospective analysis of 121 patients with MCRC followed at our center, who underwent liver metastasectomy with curative intent and who underwent primary chemotherapy between March 2004 and June 2017. Survival analyses was estimated through Kaplan-Meier method and multivariate analyses through Cox regression. The median age at diagnosis was 58 (19-79) and 61% were men. The median follow-up time was 53 months (10-143). The recurrence rate after the first metastasectomy was 73.6%. The median DFS after the first liver metastasectomy was 13 months (95% CI, 10.3-15.6). The median OS was 63 months (95% CI, 48.6-77.4). The preoperative factors which gave the worst prognosis in the analysis for OS and DFS were: the presence of ≥3 metastatic liver lesions (median OS: 101 months, CI 95% 57.4-144.6 vs 51 months, CI 95% 42.0-59.9, p = 0.010; DFS median: 18 months, CI 95% 0.0-36.9 vs 10 months, CI 95% 7.2-12.8, p = 0.013), extrahepatic metastasis (median OS: 71 months, CI 95% 58.4-83.6 vs 37 months, CI 95% 22.6-51.4, p = 0.001; median DFS: 15 months, CI 95% 12.2-17.8 vs 7 months, CI 95% 4.3-9.7, p = 0.002), pT4 (median OS: 65 months, CI 95% 50.2-79.8 vs 34 months, CI 95% 25.4-42.6, p = 0.008; Median DFS: 14 months, CI 95% 10.9-17.1 vs 5 months, CI 95% 2.9-7.1, p = 0.011), size of metastases ≥60 mm (median OS: 80 months, CI 95% 63.7-96.3 vs 51 months, CI 95% 42.8-59.2, p = 0.020; DFS median: 16 months, CI 95% 11.9-20.1 vs 10 months, CI 95% 7.4-12.6, p = 0.020). The factors which maintained a negative impact in the multivariate analysis for OS and DFS were pT4 (OS: p = 0.020, HR 1.98, CI 95% 1.1-3.5; DFS: p = 0.007, HR 2.11, CI 95% 1.2-3.6) and extrahepatic metastasis (OS: p = 0.011, HR 2.05, CI 95% 1.2-3.6; DFS: p = 0.024, HR 1.85, CI 95% 1.1-3.2). The presence of ≥3 metastatic liver lesions, extrahepatic metastasis, pT4 and the size of metastases ≥60 mm had a negative impact on OS and DFS.

Evaluation of FIB-4 and APRI in predicting the prognosis of heptocellular carcinoma patients after hepatic resection

For the APRI and FIB-4 index, which are one of the non-invasive methods of examining the degree of liver fibrosis, our paper aims to examine the implications for predicting the prognosis in hepatocellular carcinoma patients undergoing hepatectomy. Between 2006 and 2013, total 973 patients were underwent hepatic resection due to hepatocellular carcinoma and 871 patients were enrolled in our study after adjusting exclusion criteria. Statistics were performed by calculating the optimal cut off values for the recurrence free survival and overall survival of each group which are categorized by etiology and multivariate analysis were performed for evaluating the performance of index. Among the causes of HCC patients, HBV (n = 629, 72%) was the most common, and men were dominant in all groups. In each group divided by etiology, the area under the receiver operating characteristics of APRI and FIB-4 for recurrence free survival and overall survival were relatively higher in HCV patients than in other groups. After setting the cut-off value through the Youden index, univariate analysis and multivariate analysis for RFS and OS of all groups were performed, and the results of APRI values for RFS in each group were statistically significant (HBV : OR = 1.849, p = 0.001; HCV : OR = 6,548, p = 0.010; Alcohol : OR = 3.393, p = 0.004). The significance of this study is that these simple laboratory findings are meaningful in revealing the prognosis of HCC patients, which can be predicted accurately only after the pathologic staging after surgery.

The Clinical Outcomes of Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: A Nationwide Registry Study of the Korean Multiple Myeloma Working Party (KMMWP)

Background : Lenalidomide and dexamethasone (RD) is a standard of care for relapsed/refractory multiple myeloma (RRMM), but there is limited reported data on its efficacy and safety in the real clinical practice. The purpose of this study was estimate necessity of RD chemotherapy for improving survival in RRMM in real clinical fields.Methods : Data from patients at twenty two university hospitals in South Korea between December 2012 and Oct 2016 were collected retrospectively. Clinical and laboratory data were collected retrospectively by review of medical records. The study protocol was approved by the institutional review board of each participating hospital. Patient characteristics were described at the status before lenalidomide treatment start except for cytogenetics and international staging systems, which were described from the data established at the time of diagnosis. The progression free survival (PFS) was defined duration from the date of starting RD chemotherapy to the date of disease progression, relapse, or death from any causes. OS was calculated from the start of lenalidomide treatment to the date of death or the date of last follow-up. Cox proportional hazard regression model was used for a multivariate analysis for PFS and OS. Prognostic factors significant in univariate analysis for PFS or OS were entered for multivariate analysis.Results : The median age of the 527 patients was 66 years (range, 30-109 years) and the male to female ratio was 1.22:1.0. Patients previously were exposed to bortezomib only (40.0 %), both thalidomide and bortezomib (40.1%), and patients who had prior autologous stem cell transplantation were 37.2 %. Median number of cycles of RD were 6 (range, 1-37). The response rates were following: CR or stringent CR (sCR) in 84 (15.4%), VGPR in 106 (20.1%),PR in 166 (31.5%), MR in 24 (4.6%) and < MR in 101 (19.2%). Overall response rates (≥PR (partial response)) rate was 74.0 %. The differences of 2-year PFS of patients with achieved VGPR or more than VGPR and less than VGPR were 47.9% vs 30.2%, p<0.001. The 2-year OS were 66.4% vs 43.1%, p<0.001. The differences of 2-year PFS of patients treated with RD less than 6 cycles and 6 cycles or more than 6 cycles were 16.6% vs 53.4%, p<0.001. The 2-year OS were 26.2% vs 70.3%, p<0.001. In multivariate analysis, these two prognostic factors were shown significant prolonged survival (PFS; p=0.031 and p<0.001, OS; 0.017 and p<0.001). Adverse events of more than grade 2 were reported. Hematologic toxicities including cytopenia was observed only in 9.7 % of patients, infections including pneumonia in 15.1%, fatigue in 14.8%, skin rash in 7.0% and thrombosis in 3.0 %.Conclusions : Our study confirms that RD is effective and safe in RRMM. It produces prolonged survival especially in patients who received more than 6 cycles and achieved more than PR response. Toxicities from RD were tolerable for RRMM patients. DisclosuresNo relevant conflicts of interest to declare.

Mmprofiler with SKY92 Combined with ISS Identifies High and Low Risk Multiple Myeloma in the VTD Arm of Gimema-MMY-3006

SKY92 combined with ISS identifies high and low risk multiple myeloma in GIMEMA-MMY-3006 VTD armErik H. Van Beers*, Carolina Terragna*, Rowan Kuiper*, Marina Martello*, Elena Zamagni*, Giovanni Martinelli, Martin H. van Vliet*, Michele Cavo*.Introduction: Prior to this cohort, SKY92 demonstrated significance in several bortezomib-containing treatments (HOVON-65/GMMG-HD4, APEX, TT3, TT6) and thalidomide-containing treatments (HOVON-65/GMMG-HD4, HOVON-87/NMSG-18, TT2, TT3, TT6, MRC-IX). It remains unknown how this GEP-signature predicts outcome in IMiD plus proteasome inhibitor (PI) treatment. GIMEMA-MMY-3006 is the first dataset in which the front-line VTD in NDMM patients has been evaluated by SKY92 and other prognostic markers.Methods: The GIMEMA-MMY-3006 trial (NCT01134484) compared bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy prior to the autologous stem cell transplantation (ASCT) in transplant eligible NDMM patients [1]. The current analysis compares prognostic value of t(4;14), del(13), del(17), GEP and clinical characteristics in the VTD arm (GSE58133; n=114). PFS and OS were evaluated at median follow up of 3.3yrs. GEP data (U133Plus2.0 CEL files) were batch processed and GEP classifiers were calculated as reported [2]. R-ISS was constructed as described in Palumbo et al. [3], except for the missing marker t(14;16) while SKY92-ISS was constructed as described in Kuiper et al. [4] except that four classes were reduced to three (high, low, and the rest).Results: This is the first report of SKY92 evaluated in a VTD setting. The prognostic values of three risk models (ISS, SKY92-ISS and R-ISS) were compared (Table 1). A total of 36 progressions and 18 deaths occurred in 114 cases. Univariate PFS (results will be presented at the meeting). For OS, univariate analysis showed SKY92, UAMS70, IFM15, del(17), ISS (IIIvsI) and SKY92-ISS were significant. Figure 1 shows Kaplan Meier analyses for SKY92, SKY92-ISS, and R-ISS. Multivariate analysis for OS - with SKY92, del(17) and R-ISS (high risk vs others) - significance was observerd for SKY92 (HR 3.48) but not for del(17) or R-ISS (Table 2). Among the 31 R-ISS-I there were no deaths and therefore no HR (between I and III) was calculated (Figure 1C). A comparison of Figure 1B and C shows that SKY92-ISS captured more high-risk patients than R-ISS (23 vs.6). Of the 19 t(4;14) cases, eleven were also SKY92 high-risk. Of the 8 del(17) cases, 5 were also SKY92 high-risk.Both SKY92-ISS and R-ISS identified low risk patients. SKY92-ISS identified 12 more low risk cases than R-ISS (43/114, 38%, 31/105, 30%, respectively). Figure 1D shows concordance between the risk scores and association with OS (top rows) at 2 and 4y after diagnosis. None of the signatures predicted all deaths at 2 or 4y. SKY92 predicted more deaths than other markers (Figure 1D). Similar to a previous study [1] the risk models were concordant for 2 high risk and 66 standard risk cases, while discordant for 46 remaining cases. SKY92 best identified hazard for a large proportion of cases (Table 1).Conclusions: In this upfront VTD setting we observe proportions of SKY92 high risk and low risk myeloma that are comparable with previous studies with other treatments containing either bortezomib or thalidomide. SKY92-ISS identifies high risk in 20% and low risk in 38% MM patients with HR = 4.0 between high and standard risk (Fig 1A) and HR = 10.7 between high and low risk (Fig 1B) compared with R-ISS the obtained HR = infinite as there were no deaths in low risk (Fig 1C). SKY92-ISS identified a larger faction of low risk cases (38%) compared with R-ISS (30%) yet retains a very large and significant hazard ratio of 10.7 reproducing earlier validation data [1].Figure 1. Prognostic marker performance in n=114 VTD treated multiple myeloma patients. Kaplan Meier analyses for OS were stratified by A) SKY92, B) SKY92-ISS or C) R-ISS. D) shows GEP signature predictions (rows) and their overlap across all 114 cases (columns). Standard Risk (blue), High Risk (yellow), Alive at follow up (Green), dead at follow up (Red), lost to follow up (Grey).

Expression and Significance of Serum Mir-146a and Mir-30e in Patients with Secondary Hemophagocytic Lymphohistiocytosis

ObjectiveHemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome which is caused by uncontrolled activation and proliferation of CD8+ T cell , and abundant releasing of in inflammatory cytokines. It has been confirmed that miR-146a is widely participate in the regulation of intensity of inflammatory response, while miR-30e is related to the regulation of NK cell cytotoxicity. In this study, RT-PCR was used to detect the expression of serum miR-146a and miR-30e in patients with secondary HLH (sHLH). Their correlation with clinical data, and diagnosis and prognosis value in sHLH patients were explored. In addition, their relation with the proportion of cytotoxic lymphocyte subsets and the expression of perforin were explored.MethodsA total of 35 patients with sHLH and 10 healthy controls were enrolled in this study. Serum expression levels of miR-146a and miR-30e were detected by using RT-PCR. The expression of perforin protein oncytotoxic lymphocytes and the proportion of cytotoxic lymphocyte subsets were tested by flow cytometry. The clinical data of sHLH patients were collected.Results(1) The serum expression level of miR-146a in the newly diagnosed sHLH group was significantly lower than that of healthy control group (P <0.001); the serum expression level of miR-30e in the newly diagnosed sHLH group was significantly lower than that of healthy control group (P <0.001). (2) The serum expression level of miR-146a and miR-30e in the lymphoma-associated HLH group, the infection- associated HLH group, and the autoimmune-associated HLH group were compared group by group, however no significant difference was found (P >0.05). (3) ROC analysis revealed that the serum expression level of miR-146a can effectively identify sHLH patients from healthy people, with area under the curve (AUC) was 0.931; the serum expression level of miR-30e can effectively identify sHLH patients from healthy people, with area under the curve (AUC) was 0.914. (4) Correlation analysis was applied and no correlation was found between the serum expression level of miR-146a and miR-30e, and Age, WBC, HB, PLT, SF, ALB, ALT, AST, LDH, FIB, TG, ESR, sCD25, CRP level in the newly diagnosed sHLH (P >0.05). (5) According to the median of serum expression level, sHLH patients were divided in to Low expression group and High expression group. OS analysis was applied and revealed that there was no significance difference between the Low miR-146a expression group and the High miR-146a expression group (P >0.05); meanwhile there was no significance difference between the low miR-30e expression group and the high miR-30e expression group (P >0.05). However, sHLH patients were divided in to Low miR-30e/miR-146a group and High miR-30e/miR-146a group according to the median of miR-30e/miR-146a. The OS of Low miR-30e/miR-146a group was significantly longer than High miR-30e /miR-146a group (P=0.022). (6)The proportion of CD8+ T cell in Low miR-146a group was significantly lower than that in High miR-146a group (P = 0.016). The serum exression level of miR-146a was corelated with the proportion of CD8+ T cell (r=0.734, P = 0.007). However, the proportion of cytotoxic lymphocyte subsets in Low miR-146a group has no significant difference with that in Low miR-146a group (P >0.05); the serum exression level of miR-30e has no corelation with the proportion of cytotoxic lymphocyte subsets (P >0.05). (7) The expression of perforin in cytotoxic lymphocyte subsets in Low miR-30e group has no significant difference with that in Low miR-30e group (P >0.05); the serum exression level of miR-30e has no corelation with the expression of perforin in cytotoxic lymphocyte subsets (P >0.05).ConclusionThe serum expression level of miR-146a and miR-30e in the newly diagnosed sHLH group was significantly decreased, which is important in the differential diagnosis of sHLH. Individuals with lower serum expression level of miR-146a and miR-30e were more likely to be sHLH patients. The ratio of miR-30e and miR-146a (miR-30e /miR-146a) can indicate the prognosis of sHLH patients. The prognosis of sHLH patients with lower miR-30e /miR-146a was better than that of sHLH patients with higher miR-30e /miR-146a. The serum exression level of miR-146a was corelated with the proportion of CD8+ T cell. The serum exression level of miR-146a was corelated with the proportion of CD8+ T cell. Therefore, miR-146a may play a role in the deficiency of CD8+ T cell in the pathogenesis of sHLH. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Multiple Myeloma and Renal Impairment: Analysis of Induction Therapy Strategies and Outcome after Autologous Stem Cell Transplantation

Introduction: Multiple Myeloma (MM) is frequently accompanied by renal impairment (RI) at diagnosis. As MM-specific therapeutic strategies have evolved drastically within the past decades, we aimed at delivering a re-evaluation of applied treatments and outcomes according to renal function at diagnosis.Methods: In this multicenter, retrospective cohort analysis, we analyzed 366 patients who were diagnosed with MM between 1997-2016 and subsequently underwent autologous stem cell transplantation (ASCT). RI at diagnosis was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2. We carried out statistical analysis of patient groups stratified by renal function with regard to induction therapy defined as conventional chemotherapy (CT) versus immuno-chemotherapy (ICT) including either a proteasome inhibitor and/or an immunomodulator. Further, overall and progression-free survival (OS, PFS) were analyzed in the defined subgroups.Results: Of 366 patients, 287 received ICT versus 79 who had CT alone. The choice of the applied treatment strategy was highly dependent on diagnosis date, as all patients diagnosed before the year 2000 received chemotherapy alone, while all but 4 patients diagnosed after 2006 received ICT. Patients with renal impairment were just as likely to receive ICT as those without (75.9 vs. 79.5%, p=0.259). On OS analysis in the patient groups A) normal renal function/ICT (n=202), B) normal renal function/CT (n=52), C) impaired renal function/ICT (n=85), D) impaired renal function/CT (n=27), a longer survival was observed in groups A and B; however without statistical significance (p=0.080; Figure 1). On analysis of PFS, no differences were observed (p=0.784; Figure 2).Conclusions: Impaired renal function confers only a slight and statistically insignificant OS disadvantage in newly diagnosed MM patients receiving ASCT. On analysis of treatment strategy, however, it is evident that ICT attains better OS outcomes compared to CT alone. Therefore, while renal impairment remains common in patients with MM, an interdisciplinary mode of action between hemato/oncologists and nephrologists concerning the optimal induction therapy prior to ASCT is of pivotal clinical importance. The application of an adequate immuno-chemotherapy should conquer the fear of the negative impact of renal failure on outcome in patients with MM. [Display omitted] DisclosuresGisslinger:Janssen Cilag: Honoraria; Shire: Honoraria; PharmaEssentia: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria; Takeda: Honoraria. Krauth:Takeda: Honoraria; Janssen Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria; AOP Orphan Pharmaceuticals AG: Honoraria; Celgene: Honoraria; BMS: Honoraria.

Prognostic Significance of Plasmablastic Plasma Cells in the Era of Novel Agents in Multiple Myeloma

Background:Plasmablastic (PB) feature has long been identified as poor prognosis in multiple myeloma (MM), although most data was reported in the era of conventional therapy. Furthermore, PB feature does not belong to the R-ISS scoring system in part due to lack of data since the emergence of novel therapy based regimens.Methods: We have performeda retrospective multicenter analysisof all MMdiagnosed in the network area of the Poitiers academic hospital since 2005 to identify MM with PB features. PB was defined as presence of immature cells, any percentage, characterized with high proliferative index rate, centrally reviewed in Poitiers hematology laboratory by 3 hematologists.Results: 65 MM with PB were identified, of which 53,8% were in first-line therapy. Adverse cytogenetic (IMWG) was reported in 6 patients, del17p x3, t(4;14) x2, and one with both. However, 33,8% were ISS 3, and 23,1% R-ISS 3. Presence of extramedullary disease (EMD) was reported in 40%. As a whole, ORR with any triplet-based treatment containing always a proteasome inhibitor and IMiDs or alkylator was 49,2%, with 29,2% VGPR and 4,6% CR. The median PFS and OS were 6,9 and 14,9 months as a whole, respectively, and independently of diagnosis or relapse settings. We noticed that one regimen appeared to fare much better than the other, namely VRd (bortezomib, lenalidomide and dexamethasone), with a median PFS at 36,1 months [CI95%: 0-99] vs 5,5 [0,59-10,4] otherwise; p=0,014. Similarly, ASCT was associated with longer PFS and OS, 21,4 months [12,8-30,1] vs 2,83 [0-5,7], p=0,003; and 50,4 months ([29,9-70,7] vs 6,27 [1,1-11,4] p=0,001 respectively. We were not able to demonstrate that use of anthracyclines was able to control the PB clone, although it was one of our initial hypothesis. Univariate and multivariate analysis for poor OS identified acute renal failure at disease entry, presence of EMD, of del(17p), and high LDH, markers strongly associated to PB presence. We found that the % of PB correlated to poor prognosis on a linear fashion.Conclusion: This study confirms the poor prognosis of PB feature in MM even in the era of novel agents. A triplet-based association PI + IMId + dex is warranted possibly consolidated by ASCT when possible. The role of the new anti CD38 monoclonal antibody has yet to be confirmed in this population. DisclosuresSonneveld:Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy; Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding. Leleu:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Prospective Study of High Dose Foscarnet Prophylaxis for HHV-6 Related CNS Diseases in Cord Blood Transplantation for Adult Patients

Background: Umbilical cord blood transplant (UCBT) recipients showed higher incidence of HHV-6 related CNS diseases (HHV-6 RCD) than those of bone marrow (BM) or peripheral blood (PB). It causes short-term memory impairment or disorientation, which sometimes become irreversible, and convulsions in severe cases, resulted in high non-relapse mortality. We reported previously that in the group given higher doses of prophylactic Foscarnet (FCV) (≥60mg/kg), the incidence of HHV-6 RCD was reduced (Asano-Mori Y, et al. ASH 2013). We thus conducted a prospective study to assess efficacy of higher dose (120mg/kg) of prophylactic FCV to further reduce the incidence and to improve outcome of HHV-6 RCD.Patients and Methods: The study was started since May 2014 and was finished on September 2015. The protocol was approved by local IRB and UCBT recipients who gave written informed consent were included. FCV 120 mg/kg was administered prophylactically from day 7 to day 50 post UCBT.. FCV dose was adjusted according to renal function. The incidence of HHV-6 RCD, types of manifestation and severity of the symptoms, treatment response, and prognosis were evaluated.Results: Among 113 who were included in this study, 9 failed to start FCV from day 7 due to early death or renal impairment, 37 were switched to other drugs at some point before day 50 for reasons such as renal impairment or viral infections other than HHV-6 (23 changed to GCV, 10 to ACV, and 4 to CDV), and 67 received planned dose of FCV. Fifteen developed HHV-6 RCD (12 HHV-6 limbic encephalitis (LE) and 3 myelitis). The cumulative incidence of HHV-6 RCD was 11.5%. No significant risk factors before transplant associated with the development of HHV-6 RCD were identified. Six out of 22 who developed severe pre-engraftment immune reactions (PIR) developed HHV-6 RCD. PIR was shown to be a significant risk factor for HHV-6 RCD development when it was treated as a time-dependent covariate. The median onset day was day 40, and 4 out of 15 patients developed after the cessation of FCV. Only one of 12 encephalitis patients developed convulsions. The median number of copies of HHV-6 in the cerebrospinal fluid at onset was 40,400/µL. HHV-6 viral load in peripheral blood was examined on the same day of CSF examination in 13 and was not detected in 7. Six patients were treated with FCV and GCV in combination, 4 received increased dose of FCV, and 1 was switched from FCV to GCV. Two out of 4 patients who developed after the prophylactic administration of FCV resumed FCV, and the remaining 2 resumed GCV. The virus became undetectable in all 13 evaluable patients by follow-up CSF examination after treatment. The median day of viral disappearance from CSF was 19 days (8-34 days) after diagnosis. All but 2 who were unevaluable due to other complications, had their symptoms improved without sequalae. The median time from treatment intervention to symptomatic improvement was 28 days. The OS after 1 year from HHV6 encephalitis myelitis group was 46.2%, and there was no significant difference in the prognosis as 47.3% OS after 1 year from non-onset group when time-dependent co-analysis was performed (HR 1.88, 95%CI;0.49-2.84, p=0.69). Analysis of OS for 67 patients who were able to undergo preventative FCV administration and other group showed 53.2% and 38.3% respectively in 1 year, revealing a trend in which OS appeared to become higher as a result of continued prophylaxis.Conclusion: There was no difference in the incidence of HHV-6 RCD compared to the previous report even after prophylactic administration of high dose 120 mg/kg of FCV. However, there were few severely ill individuals, most of their symptoms improved due to antiviral treatment without significant sequalae. DisclosuresNo relevant conflicts of interest to declare.

Similar Event-Free Survival but Higher Incidence of Mixed T Cell Chimerism after Hematopoietic Cell Transplantation for Sickle Cell Disease Using Rabbit Versus Horse ATG: a Study from the Sickle Transplant Alliance for Research (STAR)

▪Background: Myeloablative HLA-matched sibling donor hematopoietic cell transplantation (HCT) is highly curative for children and young adults with sickle cell disease (SCD). The most common regimen used worldwide has been Busulfan, Cyclophosphamide and anti-thymocyte globulin (ATG). The optimal type of ATG for this approach remains unclear.Objective: To compare HCT outcomes of horse ATG (hATG) versus rabbit ATG (rATG) in patients with SCD undergoing HCT.Methods: Multicenter retrospective data from patients with SCD undergoing HCT were abstracted from the Sickle Transplant Alliance for Research (STAR) database. Patients undergoing myeloablative and reduced intensity conditioning HCT with matched related donors where the conditioning regimen included ATG were included in the analysis. Baseline characteristics were compared between the groups using chi-square and Wilcoxon Rank-Sum tests. Kaplan-Meier curves were used to assess time-to-event outcomes, such as overall and event free survival (EFS), and compared with log-rank tests. Death, disease recurrence (acute sickle cell symptoms/HbS >50%) and graft failure (whole blood or myeloid chimerism < 5%) were considered events for EFS. Full donor chimerism was defined as ≥95% donor. P-values less than 0.05 were considered statistically significant.Results: 103 patients (hATG = 78, rATG = 25) from 7 U.S. centers and one Canadian site were available in the database for analysis. Median age at HCT (8.1 years vs 7.6 years, p = 0.866) and gender distribution (55.1% vs 56.0% male, p = 0.939) was similar between the cohorts. Sickle cell genotype was 97.4% vs. 84% HbSS, 1.3% vs. 12.0% HbSBetazero, 1.3% vs. 0% HbSC, and 0% vs.4% other. Pre-transplant disease acute symptoms were similar between the groups. Myeloablative conditioning was used in 92.3% and 96.0% in the hATG group versus the rATG group (p=1) and the most common conditioning regimen was Busulfan and Cyclophosphamide +/- Fludarabine in both groups (93.2%). Donor age and source of graft were similar between the two groups. Median follow-up for hATG and rATG groups were 3.0 and 3.6 years respectively. The year of transplant for the two groups ranged from 1993 to 2015 (hATG) and 2003 to 2014 (rATG). Three-year OS for the entire group was 92.6% (95% CI: 87.4-98.0), with 90.1% (95% CI: 83.4-97.4) in the hATG group and 100% (95% CI: 100-100) in the rATG group (p = 0.122) (Figure 1). Three-year EFS was 90% vs. 96% (p=0.415) in hATG vs. rATG group with 2-year graft failure incidence of 0% vs. 4% (p =0.085) respectively. Limiting the analysis to transplants performed after 2000 did not materially alter the analyses for OS and EFS. Causes of death were GVHD related (n=5) and infection/sepsis (n=3) in the hATG group versus no deaths in rATG group. Six month incidence of acute grade III-IV GVHD and 3 year incidence of chronic GVHD for hATG vs. rATG groups was 3.9% vs. 0% (p=0.319) and 16.8% vs. 15.5% (p=0.549) respectively. Prevalence of full donor myeloid chimerism was similar between the two groups at Day +30, Day +100 and >6months. Prevalence of full donor whole blood chimerism was significantly lower at day+100 and 1 year (p < 0.05) in the rATG group. Full donor T cell chimerism was similar at Day 30 and Day 100, but significantly less prevalent at >6 months in the rATG group (p = 0.001) (Table 1).Discussion/Conclusion: In our cohort mortality was low overall and the hATG and rATG groups had similar OS, EFS, and similar incidence of acute grade III-IV and chronic GVHD. However the prevalence of full donor T cell chimerism at greater than 6 months after HCT was significantly lower in the rATG group.Table 1. Incidence of full donor chimerism (≥ 95%) by lymphocyte depleting antibody, %Fig 1. Overall and Event Free survival of hATG vs. rATG based conditioning regimens in HCT for SCDFig 2. Incidence of acute grade III-IV and chronic GVHD in hATG vs. rATG based conditioning regimens in HCT for SCD [Display omitted] DisclosuresGuilcher:Jazz pharmaceuticals: Consultancy; Canada Market Research: Consultancy; Patient Access Solutions: Consultancy.

Pre-Transplant Minimal Residual Disease Evaluation Performed By Molecular WT1-Based or Multicolor Flow Cytometry Assessment Overcomes the Prognostic Value of Cytogenetic and Molecular Risk Factors at Diagnosis in Advanced Acute Myeloid Leukemia Patients

BACKGROUND AND AIMSAllogeneic stem cell transplantation (HSCT) offers the only chance of cure for patients with advanced acute myeloid leukemia (AML). High levels of pre-HSCT minimal residual disease (MRD) have been reported to predict relapse risk after HSCT even in patient transplanted in first complete remission (CR). WT1 expression levels and multicolor flow cytometry (MFC) are the most common tools to evaluate MRD. The aim of this study was to analyze the role of pre-HSCT combined MRD assessment as predictor for the post-transplant relapse risk in patient transplanted beyond first CR.MATERIALS AND METHODSWe retrospectively analyzed the outcome of 92 consecutive AML patients receiving HSCT in 2nd or 3rd CR. Pre-HSCT marrow samples were analyzed for WT1 expression and MFC as MRD evaluation. Median age at transplant was 45 years. Disease phase was CR2 in 63 (68%) and CR3 in 29 patients (32%). ELN risk category at diagnosis was low in 28 (30%), intermediate in 44 (48%) and high in 20 (22%) patients. Sixty-six (71%) patients received myeloablative conditioning, whereas 26 patients (29%) received reduced intensity conditioning. Stem cell source was bone marrow in most cases and donor was an HLA-identical sibling in 18 (20%), haploidentical sibling (HAPLO) in 24 (26%) and unrelated donor in 50 (54%). Median follow-up was 64 months (95% CI 39.8 - 88.2 months).A positive MFC MRD was defined by the presence of at least 1x10-3 residual leukemic cells by 4 or 8 (since 2011) color flow-cytometry. WT1 copy number/Abl copy number 250x104 was used as cut-off value for abnormal WT1 expression.RESULTSRelapse occurred in 30 patients (33%) and two years non-relapse mortality was 29%. Three-year estimate of OS was 47.9% (median 19 months). The survival probability was significantly affected by donor source (better for HAPLO, p<0.05), ELN risk at diagnosis (better for ELN low risk, p<0.01), MRD status before HSCT measured with any method (p <0.01 for WT1-based MRD, p<0.03 for MFC based MRD) and CR status at HSCT (better for CR2, p<0.05).Specifically, among MRD negative patient a relatively low rate of relapse was observed regardless of risk at diagnosis (2-years OS of 62.2% and 52.7% among MFC MRD negative patient with ELN risk low or intermediate/high, respectively, Fig.1).The predictive value of MRD resulted independent from all other analyzed variables. However, patients with positive MRD did slightly better when undergoing HAPLO HSCT. Multivariate OS analysis revealed that the MRD evaluation by any method was the only independent predictor of OS (p <0.05 for both methods of analysis).MRD evaluation was also a strong predictor of cumulative incidence (CI) of relapse in competitive risk analysis (p<0.01 and p<0.03, respectively, for WT1 and MFC MRD). Multivariate CI of relapse analysis showed that donor source and MRD evaluation significantly influenced relapse risk (p <0.05 and <0.01, respectively).CONCLUSIONSPre transplant MRD evaluation by both WT1 and MFCon bone marrow samples is a reliable predictor of relapse risk which may overcome the prediction based on ELN risk at diagnosis. Both methods were able to efficiently predict post-transplant disease reoccurrence risk: patients with negative pre-HSCT MRD markers have a significantly better OS, while patients with positive MRD markers show an higher risk of relapse, irrespective of lower or higher ELN risk at diagnosis.Furthermore, our results seem to suggest that HAPLO donor may have a positive impact in reducing relapse rate in advanced AML patients, in particular in patients with positive MRD.Refining the baseline risk assessment based on ELN risk in patient undergoing HSCT beyond CR1 who have an higher risk of relapse is very important when evaluating optimal stem cell source and conditioning intensity and could allow to apply pre-emptive therapeutic strategies to prevent AML relapse, from donor lymphocyte infusion to other innovative approaches. [Display omitted] DisclosuresAngelucci:Roche: Other: Advisory board: biosimilars; Novartis Oncology: Other: Protocol Telesto: sterring committee Chair; Bluebird Bio: Other: Advisory board: Gene therapy in Thalassemia; Jazz: Other: Advisory board: AML; Celgene: Other: protocoll ACE 536 B-Thal 001: DMC Chair; Novartis Oncology: Other: Advisory board: iron toxicity; Novartis Oncology Swiss: Other: Invited speakers sponsored satellite meeting during ; Celgene: Honoraria, Other: Advisory: research project .

High Density of NRF2 Expression in Malignant Cells Is Associated with Increased Risk of CNS Metastasis in Early-Stage NSCLC

Simple SummaryWe retrospectively analyzed 304 patients with surgically removed non-small cell lung cancer (NSCLC). Multiplex antibody staining of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin reductase 1 (TrxR1) was conducted and scored in cytokeratin-positive (CK+) cells within the whole-tissue core as well as the tumor and stromal compartments of each tissue microarray (TMA) core. A high density of NRF2+/CK+ cells in the whole-tissue core compartment was an independent prognostic factor, with an eightfold increase in odds regarding the risk of relapse in the central nervous system (CNS). This is the first study to report a tumor-cell-associated protein biomarker for CNS relapse in early-stage lung cancer and the first trial to report the correlation between NRF2 expression and risk of CNS relapse. The results of our study may have an impact on the follow-up strategy for early-stage NSCLC patients and eventually improve their prognosis. Nuclear factor erythroid 2-related factor 2 (NRF2) protein expression promotes cancer progression in non-small cell lung cancer (NSCLC). However, its role in the clinical setting has not been established. We retrospectively analyzed data from 304 patients with surgically removed NSCLC. Multiplex antibody staining of NRF2 and thioredoxin reductase 1 (TrxR1) was conducted and scored in cytokeratin-positive (CK+) cells within the whole-tissue core as well as the tumor and stromal compartments of each tissue microarray (TMA) core. A high density of NRF2+/CK+ cells in the whole-tissue core compartment was correlated with a higher risk of central nervous system (CNS) relapse OR = 7.36 (95% CI: 1.64–33.06). The multivariate analysis showed an OR = 8.00 (95% CI: 1.70–37.60) for CNS relapse in NRF2+/CK+ high-density cases. The density of TrxR1+/CK+ cells failed to show any statistically significant risk of relapse. The OS analyses for NRF2+/CK+ and TrxR1+/CK+ cell density failed to show any statistical significance. This is the first study to report a correlation between NRF2+/CK+ cell density and the risk of CNS relapse in early-stage NSCLC. The results of our study may impact the follow-up strategy for early-stage NSCLC patients and eventually improve their prognosis.

Surgical margin clearance and extended chemotherapy defines survival for synchronous oligometastatic liver lesions of the ductal adenocarcinoma of the pancreas

BackgroundThe role of surgery for circumscribed synchronous hepatic lesions of the pancreatic ductal adenocarcinoma (PDAC) remains controversial. Thus, the aim of our study was to compare survival outcome (OS) after surgery of patients with hepatic metastases (M1surg) to patients with only localized disease.MethodsCorrelation analysis of clinicopathological data and OS after resection of M1surg patients and patients with localized PDACs (M0) was performed. Patients were included for survival analysis only if a complete staging including perineural, venous and lymphatic invasion was available.ResultsOut of the study collective, 35 patients received extended surgery (M1surg), whereas 131 patients received standardized surgery for localized disease (M0). Length of hospitalization and mortality was similar in both groups. FOLFIRNOX as an adjuvant treatment regime was administered in ~ 23 and ~ 8% of M1surg and M0 patients, respectively. In subgroup analysis of R0 resected patients and in multivariate analysis of the total cohort, there was no difference in overall survival between both groups. Only the resection status (R1 vs R0) and venous invasion (V1) were identified as independent prognostic factors. Site of recurrence in R0 resected M1surg patients and in M0 patients were homogenously distributed.ConclusionThis is the first study demonstrating a survival benefit after extended surgery for synchronously hepatic-metastasized PDACs. We found no difference in survival outcome of metastasized patients when compared to patients with localized disease. FOLFIRINOX as an adjuvant treatment regime for resected M1surg presumably is worthwhile. Larger multicenter studies are still needed to validate our results.

High PYGL Expression Predicts Poor Prognosis in Human Gliomas.

Background: PYGL has been reported as a glycogen degradation-related gene, which is up-regulated in many tumors. This study was designed to investigate the predictive value of high PYGL expression in patients with gliomas through bioinformatics analysis of the gene transcriptome and the single-cell sequencing data.Methods: The gene transcriptome data of 595 glioma patients from the TCGA database and the single-cell RNA sequencing data of 7,930 GBM cells from the GEO database were included in the study. Differential analysis was used to find the distribution of expression of PYGL in different groups of glioma patients. OS analysis was used to assess the influence of the high expression of PYGL on the prognosis of patients. The reliability of its prediction was evaluated by the AUC of ROC and the C-index. The GSEA be used to reveal potential mechanisms. The single-cell analysis was used to observe the high expression of PYGL in different cell groups to further analyze the mechanism of its prediction.Results: Differential analysis identified the expression level of PYGL is positively associated with glioma malignancy. OS analysis and Cox regression analyses showed high expression of PYGL was an independent factor for poor prognosis of gliomas (p < 0.05). The AUC values were 0.838 (1-year ROC), 0.864 (3-year ROC) and 0.833 (5-year ROC). The C index was 0.81. The GSEA showed that gene sets related to MTORC1 signaling, glycolysis, hypoxia, PI3K/AKT/mTOR signaling, KRAS signaling up and angiogenesis were differentially enriched in the high PYGL expression phenotype. The single-cell sequencing data analysis showed TAMs and malignant cells in GBM tissues expressed a high level of PYGL.Conclusion: The high expression of PYGL is an independent predictor of poor prognosis in patients with glioma.

The status of WIF1 methylation in cell-free DNA is associated with the insusceptibility for gefitinib in the treatment of lung cancer.

Targeted cancer therapy has shed light on the treatment of tumor, especially for patients with non-small cell lung cancer. However, only a limited portion of NSCLC patients carrying specific mutations showed an ideal drug response. In addition, DNA methylation status showed a great potential for cancer detection and prognosis prediction. Bisulfite sequencing was performed to analyze the DNA methylation of WIF1 promoter in cfDNA and tumor tissue samples collected from NSCLC patients. PFS and OS analyses were carried out to evaluate the prognosis of gefitinib treatment in patients with differential levels of WIF1 DNA methylation. Quantitative real-time PCR was used to analyze the expression of WIF1 mRNA, while immunohistochemistry was performed to assess the expression of WIF1 protein. Furthermore, ELISA was carried out to evaluate the WIF1 activity in plasma. The DNA methylation level of WIF1 promoter was lower in the cfDNA of NSCLC patients with a complete or partial response to gefitinib, and NSCLC patients with hypomethylated WIF1 showed better PFS and OS. The DNA methylation of WIF1 promoter in the resected tumor tissues was consistent with WIF1 DNA methylation in cfDNA, indicating that cfDNA was mainly derived from lung cancer tissues. As a result, the expression of WIF1 in tissue samples and the WIF1 activity in plasma was inhibited in patients with hypermethylated WIF1. Moreover, the cell viability of gefitinib-resistant cells was decreased by the suppressed WIF1 methylation in vitro. And the expression level of WIF1 mRNA was higher in gefitinib-resistant cells overexpressing ALKBH5, a known suppressor of WIF1 methylation. In summary, the findings of this study demonstrated that the level of WIF1 methylation in cfDNA was associated with the insusceptibility of gefitinib in the treatment of lung cancer.

Comparison of the Efficacy of S-1 Plus Oxaliplatin or Capecitabine Plus Oxaliplatin for Six and Eight Chemotherapy Cycles as Adjuvant Chemotherapy in Patients With Stage II-III Gastric Cancer After D2 Resection.

ObjectiveTo compare the efficacy of adjuvant chemotherapy with six or eight cycles of S-1 plus oxaliplatin (SOX) or Capecitabine plus oxaliplatin (XELOX) after D2 resection of GC.Design and participantsWe collected 470 cases of patients with TNM stage II and III GC who underwent D2 gastrectomy in the Harbin Medical University Cancer Hospital from January 2007 to December 2017 and received six or eight cycles of SOX or XELOX regimen. This study was designed to evaluate the prognosis of patients receiving six or eight cycles of SOX or XELOX chemotherapy and identify the appropriate number of chemotherapy cycles.ResultsAmong the 470 study participants [340 (72.3%) males; median age, 50 years (range, 24-76 years)], 355 and 115 received XELOX or SOX regimen chemotherapy, respectively. The number of 152 patients included in this study who received 6 and 8 cycles of chemotherapy in stage II and stage III without considering chemotherapy regimens were 125 and 27. The median DFS was, respectively, 14.9 months and 26.8 months (P = 0.08), the median OS was, respectively, 30.2 months and 30.8 months (P = 0.5), the difference was not statistically significant. Comprehensive survival analysis of XELOX and SOX group showed no significant difference for DFS (P = 0.29) and OS (P = 0.61). The total number of stage III GC patients who received six and eight cycles of chemotherapy was 92 and 19, respectively. The median DFS of patients who received six and eight cycles of chemotherapy was 14.6 and 23.2 months (P = 0.3), respectively. The median OS of patients who received six and eight cycles of chemotherapy was 26 and 30.6 months (P = 0.9), respectively. Comprehensive analysis of DFS (P=0.73) and OS (P=0.6) shows no difference between the XELOX group SOX groups. Subgroup analysis revealed significant differences in the gender (P = 0.05) and histological classification (P < 0.05) distribution.ConclusionRegardless of the XELOX regimen or the SOX regimen, similar survival benefits are observed in patients receiving six or eight chemotherapy cycles irrespective of the regimen used. The XELOX and SOX regimens are well tolerated in patients undergoing D2 resection of GC.

Second-line (2L) pembrolizumab (pembro) in Chinese patients (pts) with advanced melanoma: Three-year follow up (FU) of the phase 1 KEYNOTE-151 study.

e21511 Background: Pembro as 2L therapy was well tolerated and had clinically meaningful antitumor activity in Chinese pts with advanced melanoma at first analysis of the phase 1b KEYNOTE-151 study. At median FU of 7.9 mo, ORR was 16.7% (1 complete response [CR]; 16 partial response [PR]), DCR was 38.2%, median DOR was 8.4 mo, median PFS was 2.8 mo, and median OS was 12.1 mo. Any grade and grade 3/4 treatment-related adverse events (TRAEs) occurred in 84.5% and 8.7% of pts, respectively. However, long-term efficacy and safety of 2L pembro in Chinese pts with advanced melanoma are unknown. Results from 3 y of FU are presented. Methods: Eligible pts were ≥18 y, of Chinese descent, had histologically confirmed locally advanced or metastatic melanoma, and had disease progression on or after first line therapy. Pts received pembro 2 mg/kg IV Q3W for ≤35 cycles. Eligible pts who discontinued pembro with stable disease or better could receive ≤17 additional cycles of pembro (second course) upon disease progression. Primary endpoints were safety and ORR per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints included DOR and PFS per RECIST 1.1 by BICR; ORR, DOR, and PFS per irRECIST by BICR; and OS. ORR was based on the exact binomial method; DOR, PFS, and OS analyses used the Kaplan-Meier method. The full analysis set (FAS) comprised all allocated pts who received ≥1 pembro dose and had baseline data for relevant analyses. Results: Of 103 enrolled pts, 43% were male, 51% had PD-L1 positive tumors, and 80% had BRAF wild-type tumors; median age was 52 y (range, 22-77). The FAS had 102 pts. Median time from first dose to database cutoff was 44.6 mo (IQR, 39.1-46.2). At database cutoff (July 13, 2020), 14 pts (13.5%) had completed treatment, 89 pts (86.4%) had discontinued. Any grade TRAEs occurred in 88 pts (85.4%); most commonly hypothyroidism (n = 27; 26.2%), increased ALT (n = 24; 23.3%), and hypertriglyceridemia (n = 23; 22.3%), all grade 1/2. Grade 3-5 TRAEs occurred in 13 pts (12.6%). Immune-mediated AEs and infusion reactions occurred in 35 pts (34.0%); most commonly grade 1/2 hypothyroidism (n = 27; 26.2%). 3 pts discontinued pembro because of a TRAE; none died because of a TRAE. ORR per RECIST 1.1 was 17.6% (95% CI 10.8-26.4; 1 CR/17 PR); DCR was 38.2% (95% CI 28.8-48.4). Median DOR per RECIST 1.1 was 13.8 mo (range, 2.7-37.4+); 1 pt had response duration ≥36 mo. Median PFS per RECIST 1.1 was 2.8 mo (95% CI 2.7-3.5); 36-mo PFS rate was 5.0%. ORR, DOR, and PFS were similar per RECIST 1.1 and irRECIST. Median OS was 13.2 mo (95% CI 10.4-16.5); 36-mo OS rate, 22.3%.1 pt completed the first and second courses of pembro and had investigator-confirmed CR. Conclusions: 2L pembro was well tolerated and continued to provide durable responses and clinically meaningful antitumor activity in Chinese pts with advanced melanoma. These results further support use of 2L pembro in Chinese pts with advanced melanoma. Clinical trial information: NCT02821000.

A phase 1 study of neoadjuvant chemotherapy followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in pancreatic cancer.

e16268 Background: The multi-kinase inhibitor sorafenib (S) and HDAC inhibitor vorinostat (V) demonstrated synergism against preclinincal pancreatic cancer (PaCa) models. The combination of S &amp; V also potently radiosensitized pancreatic cancer cells and enhanced the activity of gemcitabine (G). This led to a phase 1 trial to determine the doses and schedule appropriate for phase 2 study of S &amp; V with weekly G and intensity modulated radiotherapy (IMRT) as neoadjuvant treatment of PaCa following chemotherapy. Methods: Using a 3+3 dose-escalation design, adult patients with resectable, borderline resectable, unresectable, and lymph node positive PaCa were enrolled to 6 dose levels. Enrolled patients had completed at least 8w of neoadjuvant chemotherapy prior to IMRT. The schedule of administration was weekly 200mg/m2 G weekly during IMRT, S &amp; V were dosed either 3x or 5x weekly during IMRT. Primary endpoint was to identify the dose and schedule for S &amp; V with G based chemoradiation. Key secondary endpoints included antitumor activity, R0 resection rate, OS. Correlative studies to evaluate a variety of biomarkers and Nanostring expression analysis on pre- and post-therapy tumor specimens were also performed. Results: 22 patients were enrolled and 21 treated at 6 dose levels. Due to thrombocytopenia limiting drug exposure, the trial was modified to reduce G to 200mg/m2/wk and S &amp; V to 3 d/wk instead of 5 d/wk. 13 patients were eligible for surgery, and 9 had R0 resections. Conclusions: Our findings indicate that the study regimen was well tolerated, typical toxicities of S (hand foot syndrome) were not observed with intermittent dosing. Uncomplicated cytopenias limited drug exposure, which was improved with intermittent S&amp;V dosing. The RP2D of the combination is S (400mg po BID 3d/wk), V (200mg po qd 3d/wk), G 200mg/m2 IV weekly, with IMRT (50.4 Gy over 28 fractions, 5d/wk). Antitumor activity was observed across dose levels, with an encouraging R0 resection rate. These results warrant further investigation of combining S and V with G and IMRT as neoadjuvant treatment of PaCa following chemotherapy. Analyses of correlative studies and OS are underway. Clinical trial information: NCT02349867. [Table: see text]