Time Of Disease Progression Research Articles

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone.

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4+ and CD8+ T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.

Abstract 424: Genomic instability changes of circulating tumor DNA reflect the responses to chemotherapy or targeted therapy in advanced gastric cancer

Abstract Background: Gastric cancer was characterized by frequent somatic copy number alterations and high genomic instability, yet the significance of genomic instability and its changes implicated by drug treatment in advanced gastric cancer (AGC) remain unclear. In this study, we investigated genomic instability changes of circulating tumor DNA (ctDNA). Methods: A total of 101 plasmas and paired blood cells from 26 patients with AGC before (N=26) and after (N=75) treatment were prospectively collected. Plasma ctDNA was separated and assessed for copy number variations (CNV) by whole genome sequencing (WGS), and we assessed the correlation between genomic indexes and therapeutic response. Results: Genomic instability with diverse patterns was observed in 20 of 26 patients (77%) prior to drug treatment. For patients with high (N=20) level genomic instability prior to drug treatment, the response rate (55%, 11/20) was significantly higher than that (17%, 1/6) in patients with low level (N=6) genomic instability (P=0.17). Notably, genomic instability changed with the administration of drugs, which reflected its correlation with therapeutic response. All ctDNAs (94%, 14/15) collected at the time of partial response (PR) after treatment displayed low-genomic instability. However, 52% ctDNAs (13/25) collected at the time of progressive disease (PD) after treatment showed high-level genomic instability. Furthermore, several patterns of CNV were categorized in ctDNAs. CNV pattern after acquiring drug resistance were largely unchanged with respect to CNV baseline patterns. Conclusions: Genomic instability based on ctDNA can be used to predict and monitor therapeutic response in gastric cancer, although validation in larger cohort would be necessary. Citation Format: Zuhua Chen, Cheng Zhang, Beifang Li, Yunyun Niu, Limeng Chen, Mengqi Zhang, Jing Yang, Sijia Lu, Jing Gao, Lin Shen. Genomic instability changes of circulating tumor DNA reflect the responses to chemotherapy or targeted therapy in advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 424.

Ganji Formulation for Patients with Hepatocellular Carcinoma Who Have Undergone Surgery: A Multicenter, Randomized, Double-Blind, Controlled Trial.

Objective. To ascertain the efficacy and safety of Ganji Formulation (GF) for patients with Hepatocellular carcinoma (HCC) who had undergone surgery. Materials and Methods. A total of 262 HCC patients who had undergone liver resection, local ablation, or transcatheter arterial chemoembolization (TACE) were divided randomly into the treatment group and control group. The former was treated with GF and the later with placebo, both for 6 months. The primary endpoint was overall survival (OS). Second endpoints were disease-free survival (DFS) or time to disease progression (TTP). Results. OS of the treatment group was significantly longer than that of the control group (P < 0.05). Subgroup analysis showed that, for patients who received TACE, the TTP was significantly longer in the treatment group than in the control group (P < 0.05). However, for patients who underwent liver resection or local ablation, there was no significant difference in DFS between the two groups (P > 0.05). Conclusion. GF could improve postoperative cumulative survival and prolong the TTP. This clinical trial number is registered with ChiCTR-IOR-15007349.

A Phase II, Multicenter, Single-Arm Study of Mipsagargin (G-202) as a Second-Line Therapy Following Sorafenib for Adult Patients with Progressive Advanced Hepatocellular Carcinoma.

Background: Mipsagargin (G-202) is a thapsigargin-based prodrug with cytotoxic activity masked by a peptide that is cleaved by prostate-specific membrane antigen (PSMA), a protease expressed in prostate cancer cells and the endothelium of tumor vasculature. It was hypothesized that PSMA-mediated activation of mipsagargin would result in disruption of the tumor vasculature, leading to a decrease in blood flow, and in direct cytotoxic effects on tumor cells, resulting in anti-tumor activity. Method: In this open-label, Phase II study, mipsagargin was administered intravenously on Days 1, 2, and 3 of a 28-day cycle to patients with hepatocellular carcinoma (HCC) who progressed on or after treatment with sorafenib or intolerant of sorafenib. Assessments included time to disease progression (TTP), response rate, progression-free survival (PFS), overall survival (OS), and safety. Blood flow metrics in hepatic lesions were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Of 25 treated patients, 19 were evaluable for efficacy. None had an objective response, 12 (63.2%) had a best response of stable disease, and 12 (63.2%) showed radiologic progression; seven patients (36.8%) were censored. The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days. Of five patients with DCE-MRI data for 11 HCC lesions, all demonstrated a reduced Ktrans (mean, 52%). The most common treatment-emergent AEs were Grade 1–2 and consisted of increased blood creatinine (68.0%), fatigue (56.0%), and nausea (44.0%). Conclusions: Mipsagargin is relatively well tolerated and promotes prolonged disease stabilization in patients with advanced HCC that had progressed on prior treatment with sorafenib. A significant decrease in Ktrans upon treatment suggests mipsagargin reduces blood flow in hepatic lesions.

Single-arm, phase II study of pyrotinib in advanced non-small cell lung cancer (NSCLC) patients with HER2 exon 20 mutation.

9089 Background: HER2 exon 20 mutation is a well-known oncogenic driver in non-small cell lung cancer (NSCLC) and its testing is recommended by NCCN guidelines for NSCLC patients. However, up to now, there has been no approved targeted therapy for this patient population. Pyrotinib is an oral, irreversible pan-Her tyrosine kinase inhibitor (TKI) against HER1, HER2 and HER4, which, combined with chemotherapy, has recently been approved in China for HER2 positive advanced breast cancer. Methods: Stage IIIB or IV NSCLC patients with HER2 exon 20 mutation (confirmed in a central lab) and previously treated with at least one platinum-based chemotherapy were enrolled in this open-label, multi-center, single-arm phase II study. Patients with active brain metastases or prior use of HER2 TKI agents were excluded. Eligible patients received pyrotinib 400 mg once daily until disease progression, intolerable toxicity or withdrawal of consent. The primary endpoint was objective response rate (ORR) according to RECIST 1.1. Secondary endpoints included safety, progression-free survival (PFS), time to disease progression (TTP), duration of response (DOR) and overall survival (OS). This trial is registered on ClinicalTrials.gov (NCT02834936). Results: Between October 20, 2016 and December 10, 2018, 60 patients (33 female, 27 male) were enrolled. The median age was 57 years (range: 40, 72). A majority were stage IV patients (95%). Over 58% of patients have been treated with two or more prior chemotherapy regimens. As of Jan 21, 2019, the ORR as evaluated by investigators was 31.7% (95% CI 20.3%, 45.0%). Median DOR was 7.0 months (95% CI 5.5, 11.0) and median PFS was 6.8 months (95% CI 4.1, 8.3). 26.7% patients reported treatment-related grade 3 AEs. Diarrhea (20.0%) was the only treatment-related grade 3 AE that occurred in ≥ 2 patients. Treatment-related grade 4 AE was reported in 1 subject (elevated gamma-glutamyl transferase). The anti-tumor activities of pyrotinib was shown in various mutation types. Conclusions: Pyrotinib as a single agent demonstrated promising anti-tumor activity and acceptable safety profile in heavily pretreated HER2 mutant NSCLC patients. Clinical trial information: NCT02834936.

SAT-LB002 Steroid Metabolome Analysis Reveals 11-Ketotestosterone as the Most Abundant Androgen in Castration-Resistant Prostate Cancer Patients on Second-Line Therapies

Introduction Metastatic castration-resistant prostate cancer (CRPC) remains a clinical challenge despite antitumoral therapies such as taxane chemotherapeutics, enzalutamide, and abiraterone acetate. Clinical studies have highlighted the benefits of these therapies on overall and progression-free survival, but the changes these treatments impose on the steroid metabolome have not yet been fully mapped. In this study, we investigated the steroid metabolomes of CRPC patients on second-line therapies before and during treatment and after clinical progression was observed. Method Plasma samples from 30 patients from the ongoing CIRCUS trial were selected. Patients were included if progression on androgen-deprivation therapy was confirmed and patients were scheduled to receive additional secondary treatment with antiandrogens (enzalutamide (n=10) or apalutamide (n=1)), abiraterone + prednisone (n=2), docetaxel + prednisone (DP, n=10) or cabazitaxel + prednisone (CP, n=14). Seven patients completed two treatments during their enrollment in CIRCUS. Following liquid-liquid extraction of steroids from plasma, multi-steroid profiling by liquid chromatography-tandem mass spectrometry was carried out targeting 16 steroid hormones from classic and 11-oxygenated androgen pathways as well as mineralocorticoid and glucocorticoid biosynthetic pathways. Results Accurate quantification was achieved for all targeted steroids with the exception of dihydrotestosterone and androstenedione. The most abundant active androgen in CRPC patients was 11-ketotestosterone (11KT) with a median concentration of 0.46 nM (range 0.03 - 2.39 nM), whereas the median testosterone concentration was 0.14 nM (range 0.03 - 0.76 nM). 11KT and its precursors were suppressed by CP treatment. Analysis of all patients who started treatment with glucocorticoids revealed a potent suppression of 11KT by 88.5% (range 17.9 - 97.5%) and testosterone by 70.1% (range 24.1 - 95%), as well as suppression of 11-oxygenated androgen precursor steroids. Increased 11KT levels were observed in the DP-treated patients at the time of progressive disease. Discussion In this study, we present in-depth characterization of the previously unexplored steroid metabolomes in CRPC patients revealing 11KT as the most abundant androgen. 11KT has been shown to bind and activate the AR with similar potency to testosterone and our findings suggest that the 11-oxygenated androgens may be the dominant AR agonists in the CRPC setting. Routine quantification of testosterone alone may therefore underestimate the androgenic potential in CRPC patients. Suppression of adrenal androgens, including 11KT, was achieved by glucocorticoid treatment, which may explain the beneficial effects of glucocorticoids in CRPC patients. Funding This project was funded by the Daniel den Hoed foundation. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Activation of central/effector memory T cells in advanced gastric cancer patients treated with antiprogrammed death-1 antibody.

54 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances antitumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 (PD-L1) and has shown efficacy for advanced gastric cancer (AGC) in the salvage line. However, specific subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood mononuclear cells of 20 AGC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). The proportion of immune cell subsets were systematically analyzed by flow cytometry, including the expression of costimulatory and coinhibitory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T cell antigen-4 (CTLA-4), CD28, OX40, and inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were analyzed. Results: Median progression free survival (PFS) of the whole patients was 51 days (95% CI 35–83). After a single course of nivolumab, patients showed a significant increase in activated effector memory and activated effector subsets of CD4+/CD8+ T cells (p = 0.018, 0.018, 0.032, 0.024). At the time of PD, proportions of myeloid dendritic cell, IgM memory B cell and Tfh-Th1/17 cell subsets decreased (p = 0.024, 0.013, 0.0039). On the other hand, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells increased at the time of PD (p = 0.013, 0.032, 0.042, 0.042). Significant positive correlations were found between PFS and the proportion of LAG3 positive CD4+/CD8+ T cells (p = 0.0056, 0.0054), OX 40 positive CD4+/CD8+ T cells (p = 0.0034, 0.0006) prior to the initial nivolumab therapy. Conclusions: Nivolumab therapy enhances activation of effector memory and effector subsets of CD4+/CD8+ T cells. The expression level of LAG3 and OX40 on T cells might be correlated with efficacy of nivolumab therapy.

Hematologic Markers as Prognostic Factors in Nonmetastatic Esophageal Cancer Patients under Concurrent Chemoradiotherapy.

Nonmetastatic esophageal cancer can demonstrate a high local recurrence rate even under the standard treatment. We evaluated platelet counts before and after concurrent chemoradiotherapy (CCRT), neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio for predicting esophageal cancer prognosis under CCRT. Newly diagnosed patients with esophageal cancer (stages IA–IIIC) who underwent CCRT during January 2013–December 2017 were enrolled. The data were collected retrospectively. Overall survival (OS), time to progressive disease (TPD), and time to metastasis (TM) were recorded for indicating prognosis. Kaplan–Meier curves were plotted and univariate and multivariate analyses were performed. In total, 105 patients were enrolled. The stages of esophageal cancer and surgery were associated with prognosis (i.e., OS, TPD, and TM). Based on TPD and TM, women had better prognosis than men. In the univariate analysis, high pre- and post-CCRT platelet counts (>300,000/μL), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) as well as low lymphocyte percentage were significantly associated with poor prognosis. However, in the multivariate analysis, only post-CCRT high platelet count (>300,000/μL) remained significantly associated with poor prognosis (P = .041, .045, and .023 for OS, TPD, and TM, respectively). Poor prognosis was observed in patients with high platelet counts, PLR, NLR, and low lymphocyte percentage. Surgery was an independent factor predicting better prognosis. Our findings may have clinical significance with regard to therapeutic decision-making.

Monitoring serum proangiogenic cytokines from hepatocellular carcinoma patients treated with sorafenib.

Several factors, including proangiogenic cytokines, have been reported as predictive markers for the treatment effect of sorafenib in patients with hepatocellular carcinoma (HCC); however, most of them were determined based on one-time measurements before treatment. We consecutively recruited 80 advanced HCC patients who were treated with sorafenib prospectively. Serum levels of eight proangiogenic cytokines and the appearance of adverse events were monitored periodically, and their correlations with the prognoses of the patients were evaluated. Among six significant risk factors for overall survival in univariate analyses, high angiopoietin-2 (hazard ratio, 2.06), high hepatocyte growth factor (hazard ratio, 2.08), and poor performance status before the treatment (hazard ratio, 2.48) were determined as independent risk factors. In addition, high angiopoietin-2 at the time of progressive disease was a marker of short post-progression survival (hazard ratio, 4.27). However, there was no significant variable that predicted short progression-free survival except the presence of hepatitis B virus surface antigen. Predictions of overall survival and post-progression survival were possible by periodically measuring serum proangiogenic cytokines, especially angiopoietin-2, in patients with HCC treated with sorafenib.

MS10.4 Prognostic Impact of Syntax II Score In Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: Analysis of An 8-Year All-Comers Registry

The purpose of the study was to evaluate the efficacy of metastasectomy for urinary tract carcinoma (UTC) and to determine prognostic factors that affect survival.Data from a total of 30 patients with metastatic UTC who underwent a metastasectomy between February 2000 and July 2014 were analyzed retrospectively. Time to disease progression (TTP) and overall survival (OS) from metastasectomy, and potential prognostic factors were evaluated.The lung was the most frequent site of metastasectomy (n = 24) followed by the liver (n = 3) and lymph nodes (n = 3). With a median follow-up duration of 54.2 months, the median TTP was 15.2 months and the median OS was 30.0 months (95% confidence interval, 15.1-42.9) with a 3-year survival rate of 41%. In multivariate analysis, initial stage IV disease (P = .047), pure urothelial pathology (P = .034), and nonpulmonary metastasectomy (P = .040) were independent prognostic factors for a shorter TTP. Nonpulmonary metastasectomy was an independent factor affecting OS (P = .001).A metastasectomy has the potential to contribute to better oncologic outcome in select patients with metastatic UTC, especially those with a single rather than multiple and pulmonary rather than nonpulmonary metastases due to recurrent rather than initially metastatic urinary tract cancer.

Results of using tegafur in combination with irinotecan and oxaliplatin in patients with advanced colorectal cancer

A study that enrolled 30 patients with advanced colorectal cancer, who had not previously received any specific drug treatment, was conducted to develop and study a three-component regimen with oral fluoropyrimidine tegafur (Ftorafur) in outpatient practice. The study evaluated the time to disease progression (TDP), the overall survival (OS) of patients, who received irinotecan + oxaliplatin + Ftorafur in the first-line therapy, as well as the effectiveness and safety of this regimen. 6 patients received a 3-week chemotherapy cycle (Fig. 1), 24 patients – a 2-week chemotherapy cycle (Fig. 2). The preliminary results of the study have been obtained. The median OS was not reached, the median TDP was 8.5 months. In Group I, there was partial regression of metastasis in 3/6 patients, and prolonged disease stabilization (≥ 6 months) in 3 patients. The therapeutic effect (partial remission + long-term stabilization ≥ 6 months) was observed in all patients. The duration of TDP was from 6 to 15 months. In group II, the effect was evaluated in 24 patients, who received at least 2 chemotherapy cycles. 14/24 patients had a partial response (PR), of which 4 (16.6%) patients were radically operated, 6 patients elicited disease stabilization. Thus, control over the disease was achieved in 83.33% of patients in Group II. Oxaliplatin combined with irinotecan and fluorafur was effective, had an acceptable toxicity profile, and therefore, can be used in debilitated patients with disseminated disease.

PO-112 The role of transcribed ultraconserved regions Uc160 and Uc346 in colorectal cancer progression

IntroductionExpression of Transcribed Ultra Conserved Regions (Transcribed Ultra Conserved Regions, T-UCRs) is often deregulated in many types of cancer, including colorectal cancer (CRC). Our previous results showed that T-UCRs Uc160 and Uc346 are methylated in CRC. Additionally, their tumour methylation is associated with time to disease progression (TTP) and appears to be a promising biomarker for CRC. However, their role in CRC progression has not been elucidated to date.Material and methodsAim of the study was to investigate the role of Uc160 and Uc346 in proliferation, motility and migration in colon cancer cells. For that purpose, Uc160 and Uc346 were cloned into plasmids and three colon cancer cell lines (HT-29, Caco-2 and DLD-1) were transiently transfected. After overexpression of Uc160 and Uc346, proliferation (MTT assay), motility (scratch wound healing assay) and migration (transwell migration assay) rates were evaluated.Results and discussionsProliferation rates, 48 hour after overexpression, were higher in the transfected cells in all cell lines, compared with the control cells (mock transfected). The most significant differences in proliferation rates were noticed for Uc160 overexpression in Caco-2 (p=0.008) and Uc346 overexpression in DLD-1 cells (p=0.033). Similar results were observed in motility assay, with cells overexpressing Uc160 or Uc346 having higher motility rates compared to control cells in all cell lines. More specifically, most significant differences in motility rates were observed in HT-29 and DLD-1 cells overexpressing Uc160 or Uc346 (p=0.017, p=0.041 and p=0.023, p=0.004 respectively). Further analysis of DLD-1 cells migration confirmed the above results, with higher number of Uc160 or Uc346 overexpressing cells migrating compared to the control cells (p=0.005 for both T-UCRs).ConclusionT-UCRs Uc160 and Uc346 appear to affect the proliferation, motility and migration rates of colon cancer cells, implicating a complex role in CRC progression.

Abstract CT095: Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients (pts) bearing MGMT methylation

Abstract Backgroud Metastatic colorectal cancer (mCRC) pts bearing promoter methylation of the DNA repair gene, O-6-methylguanine-DNA methyltransferase (MGMT), are suitable for treatment with temozolomide (TMZ) with an expected response rate up to 10% even in the chemorefractory setting. Additionally, the reintroduction of a previously used chemoterapeutic agent with potentially retained sensitivity is often used. We hypothesized that the combination of irinotecan, another DNA damaging agent, and TMZ (TEMIRI regimen) in pts with irinotecan-sensitive, MGMT methylated, microsatellite stable (MSS) mCRC may be a novel treatment approach. Methods Pts with mCRC bearing MGMT methylation were identified in two Italian institutions. Key inclusions criteria were: MSS mCRC, progression after at least two prior chemotherapy lines for advanced disease, irinotecan free interval (IFI) ≥ 3 months, as defined by the time elapsed from the last irinotecan-based regimen and the time of progressive disease. MGMT promoter methylation and MSS status were confirmed centrally. Eligible pts received a maximum of 6 cycles of TEMIRI regimen (TMZ 150mg/sqm on days 1-5 plus irinotecan 100mg/sqm on days1,15 every 28 days) followed by maintenance with single-agent TMZ until progression, unacceptable toxicity or consent withdrawal. Primary endpoint of the study was overall response rate (ORR). Setting p0 = 10%, and p1 = 35%, with 1-sided-α and β errors of 0.05 and 0.20, 25 patients were required. Null hypothesis would have been rejected if RECIST response had been observed in at least 6 patients. Exploratory endpoints included the correlation of activity/efficacy parameters with biomarkers, including MGMT immunohistochemistry (IHC) and MethylBEAMing (MB). Results Twenty-five pts were enrolled between December 2014 and June 2017. Seventeen pts (68%) had extensive metastatic disease. The majority of pts was heavily pretreated: 68% received more than 3 lines of therapy. Median IFI was 6.8 months. The primary endpoint was met: partial responses (PR) according to RECIST v1.1 were detected in six out of 25 patients (ORR 24%, 95% CI, 11%-43%). Median progression free survival (PFS) and overall survival (OS) were of 4.4 and 13.8 months, respectively. Treatment was well tolerated with neutropenia being the most common G3-G4 adverse event (8%) followed by diarrhea (4%). MGMT IHC had a negative predictive value of 100% as all pts whose cancer was MGMT-positive were non-responders. Additionally, pts with MGMT-negative/low tumors had a significantly longer mPFS than those with MGMT-positive ones (6.9 versus 2.0 months; HR=0.29, 95%CI, 0.02-0.41; p=0.003) while no significant difference in OS was observed (17.3 versus 13.8 months; HR=0.56, 95%CI: 0.13-1.85; p=0.303). Similarly, patients with methylation percentage ≥63 by MB had a significantly longer mPFS than others (6.6 versus 3.8 months; HR=0.46, 95% CI, 0.13-0.95; p=0.049), with no OS differences (15.5 versus 12.7 months; HR=0.75, 95% CI 0.24-2.11; p=0.327). Conclusions Given the disappointing results of the available treatments in the chemorefractory setting, TEMIRI regimen is a safe and promising approach for pretreated MGMT-methylated, MSS mCRC pts Citation Format: Federica Morano, Salvatore Corallo, Ludovic Barault, Monica Niger, Rosa Berenato, Roberto Moretto, Giovanni Fucà, Giovanni Randon, Maria Antista, Antonino Belfiore, Alessandra Raimondi, Federico Nichetti, Francesca Vita, Federica Perrone, Massimo Milione, Giancarlo Pruneri, Alfredo Falcone, Maria Di Bartolomeo, Federica Di Nicolantonio, Filippo De Braud, Chiara Cremolini, Filippo Pietrantonio. Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients (pts) bearing MGMT methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT095.

Impact of body mass index on the efficacy of endocrine therapy in patients with metastatic breast cancer - A retrospective two-center cohort study

BakgroundThe aim of this study was to investigate the impact of body mass index (BMI) on the efficacy of endocrine therapy in postmenopausal women with metastatic hormone receptor breast cancer (HR+BC) as well as to identify if the potential difference in efficacy was associated with Fulvestrant only or both aromatase inhibitors (AIs) and Fulvestrant. MethodsA consecutive cohort of postmenopausal women with HR+metastatic breast cancer that have received endocrine therapy including Fulvestrant as a metastatic treatment strategy at the Departments of Oncology in Eskilstuna and Uppsala, Sweden, between 2008 and 2016 were identified. The primary outcome of the study was time to disease progression (TTP) during the treatment with Fulvestrant in overweight and obese women compared to patient with normal BMI. ResultsIn total, 173 patients were enrolled in the study cohort, amongst these, 141 patients received both Fulvestrant and AIs and 32 received only Fulvestrant. No statistical significant association was observed between the three BMI categories and TTP, during Fulvestrant treatment (p = 0.136). The rates of objective response and clinical benefit due to Fulvestrant were similar among patients with normal weight, overweight and obesity, respectively. ConclusionsNo difference in treatment efficacy was seen between normal, overweight and obese women with metastatic HR+BC, when treated with Fulvestrant. Until further research with prospective studies is available, there is no evidence to support any modification in how Fulvestrant treatment is used in patients with metastatic breast cancer in regard to BMI.

Effect of chemotherapy combined with bioimmune therapy on clinical efficacy and survival of advanced prostate cancer

Objective To investigate the effect of chemotherapy combined with biological immunotherapy on clinical efficacy and survival of advanced prostate cancer. Methods Ninety-six patients with advanced prostate cancer who were treated from September 2013 to March 2016 in our hospital were randomly divided into two groups. The control group was given chemotherapy alone, the observation group was given chemotherapy combined with biological immunity for treatment. The clinical efficacy and immunohistochemical response of patients with advanced prostate cancer were compared and analyzed. After 4 months of treatment, the patients were followed up for 1 year. The mortality, survival and time to disease progression (TTP) as well as the occurrence of adverse reactions of the two groups were observed. Results After treatment, the total effective rate of the observation group was 87.5% (42/48), which was significantly higher than that of the control group [68.8%(33/48]. There was significant difference between the two groups (P<0.05). The numbers of Tlymphocytes, T helper cells, Tsuppressor cells, natural killer cells and naturak killer T were significantly higher than that in the control group in the external T lymph. There was a significant difference between the two groups (P <0.05). After 1 year of follow-up, the mortality rate of the observation group was lower than that of the control group, and the survival time (36.6 ± 5.4) months was higher than that of the control group (20.7 ± 7.2) months, TTP of the observation group was higher than that of the control group [(29.8 ± 5.7) months vs.(19.7±9.3)months] (P<0.05). The adverse reaction rate (22.9%) in the observation group was significantly lower than that in the observation group (43.8%), and the difference between the two groups was statistically significant (P<0.05) . Conclusions Chemotherapy combined with biological immunotherapy is effective in advanced prostate cancer, which can effectively enhance the activity of immune function cells, prolong survival time, TTP, reduce mortality, reduce the incidence of adverse reactions and improve the quality of life after treatment. Key words: Prostatic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Immunotherapy

Apatinib is effective for treatment of advanced hepatocellular carcinoma.

As treatment options for hepatocellular carcinoma (HCC) are currently limited, we evaluated the efficacy and safety of oral apatinib, a VEGFR-2 inhibitor, on patients with advanced HCC. Twenty-two patients from Tianjin Medical University Cancer Institute and Hospital were enrolled for evaluation. Apatinib was administered at 500 mg/day or 250 mg/day continuously. Clinical endpoints were time to disease progression (TTP), overall survival (OS), and safety. The median TTP of treated patients was 10.4 months (95% CI 3.4 -17.5). At the last follow-up, 50% patients had survived longer than 11.4 months from the first dose. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 0%, 40.9%, 40.9%, and 18.2%, respectively. The most common apatinib-related adverse events were hand-foot skin reaction (HFSR) (81.8%) and diarrhea (77.3%). Hypertension (27.3%) and HFSR (13.6%) were the most frequent grade 3/4 adverse events. In summary, results of this small study indicate that apatinib is well tolerated and extremely effective for the treatment of advanced HCC. It is therefore imperative to design and carry out well-controlled clinical trials to confirm its efficacy.

PDCT-15. MULTIMODAL IMMUNOTHERAPY AS PART OF MULTIMODAL TREATMENT FOR DIPG

Because some tumor antigens in DIPG are defined, the immune system might provide long-term tumor control via memory T cell activity. Our concept consists of induction of intratumoral immunogenic cell death through infusion of Newcastle Disease Virus (NDV) together with local application of modulated electrohyperthermia (mEHT) and injections of autologous mature monocyte-derived dendritic cells (DCs) loaded with NDV/mEHT-induced serum-derived antigenic microparticles + NDV. Treatment is provided on individual basis. Data were retrospectively collected. 36 DIPG children with median age 5.5y (range 2-19y) were treated with immunotherapy, 24 of them as part of primary treatment (DIPGprim) and 12 at time of progressive disease after first line treatment (DIPGprog). 81% of DIPGprim children had a Lansky score >70. At start of immunotherapy, 33% of patients had deficient IFN-g expression in the CD4+ T cells. Diminished NK function was observed in 75%. The repetitive NDV infusions, the modulated electrohyperthermia and the production and administration of the DCs all were feasible. No major toxicity was observed. We detected the increase of GBM antigen cross-reacting IFN-g-producing T cells in those patients that could be immunomonitored. Data were fixed at 04/04/2017. Median PFS was 8.36m. Rescue after progression was mainly re-irradiation. Median OS was 14.23 months. 18m OS was estimated as 35% (asymmetrical 95%CI: +25.68, -24.25). Median OS of the 10 DIPGprog children calculated from last event prior to immunotherapy was 5.96m. These clinical experiences support the concept that immunotherapy can be considered as part of multimodal treatment for patients with DIPG at an early stage of their disease. Its effect is likely located at an improvement of long-term OS. The latter read-out, together with the individualized treatment approach, makes the scientific steps towards evidence-based efficacy demonstration very challenging.

Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials.

Early-phase trials in patients with recurrent neuroblastoma historically used an objective "response" of measureable disease (Response Evaluation Criteria In Solid Tumors [RECIST], without bone/bone marrow assessment) to select agents for further study. Historical cohorts may be small and potentially biased; to the authors' knowledge, disease recurrence studies from international registries are outdated. Using a large recent cohort of patients with recurrent/refractory neuroblastoma from Children's Oncology Group (COG) modern-era early-phase trials, the authors determined outcome and quantified parameters for designing future studies. The first early-phase COG trial enrollment (sequential) of 383 distinct patients with recurrent/refractory neuroblastoma on 23 phase 1, 3 phase 1/2, and 9 phase 2 trials (August 2002 to January 2014) was analyzed for progression-free survival (PFS), overall survival (OS), and time to disease progression (TTP). Planned frontline therapy for patients with high-risk neuroblastoma included hematopoietic stem cell transplantation (approximately two-thirds of patients underwent ≥1 hematopoietic stem cell transplantation); 13.2% of patients received dinutuximab. From the time of the patient's first early-phase trial enrollment (383 patients), the 1-year and 4-year PFS rates ( ± standard error) were 21% ± 2% and 6% ± 1%, respectively, whereas the 1-year and 4-year OS rates were 57% ± 3% and 20% ± 2%, respectively. The median TTP was 58 days (interquartile range, 31-183 days [350 patients]); the median follow-up was 25.3 months (33 patients were found to be without disease recurrence/progression). The median time from diagnosis to first disease recurrence/progression was 18.7 months (range, 1.4-64.8 months) (176 patients). MYCN amplification and 11q loss of heterozygosity were prognostic of worse PFS and OS (P = .003 and P<.0001, respectively, and P = .02 and P = .03, respectively) after early-phase trial enrollment. This recent COG cohort of patients with recurrent/refractory neuroblastoma is inclusive and representative. To the authors' knowledge, the current study is the first meta-analysis of PFS, TTP, and OS within the context of modern therapy. These results will inform the design of future phase 2 studies by providing a) historical context during the search for more effective agents; and, b) factors prognostic of PFS and OS after disease recurrence to stratify randomization. Cancer 2017;123:4914-23. © 2017 American Cancer Society.

Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial

BackgroundCALGB 100104 (Alliance) studied lenalidomide vs. placebo following autologous stem cell transplant (ASCT) for newly diagnosed myeloma patients, demonstrating improved time to progression (TTP) and overall survival (OS), and an increase in second primary malignancies (SPM) for lenalidomide at 34-months median follow-up. Here we report an updated intent-to-treat analysis at 91-months median follow-up.MethodsPatients were eligible if they had active myeloma, had received at most two induction regimens and had achieved stable disease or better in the first 100 days after ASCT. In this phase 3 study, 460 patients were randomised in a double-blind manner to either lenalidomide (n=231) or placebo (n=229) utilizing a permutated-block randomisation with fixed block size. Randomisation was stratified by three factors: normal or elevated β2-microglobulin level at registration (≤2·5 mg/L vs > 2·5 mg/L), prior use or nonuse of thalidomide during induction therapy, and prior use or nonuse of lenalidomide during induction therapy. The starting dose was 10 mg daily, escalated to 15 mg daily after three months. The primary endpoint was TTP (time of progressive disease or death from any cause) using intent-to-treat analysis. After three interim analyses, the study was unblinded at median follow-up of 18 months and 86/128 placebo patients without progressive disease chose to cross over to lenalidomide. This study is registered with ClinicalTrials.gov identifier NCT00114101; new patients are no longer being recruited, but some patients remain on treatment and in follow-up.FindingsThe median TTP for lenalidomide is 57·3 months (95% CI 44·2–73·3) and 28·9 months (95% CI 23·0–36·3) for placebo (hazard ratio (HR): 0·57, 95% CI 0·46–0·71, p<0·0001). The TTP benefit with lenalidomide was observed regardless of whether patients were in a complete response at time of randomisation or whether they had received thalidomide or lenalidomide induction therapy. The most common grade 3–4 adverse events were neutropenia (116 (50%) of 231 patients in the lenalidomide arm and 37 (16%) of 229 patients in the placebo arm) and thrombocytopenia (34 patients (15%) in the lenalidomide arm and 11 patients (4·8%) in the placebo arm. Eighteen haematological (7·8%) and 14 solid tumour (6·1%) SPMs have been diagnosed following randomisation and prior to disease progression in the lenalidomide arm vs. three haematological (1·3%) and nine solid tumour (3·9%) SPMs in the placebo arm. Of the placebo SPMs, three haematological and five of nine solid tumour SPMs were in the crossover subgroup.InterpretationDespite an increase in haematological adverse events and SPMs, lenalidomide maintenance therapy following ASCT significantly improves TTP and can be considered a standard of care.

Transcatheter hepatic arterial chemoembolization and sorafenib for hepatocellular carcinoma: a meta-analysis of randomized, double-blind controlled trials.

We performed a meta-analysis of transcatheter hepatic arterial chemoembolization (TACE) combined with sorafenib for hepatocellular carcinoma (HCC), which included 4 double-blind, randomized controlled trials (RCTs) that investigated the effects of TACE combined with sorafenib (experimental groups) on time to disease progression (TTP), overall survival (OS), and various sorafenib-related adverse events, compared to those in the placebo (control) groups. A total of 877 HCC cases from 14 countries, including China and the USA, were included in our meta-analysis. The TTP increased significantly in the experimental groups (hazard ration [HR]: 0.82; 95% CI: 0.69–0.97; p = 0.02), but OS did not improve significantly (HR: 0.97; 95% CI: 0.72–1.29; p = 0.82), compared with the control groups. The risks of hand and foot skin reactions (HFSR), rash, fatigue, and diarrhea were significantly greater in the experimental groups (p < 0.05 for all), compared to those in the control groups, whereas the risk of nausea was statistically similar (p > 0.05). Among these, the risk of HFSR was highest (risk ratio [RR]: 5.93; 95% CI: 2.00–17.53; p = 0.001), and a subgroup analysis of studies that lacked significant heterogeneity in the HFSR data showed a higher risk of HFSR (RR: 10.96; 95% CI: 5.54–21.69; p < 0.05). In conclusion, although TACE plus sorafenib increases TTP, it does not improve OS. Therefore, the risk of the adverse events of TACE plus sorafenib should be considered as a potential therapeutic limitation.