bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic impact of tumor budding in stage II colon cancer: A prospective study (SACURA trial).
Authors: Ueno Hideki , Ishiguro Megumi , Nakatani Eiji , Ishikawa Toshiaki , Uetake Hiroyuki , Murotani Kenta , Matsui Shigeyuki , Tomita Naohiro , Shimada Yasuhiro , Takahashi Keiichi , Kotake Kenjiro , Watanabe Masahiko , Mochizuki Hidetaka , Teramukai Satoshi , Sugihara Kenichi ,   SACURA Study Group
Published: September 2018

3609

Background: Growing number of studies indicate tumor budding is a significant prognostic factor in colorectal cancer (van Wyk, et al. Cancer Treat Rev 2015), but this has been shown only in retrospective studies. We prospectively evaluated prognostic factors in stage II colon cancer to determine their prognostic value in a multi-institutional phase III study (SACURA trial, ASCO2016 abst#3617). Methods: A total of 991 patients with curatively resected stage II colon cancer (2006–2010; 136 institutions) were included in the study. Tumor budding was defined as an isolated cancer cell or a cluster composed of fewer than five cells in the invasive frontal region, and was graded based on its number within a microscopic field of a 20x objective lens (0.785 mm2) in the hotspot. Tumors with < 5, 5–9, and ≥10 budding foci were classified as grades G1, G2, and G3, respectively. All clinical and pathological data including the grade of budding were prospectively recorded and prognostic analyses were performed at 5 years after the completion of registration. Results: According to budding grading, 376, 331 and 284 tumors were classified as G1, G2, and G3, and 5-year relapse-free survival (RFS) rate was 90.9%, 85.1%, and 74.4%, respectively ( P < 0.0001). Budding grade was significantly associated with the incidence of recurrence in the liver, lung, lymph node, and peritoneum ( P < 0.0001–0.01). Among conventional factors, T stage and the serum CEA levels were associated with RFS, however, tumor grade, lymphatic and venous invasions, and the number of lymph node examined were not significant factors. Multivariate analysis for RFS showed budding, along with T stage, exerted an independent influence on prognostic outcome. Budding grade surpassed T stage and tumor grade in the ability to stratify patients by RFS (Harrell’s c-index, 0.63, 0.59, and 0.54, respectively). Conclusions: Our prospective study indicates that the grade of tumor budding is more informative for prognostic prediction than conventional prognostic factors in stage II colon cancer. The role of this prognostic factor should be highlighted in the adjuvant treatment setting, and conversely, some of prognostic factors adopted in clinical guidelines may need to be reconsidered. Clinical trial information: NCT00392899.
Recurrence risk factors and outcome stratification in stage II colon cancer patients: A subanalysis of the SACURA trial.
Authors: Ishiguro Megumi , Nakatani Eiji , Ueno Hideki , Ishikawa Toshiaki , Uetake Hiroyuki , Shimada Yasuhiro , Takahashi Keiichi , Kotake Kenjiro , Watanabe Masahiko , Tomita Naohiro , Mochizuki Hidetaka , Teramukai Satoshi , Sugihara Kenichi
Published: September 2018

3611

Background: Efficacy of adjuvant chemotherapy for stage II colon cancer is still controversial. We conducted the SACURA trial, a phase III study which evaluated the superiority of 1-year adjuvant treatment with oral tegafur-uracil (UFT) to surgery alone in stage II colon cancer. However, survival benefit of 1-year UFT to surgery alone was not demonstrated (ASCO2016 abst#3617). We herein aimed to identify risk factors for recurrence in the stage II patients “without adjuvant chemotherapy”, and to stratify the prognosis by using these factors. Methods: Among a total of 982 patients without adjuvant chemotherapy enrolled to the SACURA trial, we extracted the factors correlated to recurrence using a univariate and multivariate Cox proportional hazard model. 943 and 935 patients in the surgery alone group and UFT group were divided to subgroups according to the number of risk factors, and the recurrence rate in each subgroup was evaluated. Results: Among the conventional clinicopathological characteristics, the multivariate analysis identified pT4, elevated CEA, and examined lymph nodes less than 12 as significant risk factors for recurrence. The rate of patients with 0, 1, 2, and 3 risk factors were 45.0%, 42.4%, 11.5%, and 1.1%, respectively. The recurrence rate for each subgroup was shown in the table: the recurrence rate increased with number of risk factors, while 10.2% of patients without any risk factors developed recurrence. Difference in the recurrence rate between the treatment groups was significant in patients without risk factor, marginal in patients with 1 risk factor, and none in patients with >1 factors. Conclusions: pT4, elevated CEA, and examined lymph nodes less than 12 were identified as risk factors for recurrence in stage II colon cancer patients. The recurrence rate was divided by the number of these risk factors, but we could not extract the very-low risk group in whom adjuvant therapy is unnecessary. Induction of novel risk factors other than conventional clinicopathological characteristics is recommended. Clinical trial information: NCT00392899. [Table: see text]
Clonal evolution in locally advanced rectal cancers in response to neoadjuvant chemoradiotherapy.
Authors: Toomey Sinead , Carr Aoife , Gunther Jillian Rebecca , Fay Joanna , O'Grady Anthony , Weksberg David , Piraino Scott W , Kay Elaine , O'Neill Brian , Krishnan Sunil , Furney Simon J , Hennessy Bryan
Published: September 2018

3616

Background: Locally advanced rectal cancer, LARC (T3/4 and/or N+) is currently treated with neoadjuvant chemoradiotherapy (NACRT), however clinicopathological response is variable. Monitoring clonal evolution in response to NACRT may identify mutations driving therapeutic resistance or tumor growth after treatment. Methods: Fresh-frozen pre- and post-NACRT tumor and matched normal tissue from LARC patients were stratified into good (RCPath A), intermediate (RCPath B) and poor (RCPath C) responders. Following histological review, targeted exome capture was performed using an Agilent SureSelect Human all Exome V3 kit. Samples were sequenced to a minimum of 100X coverage on an Illumina HiSeq2000, and clonal evolution was assessed in matched pre- and post-NACRT tumor samples. Results: The median somatic mutation burden in pre-treatment samples was 114 (IQR 19-207). Two tumors were microsatellite (MSI) unstable and had elevated mutational burdens. The least evolution occurred in the poor responders, where there was little change in clonal composition after treatment, and driver mutations in genes including TP53 and APC were retained. On average 79% of pre-treatment mutations were retained post-treatment in poor responders and 33% of mutations were retained in intermediate responders. Many of the intermediate responders had loss of driver mutations including TP53 from the pre-treatment sample, but also shared a number of mutations in genes including PIK3CA and BRAF between pre- and post-treatment samples. There was also increased frequency in the post-treatment samples of clones that were not present in the pre-treatment samples. In one intermediate responder, all 47 mutations that were present in the pre-treatment sample including the driver mutations TP53 and APC were absent in the post-treatment sample, while 10 completely new mutations were identified. Conclusions: Dynamic mutational processes occur in LARC following selective pressures of exposure to NACRT, including changes in somatic mutation presence or frequency after treatment, owing to persistence or loss of sub-clones. As NACRT can profoundly affect the LARC genome, monitoring molecular changes during treatment may be clinically useful.
Phase III multi-centre open-label randomized controlled trial of selective internal radiation therapy (SIRT) versus sorafenib in locally advanced hepatocellular carcinoma: The SIRveNIB study.
Authors: Chow Pierce H. W. , Gandhi Mihir ,   Asia-Paciifc Hepatocellular Carcinoma Trials Group
Published: September 2018

4002

Background: The optimal therapeutic regime for locally advanced hepatocellular carcinoma (HCC) with and without vascular invasion remains unclear. This study evaluates the efficacy of Selective Internal Radiation Therapy using SIR-Spheres yttrium-90 microspheres (Y90) versus sorafenib in Asian Barcelona Clinic Liver Cancer (BCLC) stage B and C patients without extra-hepatic metastasis. Methods: This investigator-initiated multi-center trial randomized eligible patients with locally advanced inoperable HCC to single injection of Y90 or sorafenib (oral 400mg BD) till progressive disease or unacceptable toxicity. The sample size, assuming type I error (two-sided) of 0.05 and power of 90% was 360 patients. Final analysis was planned at 266 reported deaths. Results: 360 patients (182 Y90, 178 sorafenib) were enrolled from 27 centers in 11 Asian countries. BCLC C patients without extra-hepatic metastasis comprised 41.4% of patients, 30.6% had portal vein thrombosis (PVT), 88.6% were Child-Pugh A, 57.2% were hepatitis B and 15.0% were hepatitis C. Altogether 28.6% and 9.0% of patients in the Y90 and sorafenib arms respectively failed to receive planned therapy. Intention-to-treat analysis was carried out with the overall survival (OS) in the Y90 and sorafenib arms being 8.54 and 10.58 months respectively (Hazard ratio (HR) 1.17, p =0.203). Tumour response rate (TRR) was 16.5% and 1.7% (p < 0.001) respectively. Time-to-tumor -progression (TTP) was 5.88 vs 5.36 (overall) (HR 0.93) and 6.08 vs 5.39 (liver-specific) (HR 0.91) months for Y90 and sorafenib respectively. Progression-free-survival (PFS) was 5.29 vs 5.06 (overall) (HR 0.94) and 5.85 vs 5.06 (liver-specific) (HR 0.92) months respectively. At least one severe adverse event was found in 27.7% and 50.6% of patients in the Y90 and sorafenib arms respectively. Conclusions: Asian patients with locally advanced HCC without extra-hepatic metastasis treated with Y90 have statistically significant better TRR, and fewer SAEs when compared with those treated with sorafenib. There were no statistically significant differences in OS between Y90 and sorafenib. Clinical trial information: NCT01135056.
Intergroup phase III trial of neo-adjuvant chemotherapy, followed by chemoradiation and surgery with and without cetuximab in locally advanced esophageal carcinoma: First results from the SAKK 75/08 trial.
Authors: Ruhstaller Thomas , Thuss-Patience Peter C. , Hayoz Stefanie , Schacher-Kaufmann Sabina , Riera-Knorrenschild Jorge , Schnider Annelies , Plasswilm Ludwig , Budach Wilfried , Eisterer Wolfgang , Hawle Hanne , Mariette Christophe , Hess Viviane , Mingrone Walter B. , Wagner Anna Dorothea , Girschikofsky Michael , Schmidt Sven-Christian , Bitzer Michael , Bedenne Laurent , Brauchli Peter , Stahl Michael ,   Swiss Group for Clinical Cancer Research (SAKK), German Esophageal Cancer Study Group, Austrian "Arbeitsgemeinschaft Medikamentose Tumortherapie" (AGMT), Federation Francophone de Cancerologie Digestive (FFCD)/Federation de Recherche en Chirurgie (FRENCH)
Published: September 2018

4019

Background: We compared chemoradiotherapy followed by surgery with the addition of neoadjuvant and adjuvant cetuximab (cetux) in patients with esophageal carcinoma. Methods: Pts with resectable esophageal cancer (T2N1-3;T3-4aNx) received two cycles of induction chemotherapy (docetaxel 75mg/m2, cisplatin 75mg/m2) followed by chemoradiation (45 Gy, docetaxel 20mg/m2 and cisplatin 25mg/m2 weekly) and surgery or the same treatment with addition of neoadjuvant cetux 250mg/m2 weekly and adjuvant cetux 500mg/m2 bi-weekly for three months. Primary endpoint was progression-free survival (PFS). After a median follow-up of 4y 166 of the planned 180 events occurred (plateau reached). Results: 300 pts were treated between 2010-13: 88% male, median age 61y, 63% adenocarcinoma, 85% cT3/4a, 90% cN+. 84% completed neoadjuvant therapy, 87% were operated (cetux: 89%, control: 86%), 67% started and 50% completed adjuvant cetux-therapy. The R0 resection rate was 95% in the cetux-arm and 97% in the control-arm, there were 10 and 14 treatment-related deaths and 9 and 4 postoperative in-hospital deaths, respectively. Major differences in adverse events (grade >2) with addition of cetux were higher rate of allergic reactions and hypomagnesemia, but lower rate of dysphagia (-15%) and esophagitis (-4%) during chemoradiation. Conclusions: The addition of cetuximab to a multimodal therapy showed a statistically significant reduction of loco-regional recurrences which led to a statistically non-significant, but clinically relevant improvement of PFS and OS. Clinical trial information: NCT01107639. [Table: see text]
Short-term outcomes from a multi-institutional, phase III study of laparoscopic versus open distal gastrectomy with D2 lymph node dissection for locally advanced gastric cancer (JLSSG0901).
Authors: Lee Sang-Woong , Etoh Tsuyoshi , Ohyama Tetsuji , Inaki Noriyuki , Sakuramoto Shinichi , Yoshida Kazuhiro , Koeda Keisuke , Hosoda Kei , Kunisaki Chikara , Kojima Kazuyuki , Yasuda Takashi , Takagane Akinori , Misawa Kazunari , Kinoshita Takahiro , Yajima Kazuhito , Takiguchi Shuji , Hiki Naoki , Shiraishi Norio , Kitano Seigo ,   The Japanese Laparoscopic Surgery Study Group
Published: September 2018

4029

Background: The safety of laparoscopic gastrectomy for advanced gastric cancer is controversial. We conducted a multi-institutional, randomized controlled trial to compare short- and long-term outcomes of laparoscopic distal gastrectomy (LAP) with D2 lymph node dissection for advanced gastric cancer in comparison to open distal gastrectomy (OP) in Japan (UMIN000003420). We herein demonstrate short-term outcomes of this trial. Methods: Patients with potentially curable gastric cancer (T2-T4, N0-2 and M0) by distal gastrectomy were eligible for inclusion. Between November 2009 and July 2016, 507 patients were randomly assigned to either the LAP group (n = 252) or the OP group (n = 255). Only credentialed surgeons in both the procedures from 37 Japanese institutions participated in the study. The primary endpoint was 5-year relapse free survival. Secondary endpoints were 5-year overall survival, adverse events and short-term clinical outcomes. Results: According to study protocol, 47 patients among the total eligible patients were excluded because of distant metastasis or tumor extension intraoperatively. The remaining 460 patients underwent distal gastrectomy with D2 lymph node dissection and were analyzed as per protocol. Estimated blood loss was lower in LAP than in OP (30 vs. 150 ml, P < 0.001) and operative time was longer in LAP than in OP (291 vs. 205 min, P < 0.001). Post-operative analgesics use was less in LAP than in OP (38.3 vs. 53.6 %, P = 0.001), and first day of flatus was shorter in LAP than in OP (2 vs. 3 days, P < 0.001). There were no significant differences in all grade intra-operative complications (LAP 0.9% vs. OP 2.6%, P = 0.285). In addition, there were no significant differences in grade 3 and higher post-operative complications between the two groups (LAP 3.1% vs. OP 4.7%, P = 0.473). Hospital mortality was 0.4 % in each group. Conclusions: Credentialed surgeons could safely perform laparoscopic distal gastrectomy with D2 lymph node dissection for locally advanced gastric cancer. The laparoscopic approach could be accepted without increasing major surgical complications in this setting. Clinical trial information: 000003420.
Phase II study of intraperitoneal docetaxel plus capecitabine/cisplatin for gastric cancer with peritoneal metastasis: XP+IP DOC trial.
Authors: Fukushima Ryoji , Ishigami Hironori , Miwa Hiroto , Imano Motohiro , Kobayashi Daisuke , Tsuji Yasushi , Hidemura Akio , Kusumoto Tetsuya , Omori Takeshi , Yabusaki Hiroshi , Ohashi Norifumi , Ota Mitsuhiko , Yamaguchi Hironori , Kitayama Joji ,   Japan Intraperitoneal Chemotherapy Study Group (JIPG)
Published: September 2018

4039

Background: Intraperitoneal (IP) chemotherapy with taxanes provides sustained high local concentrations, and the efficacy of IP paclitaxel (PTX) has been shown in ovarian cancer. We previously reported the safety and efficacy of IP PTX plus systemic chemotherapy in clinical trials. Capecitabine/cisplatin (XP) is one of the standard regimens for the first-line treatment of advanced gastric cancer worldwide. We designed a new regimen combining IP docetaxel (DOC) with XP, and the recommended dose of IP DOC was determined to be 10 mg/m2 in a phase I study. A phase II study of XP plus IP DOC was performed in gastric cancer patients with peritoneal metastasis. Methods: Gastric cancer patients with peritoneal metastasis confirmed by diagnostic imaging, laparoscopy or laparotomy were enrolled. DOC was administered intraperitoneally at 10 mg/m2 on days 1 and 8. Cisplatin was administered intravenously at 80 mg/m2 on day 1, and capecitabine was administered at 1000 mg/m2 bid for 14 consecutive days, repeated every 21 days. The primary endpoint was the 1-year overall survival (OS) rate. Secondary endpoints were response rate, negative conversion rate on peritoneal cytology and safety. Results: Out of 50 patients enrolled, 48 patients received protocol treatment, and were evaluated for OS and toxicity. The median number of courses was 6 (range 1-15). The 1-year OS rate was 75% (95% confidence interval, 60-85%). The best overall response was stable disease in all the three patients with target lesions. Cancer cells ceased to be detected by peritoneal cytology in 28 (76%) of 37 patients. Nineteen patients underwent gastrectomy after response to chemotherapy. The incidences of grade 3/4 hematological and non-hematological toxicities were 42% and 48%, respectively. The frequent grade 3/4 toxicities included neutropenia (21%), leukopenia (8%), anemia (29%), anorexia (25%) and nausea (17%). Infection of the intraperitoneal port was observed in one patient. There were no treatment-related deaths. Conclusions: Combination chemotherapy of XP plus IP DOC regimen is well tolerated and active in gastric cancer patients with peritoneal metastasis. Clinical trial information: UMIN000016469.
Prognostic and predictive factors for overall survival (OS) in metastatic esophagogastric cancer (EGC): A meta-analysis.
Authors: ter Veer Emil , van Kleef Jessy Joy , Schokker Sandor , Van Der Woude Stephanie , Laarman Marety , Haj Mohammad Nadia , van Oijen Martijn G.H. , Van Laarhoven Hanneke W.M.
Published: September 2018

4048

Background: Prognostic and predictive factors for metastatic EGC are important to estimate prognosis, inform clinical decision-making and design future trials. We performed a systematic review with meta-analysis to identify these factors. Methods: We searched Medline, EMBASE and CENTRAL for phase 2/3 randomized controlled trials (RCTs) until January 2016 on palliative chemotherapy and targeted therapy for metastatic EGC. Prognostic and predictive factors were identified from respectively multivariate cox regressions and stratified treatment comparisons. Hazard Ratio’s (HR) for OS were extracted and pooled with meta-analysis if possible. Prognostic factors were considered independent if the multivariate HR was significant (P≤0.05). Predictive factors were clinically relevant if P for subgroup interaction was ≤0.20 and the HR in one of the subgroups was significant (P≤0.05). Results: We identified 47 RCTs (14,853 patients), wherein 54 potential prognostic and 40 predictive factors were reported. Eight independent prognostic factors for poor OS reported in ≥2 RCTs based on ≥300 patients were: performance status of ≥1 vs 0 (pooled HR, 95% confidence interval: 1.47, 1.25-1.73) or 2 vs 0-1 (1.52, 1.32-1.76); metastatic vs locally advanced disease (1.55, 1.39-1.72); diffuse vs intestinal/other histology (1.38, 1.12-1.71); ≥3 vs < 2 metastatic sites (1.35, 1.07-1.70); presence of metastases in peritoneum (1.24, 1.01-1.51) or liver (1.45 (1.28-1.64); measurable vs non-measurable disease (1.31, 1.04-1.66); and no prior vs prior surgery (1.33, 1.16-1.53). Predictive factors for specific treatment comparisons based on ≥300 patients were: age (≥65 vs < 65); performance status; tumor location (GEJ vs stomach); disease stage; number of metastatic sites; peritoneal metastasis; measurable disease; histology; HER2; KRAS; VEGF A; and Neuropilin-1 for first line treatments; and time to progression on first line therapy ( < 3, 3-6 or ≥6 months) for second-line treatments. Conclusions: Eight independent prognostic factors for OS and thirteen clinically relevant predictive factors for treatment efficacy of EGC were found.
Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer.
Authors: Kelly Ronan Joseph , Zaidi Ali Hussainy , Smith Matthew A , Omstead Ashten N , Kosovec Juliann E , Matsui Daisuke , Martin Samantha A , DiCarlo Christina , Werts E. Day , Silverman Jan F , Wang David H. , Jobe Blair Anderson
Published: September 2018

4060

Background: PD-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25%. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with CRT in earlier stage esophageal cancer may prevent metastatic disease in a greater proportion of patients. This study assessed the impact of CRT on the immune microenvironment and the expression patterns of multiple immune checkpoints to optimally design neoadjuvant clinical trials. Methods: To determine the effects of CRT on resected esophageal adenocarcinomas (EAC), we examined the immune microenvironment pre and post CRT using IHC, LCM followed by qRT-PCR, and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 sensitization, esophagojejunostomy were performed on rats to induce gastroduodenoesophageal reflux and EAC formation. First, tumor bearing animals were dosed with single fraction 13 Gy or 16 Gy radiation to determine safety, dose correlation, and PD-L1 sensitization using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual tumor bearing animals were determined using serial endoscopic biopsies at baseline, 1, 5 and 9 weeks post 16 Gy radiation. Results: The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including – TIM3, GITR, IDO1, LAG3, CD137, OX40 and KIR. The animal model results indicated PD-L1 upregulation is dose dependent and transiently elevated post radiation exposure. Conclusions: Collectively, these findings provide insights into the evolving immune landscape after CRT and have significant implications for future neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors. Currently, we are conducting a neoadjuvant trial assessing Nivolumab or Nivolumab/Ipilimumab in combination with CRT in stage II/III operable esophageal cancer.
Efficacy of regorafenib (REG) in patients with hepatocellular carcinoma (HCC) in the phase III RESORCE trial according to alpha-fetoprotein (AFP) and c-Met levels as predictors of poor prognosis.
Authors: Teufel Michael , Köchert Karl , Meinhardt Gerold , Bruix Jordi
Published: September 2018

4078

Background: REG is a multikinase inhibitor which improved overall survival (OS; HR 0.63, 95% CI 0.50, 0.79; P<0.0001) and time to progression (TTP; HR 0.44, 95% CI 0.36, 0.55; P<0.0001) compared with placebo in patients with HCC who progressed during prior sorafenib treatment in the RESORCE trial. This exploratory analysis evaluated the impact of baseline AFP and c-Met on REG treatment benefit (OS and TTP) in the RESORCE trial. Methods: Circulating AFP and c-Met protein (shed ectodomain) levels were quantified by a Luminex assay (Myriad RBM) in plasma samples collected at baseline from patients enrolled in the RESORCE trial. Valid biomarker data were available from 497 (AFP) and 499 (c-Met) out of 573 patients. Patients were subgrouped according to the median protein concentration (high vs low), and the treatment effect HR and its 95% CI were evaluated using a Cox proportional hazards model. The predictive effect was modeledas a protein–treatment interaction effect and subjected to Akaike information criterion (AIC)-based selection to assess its association with OS and TTP. Results: Baseline characteristics of patients were balanced across protein subgroups. While increased levels of both AFP (HR 1.09, 95% CI 1.07, 1.12; P<0.001) and c-Met (HR 1.32, CI 95% 1.06, 1.63; P=0.011) were associated with a worse prognosis for OS, increased AFP levels were also associated with poor prognosis for TTP (HR 1.05, 95% CI 1.03, 1.07; P<0.001). REG treatment benefit for both OS and TTP was independent of AFP and c-Met protein expression (Table). The protein–treatment interaction effect was not statistically significant. Conclusions: The treatment benefit of REG in patients with HCC was independent of AFP and c-MET protein expression at baseline. So far, no single protein has been associated with REG clinical benefit. Clinical trial information: NCT01774344. [Table: see text]
Phase Ib trial of tepotinib in Asian patients with advanced hepatocellular carcinoma (HCC): Final data including long-term outcomes.
Authors: Qin Shukui , Kim Tae-You , Lim Ho Yeong , Ryoo Baek-Yeol , Scheele Jürgen , Zhou Dongli , Becker Andreas , Cheng Ann-Lii
Published: September 2018

4087

Background: The incidence of hepatocellular carcinoma (HCC), a leading cause of cancer death, is increasing with the increasing incidence of chronic liver disease. Sorafenib, the only approved systemic therapy for advanced HCC, provides modest improvement in overall survival. Preclinical studies suggest c-Met is a valid target in HCC, but non-selective TKIs with c-Met inhibitory activity have not shown efficacy in trials, possibly due to lack of c-Met inhibition. Tepotinib (MSC2156119J) is a highly selective c-Met inhibitor that has favorable safety and promising activity, particularly against c-Met+ solid tumors. We report the final results of a phase Ib trial of tepotinib in patients (pts) with advanced HCC. Methods: Pts were Asian adults with confirmed HCC of BCLC Stage C, Child-Pugh Class A liver function without encephalopathy, and ECOG PS 0–2. Pts received tepotinib 300, 500 (the RP2D) or 1,000 mg/day on a 21-day cycle. c-Met expression status was retrospectively determined by IHC. Results: 27 pts were enrolled (median age 57 [38-69]; male 23; ECOG PS 0/1 11/16); 7 received tepotinib 300 mg/day, 14 500 mg/day, and 6 1,000 mg/day (3 with dose reduction). No DLTs were observed. 22 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), most commonly diarrhea (n = 10), nausea (8), elevated AST (7), and elevated ALT (6). 9 pts had grade ≥3 TRTEAEs, including elevated AST (3) and elevated ALT (3). Best overall response (BOR) was partial response (PR) in 2 pts, one of whom received tepotinib 500 mg (response duration 16.1 months) and one 1,000 mg (4.4 months); both had c-Met+ tumors. A further 8 pts had a BOR of stable disease (SD), 1 pt non-complete response (CR)/non-progressive disease (PD), and 14 pts had PD (2 pts not evaluable). Five pts had progression free survival > 8 months. PK were as expected from previous studies. Conclusions: Tepotinib at doses of up to 1,000 mg/day was well tolerated by Asian pts with advanced HCC and a maximum tolerated dose was not reached. Antitumor activity was observed, particularly in pts with c-Met+ tumors. The ongoing phase II part of this study is comparing the efficacy and safety of first-line tepotinib and sorafenib in pts with c-Met+ HCC. Clinical trial information: NCT01988493.
Biomarker prediction of efficacy to vandetanib plus gemcitabine in a phase II double blind multicenter randomized placebo-controlled trial in locally advanced or metastatic pancreatic carcinoma.
Authors: Neoptolemos John P. , Palmer Daniel , Greenhalf William , Ghaneh Paula , Jackson Richard , Evans Anthony , Shaw Victoria , Wadsley Jonathan , Valle Juan W. , Wasan Harpreet , Falk Stephen , Cunningham David , Coxon Fareeda Y. , Ross Paul J. , Wadd Nick , Hickish Tamas , Costello Eithne , Campbell Fiona , Rawcliffe Charlotte , Middleton Gary William
Published: September 2018

4104

Background: We investigated the potential of biomarkers to predict efficacy of vandetanib and gemcitabine in patients with locally advanced (N = 41) or metastatic (N = 101) pancreatic cancer in a phase II double-blind multicentre randomised placebo-controlled trial. Methods: All patients were 18y or above, (ECOG = 0-2), with at least 3 mths life expectancy had gemcitabine (1000mg/m2 30min iv wkly for 7 wks, followed by a 1wk break, then cycles of wkly treatment for 3wks with a 1-wk break) and randomly assigned to 300mg/d vandetanib or placebo once daily until disease progression. The primary outcome was overall survival (OS) by intention to treat. A panel of potential biomarkers was tested to predict best survival with vandetanib and gemcitabine. Results: 142 patients were randomised, median FU = 24·9 mths with 131 deaths. The median (95% CI) OS in the 70 gemcitabine-placebo patients was 8·95 (6·55-11·7) mths and 8·83 (7·11-11·6) mths in the 72 gemcitabine-vandetanib patients (HR = 1·21, 95% CI = 0·85, 1·73; log rank X21df = 1·1; P = 0·303). A CTCAE V.4.02 rash grade 2 or above occurred in 4 (6 %) of 70 placebo patients versus 14 (19%) of 72 vandetanib patients. The median OS for the 14 vandetanib patients and with rash was 11·92 (10·89 – NA) mths, 7·76 (4·34 – 11·5) mths for the 58 vandetanib patients and without rash and 8·95 (6·55 – 11·7) mths for the gemcitabine-placebo patients (log rank Χ2 2df = 7·23; P = 0·03). We identified two biomarkers that could select patients for response to vandetanib (JN101, JN102). The biomarker combination was present in 26 patients with median OS of 12.1 (10.9, 16.0) mths versus 8.15 (6.67, 11.7) mths for 23 patients with the same biomarker profile in the placebo group (HR = 0.53 [0.29, 0.97], p = 0.0396). A logistic regression model showed that patients with JN102 were more likely to develop a rash (OR =0.81 [0.713, 0.925] p = 0.002). Conclusions: A two biomarker combination and a rash grade 2 or above may predict response to vandetanib and gemcitabine. This requires prospective evaluation. Clinical trial information: 96397434.
A phase Ib/II study of cancer stemness inhibitor napabucasin (BBI-608) in combination with gemcitabine (gem) and nab-paclitaxel (nabPTX) in metastatic pancreatic adenocarcinoma (mPDAC) patients (pts).
Authors: Bekaii-Saab Tanios S. , Starodub Alexander , El-Rayes Bassel F. , O'Neil Bert H. , Shahda Safi , Ciombor Kristen Keon , Noonan Anne M. , Hanna Wahid Tewfik , Sehdev Amikar , Shaib Walid Labib , Mikhail Sameh , Neki Anterpreet S. , Oh Cindy , Li Youzhi , Li Wei , Borodyansky Laura , Li Chiang
Published: September 2018

4106

Background: Cancer stem cells are fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapy and targeted agents. Methods: A phase Ib/II multi-center study in mPDAC pts was performed to confirm the RP2D, PK profile and evidence of anticancer activity of napabucasin in combination with nabPTX and Gem. Pts received napabucasin 240 mg BID with weekly nabPTX 125 mg/m2 and gem 1000 mg/m2for 3 out of every 4 weeks until disease progression (PD) or other discontinuation criterion. Results: Of 71 intent to treat (ITT) pts enrolled, 49 (69%) were treatment-naïve and 22 (31%) received neoadjuvant treatment. There were no significant PK interactions, dose-limiting or unexpected toxicities. Most common adverse events (AEs) included grade 1 diarrhea/cramping, nausea and fatigue with grade 3 AEs noted in 12 pts: fatigue (8), electrolyte imbalance (2), diarrhea (1), dehydration (1), nausea (1) and weight loss (1). Among pts who received RECIST evaluation (60), disease control (DCR; CR+PR+SD) was observed in 55 (92%), with 1 CR (2%) and 26 PR (43%) (31 - 78% regression). Of 11 pts with non-evaluable disease, treatment stopped due to compliance (4), consent withdrawal (3), clinical PD (1), toxicity (1), insurance (1) and death (1). Among 71 ITT pts, DCR was observed in 55 (77%), with 1 CR (1.4%) and 26 PR (37%). Maturing median progression free survival and overall survival (OS) in ITT pts is >7.1 and >10.4 m, respectively. Conclusions: This study showed that napabucasin can be combined with nabPTX and gem, with encouraging signs of efficacy in mPDAC now being confirmed in a phase 3 study. Clinical trial information: NCT02231723. [Table: see text]
Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT).
Authors: Motzer Robert J. , Haas Naomi B. , Donskov Frede , Gross-Goupil Marine , Varlamov Sergei , Kopyltsov Evgeny , Lee Jae-Lyun , Melichar Bohuslav , Rini Brian I. , Choueiri Toni K. , Zemanova Milada , Wood Lori A , Fahlenkamp Dirk , Reaume Martin Neil , Stenzl Arnulf , Bao Weichao , Aimone Paola , Doehn Christian , Russo Paul , Sternberg Cora N.
Published: September 2018

4507

Background: PROTECT (NCT01235962) evaluated the efficacy and safety of pazopanib (PAZ) versus placebo in patients (pts) with locally advanced renal cell carcinoma (RCC) post nephrectomy. Methods: 1538 pts with resected pT2 (high grade), pT3 or greater clear cell RCC were randomly assigned to PAZ or placebo for 1 year. The starting dose (800 mg) following treatment of 403 pts was lowered to 600 mg to improve tolerability and primary endpoint was changed to disease-free survival (DFS) with PAZ 600 (N = 1135). Primary analysis was performed after 350 DFS events in intent-to-treat (ITT) PAZ 600, and DFS follow-up analysis was performed after an additional 12 months. Secondary endpoints included DFS with ITT PAZ 800 and ITT ALL, and safety. Results: Disease characteristics were similar between arms. The primary analysis results of DFS ITT 600 were not significant [HR: 0.862; 95% CI, 0.699, 1.063; p = 0.165] (Table). The secondary endpoint of DFS in ITT PAZ 800 and ITT ALL yielded 31% and 20% risk reduction, respectively. Updated DFS analysis in ITT 600 showed a higher HR with longer follow up. Increased ALT and AST were the most common adverse events leading to treatment discontinuation in the PAZ 600 (ALT 16% and AST 5%) and PAZ 800 (ALT 18% and AST 7%) groups. Conclusions: The study did not meet the primary DFS endpoint in ITT 600; however, a 31% decrease in the risk of recurrence was observed in ITT 800. The safety profiles in the 600 mg and 800 mg groups were similar and consistent with PAZ prior experience. Clinical trial information: NCT01235962. [Table: see text]
DNA damage repair and response (DDR) gene alterations (alt) and response to PD1/PDL1 blockade in platinum-treated metastatic urothelial carcinoma (mUC).
Authors: Teo MinYuen , Seier Kenneth , Ostrovnaya Irina , Regazzi Ashley Marie , Kania Brooke Elizabeth , Moran Meredith Maisie , Cipolla Catharine Kline , Bluth Mark J. , Chaim Joshua , Al-Ahmadie Hikmat , Solit David B. , Funt Samuel , Wolchok Jedd D. , Iyer Gopa , Snyder Charen Alexandra , Bajorin Dean F. , Rosenberg Jonathan E. , Callahan Margaret K.
Published: September 2018

4509

Background: Somatic DDR alts are associated with increased mutation load (ML) and improved clinical outcomes for platinum-treated mUC (Teo et al, CCR 2017). We examined the relationship between DDR alts and response to PD1/PDL1 blockade. Methods: mUC pts enrolled to phase 2 trials of atezolizumab or nivolumab who had targeted exon sequencing of 410 genes (MSK-IMPACT) were identified. Pts were dichotomized based on presence of alts in a panel of 34 DDR genes. Analyses were performed based on: (1) any DDR alts and (2) deleterious DDR alts (frameshift, splice site, nonsense or Hotspot point mutations). Study endpoint was overall response (OR) per RECIST. ML was defined as total number of nonsynonymous mutations by MSK-IMPACT. Fisher exact, Wilcoxon rank sum, and stratified logistic regression were used. Results: Fifty two pts were identified (atezo: n=18, nivo: n=34). Median age was 67 years (range: 32 – 84) and majority (44) was male. Median platinum-free interval was 10.2 months (range: 0.3 – 150.4). DDR and deleterious DDR were seen in 25 (48.1%) and 14 (26.9%) pts (including 2 MSI and 1 POLE). OR rate was 46.2%. Responses were associated with DDR alts but not with age, gender, treatment, platinum-free interval or ML (table). In univariate logistic regression model, DDR status was associated with OR (p<.001) while a trend was observed with ML as a continuous variable (p=.051). While DDR alts were associated with higher ML (all: p=.001, deleterious: p=.004), the effect of DDR alts on OR remained significant regardless of ML (>median: p=.027; ≤median: p=.023), indicating that the effect of DDR was independent of ML. Conclusions: DDR alts appeared to be associated with OR to PD1/PDL1 blockade and should be integrated into future validation efforts along with other potential predictors of response. [Table: see text]
Association of on-treatment plasma HGF levels with overall survival (OS) in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (INF) +/- bevacizumab (BEV): Results from CALGB 90206 (Alliance).
Authors: George Daniel J. , Halabi Susan , Starr Mark D. , Hurwitz Herbert , Brady John C. , Barak Ian , Morris Michael J. , Rini Brian I. , Small Eric Jay , Kim Won , Taplin Mary-Ellen , Nixon Andrew B.
Published: September 2018

4522

Background: Elevated baseline HGF levels were associated with shorter OS in pts treated with BEV+INF. We evaluated on-treatment HGF levels to describe treatment-related changes and associations with outcome. Methods: We analyzed baseline EDTA plasma samples from 310 pts (148 INF; 162 BEV+INF) using an optimized multiplex ELISA platform for HGF at baseline and after 4-weeks (wks) on treatment. Primary endpoint of this analysis was OS. The Kaplan-Meier estimated the OS distribution and the proportional hazards model tested the prognostic importance of change at 4-wks from baseline in HGF levels in predicting OS, adjusting for treatment arm, bone metastases and stratification variables. Results: The median baseline HGF level in 310 pts was 161.4 pg/ml. Elevated HGF at 4-wks (>median) was associated with a worse OS (median OS = 14 vs 27 months; adjusted hazard ratio (HR)= 1.75, p< 0.0001). Only 9/155 pts (5.8%) with baseline HGF levels ≤ median developed elevated HGF (>median) at 4-wks; 66/155 pts (43%) with baseline HGF levels >median lowered HGF (<median) at 4-wks from baseline. Compared to pts with persistently elevated HGF levels, a decline in HGF levels at 4-wks (< median) was associated with improved OS (19 vs 13 months, adjusted HR=1.41, p=0.043). Conclusions: In RCC pts with low baseline HGF levels (< median), levels remain consistently low and are associated with improved OS. Conversely, in pts with high baseline HGF levels results are split; some patients continue to have high levels on treatment and are associated with a worse OS, suggesting that, HGF predicts for therapeutic benefit and represents a potential mechanism of resistance. Support: U10CA180821, U10CA180882. Clinical trial information: NCT00072046 .
Immune response results from vesigenurtacel-l (HS-410) in combination with BCG from a randomized phase 2 trial in patients with non-muscle invasive bladder cancer (NMIBC).
Authors: Steinberg Gary D. , Shore Neal D. , Karsh Lawrence Ivan , Bailen James L. , Bivalacqua Trinity , Chamie Karim , Cochran James S. , David Richard , Grubb Robert L. , Harb Wael A. , Holzbeierlein Jeffrey M. , Kamat Ashish M. , Trabulsi Edouard John , Walsh William Vincent , Williams Michael Brandon , Wolk Fredrick , Woods Michael , Price Melissa Leigh , Early Brandon , Schreiber Taylor Houghton
Published: September 2018

4531

Background: Vesigenurtacel-L (HS-410) is a vaccine comprised of an allogeneic cell line, selected for high expression from a series of bladder tumor antigens, and transfected with gp96-Ig. Cell-secreted gp96-Ig delivers these cell-derived antigens to a recipient's own antigen presenting cells, activating CD8+ cytotoxic T cells. Here we present the secondary immune outcomes from a randomized Phase 2 trial with HS-410 in combination with BCG in NMIBC. Trial ID NCT02010203. Methods: 78 patients with intermediate- (n = 5) or high-risk (n = 73) NMIBC who are either BCG-naïve or recurrent, with or without carcinoma in situ (CIS), were enrolled 1:1:1 to one of two doses of HS-410 (either 106 or 107cells/dose) or placebo in combination with 6 weeks of induction BCG, followed by 6 more weeks of HS-410 in the induction phase. Maintenance treatment consisted of 3-weekly treatments at the following timepoints: 3 mo., 6 mo., 12 mo. Concurrently, 16 patients (1 int. risk, 15 high-risk) were enrolled in an open-label monotherapy HS-410 arm for patients who did not receive BCG. The primary endpoint was 1-year RFS. Secondary immune evaluations include ELISPOT, tumor IHC, tumor antigen profiling, flow cytometry, urine cytokine analysis, and T cell receptor sequencing. Results: HS-410 treatment was well tolerated; AE profiles were similar across the treatment arms. HS-410 antigen expression showed prominent overlap with patient tumors. IFNγ ELISPOT assay demonstrated a high baseline response to HS-410; responses to overlapping peptide pools of HS-410 derived antigens defined immune responders (doubling of IFNγ-secreting cells). IHC demonstrated that ~60% of NMIBC patient tumor biopsies were TIL negative at baseline (n = 84), but that only ~15% of tumor biopsies were TIL negative post treatment (n = 40). Thus, TIL status may be used to define a responder and non-responder population to HS-410. Conclusions: Vesigenurtacel-L is well-tolerated, and immunologic responses consistent with vaccine mechanism of action may correlate with efficacy and suggest future biomarkers. Vesigenurtacel-L warrants further investigation as a potential treatment for NMIBC. Clinical trial information: NCT02010203.
Efficacy and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC) and brain metastases: Preliminary results from the GETUG-AFU 26 (Nivoren) study.
Authors: Escudier Bernard J. , Chabaud Sylvie , Borchiellini Delphine , Gravis Gwenaelle , Chevreau Christine , Brachet Pierre Emmanuel , Geoffrois Lionnel , Laguerre Brigitte , Mahammedi Hakim , Negrier Sylvie , Rolland Frederic , Gross Goupil Marine , Habibian Muriel , Albiges Laurence
Published: September 2018

4563

Background: Nivolumab (N) has been shown active in patients (pts) with mRCC after failure of 1 or 2 TKIs. Efficacy and safety of N in pts with brain metastases (BM) from RCC is still unknown. The aim of this study is to report preliminary data of the Nivoren study in pts with BM. Methods: GETUG-AFU 26 (Nivoren) is a prospective phase 2 study assessing safety and efficacy of N in a broader mRCC patient population than those recruited in the pivotal phase 3, including pts with BM (previously treated or not, but not requiring steroids), with previous mTOR inhibitor, with PS 2 as well as in previously highly pretreated pts. N was given every 2 weeks at 3mg/kg, until disease progression or unacceptable toxicity. Treatment was allowed beyond progression in case of clinical benefit. All pts had brain CT scan or MRI at baseline. Results: Up to December 2016 , 588 pts have been enrolled including 55 pts with BM (35 (67%) ,6 (12%) and 11 (21%) with 1, 2 or > 2 BM, respectively. Of those 55 pts, 10 pts (23%) were PS 2 and 25 (58%) PS 1, and 16 patients (29%) had received more that 2 lines of therapy. No previous treatment for BM was performed in 67% (n = 37), while 9% had previous brain surgery (n = 5 ;) or brain radiation (n = 17 (31%). 2/55 pts never received N. Median duration of therapy in BM pts was 2.4 months (varying from 0 to 9) with a 3-months PFS of 60% (IC95% = 45 – 73). Median OS is not reached at the time of this analysis. Among 44 pts with assessment of response on BM, 10 (23%) had objective response while 21 (48%) had local progressive disease. Neurologic deterioration requiring steroids was observed in 15 pts (32%) . Updated data will be presented at the meeting. Conclusions: This is the first large study to report preliminary safety and efficacy of N in RCC pts with BM. Safety of N in this pt population appears to be acceptable, although some pts do require steroids because of brain progressive disease. Objective response in the brain was observed in 23% of pts. Further follow up is required to determine the real benefit of N in this group of mRCC pts. Clinical trial information: NCT03013335.
Sunitinib in patients with metastatic renal cell carcinoma: Clinical outcome according to IMDC risk group.
Authors: Rini Brian I. , Hutson Thomas E. , Figlin Robert A. , Lechuga Mariajose , Valota Olga , Serfass Lucile , Casey Michelle , Motzer Robert J.
Published: September 2018

4584

Background: In a phase III study (NCT00083889), treatment-naïve patients (pts) with metastatic renal cell carcinoma (mRCC) of all prognostic risk groups were treated with sunitinib or interferon-α (IFN-α). Since sunitinib has become the reference standard of care and serves as the comparator in multiple randomized trials sometimes restricted to prespecified risk groups, a retrospective analysis of outcome according to prognostic group from the phase III study was performed. Methods: Investigator-assessed efficacy data were analyzed for pts based on risk group (International mRCC Database Consortium [IMDC] criteria). The objective was to determine objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) benchmarks by risk group. Results: Of sunitinib-treated pts, 134 were favorable, 205 were intermediate, and 34 were poor risk. The median sunitinib treatment duration/median number of cycles was 16.7 mo/12 cycles, 11.0 mo/8 cycles and 2.6 mo/2.0 cycles for favorable-, intermediate-, and poor-risk pts, respectively. ORR, PFS, and OS benchmarks for sunitinib-treated pts are shown in the Table. In sunitinib-treated intermediate-risk pts with 1 vs 2 risk factors, respectively: ORR was 43.3% vs 40.8%, mPFS (95% confidence interval [95% CI]) was 11.2 (9.7–13.6) vs 8.5 (5.6–10.7) mo, and mOS (95% CI) was 28.2 (23.0–not estimable) vs 16.3 (13.2–19.4) mo. Conclusions: This retrospective analysis provides ORR, PFS, and OS benchmarks for current and future clinical trial interpretation in mRCC pts with different prognostic risk treated with sunitinib. [Table: see text]