bluuebunny/crossref_metadata_2025 huggingface dataset:
ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations.
Authors: Mazzaferro Vincenzo , El-Rayes Bassel F. , Cotsoglou Christian , Harris William Proctor , Damjanov Nevena , Masi Gianluca , Rimassa Lorenza , Personeni Nicola , Braiteh Fadi S. , Zagonel Vittorina , Papadopoulos Kyriakos P. , Hall Terence , Wang Yunxia , Abbadessa Giovanni , Schwartz Brian E. , Kazakin Julia , Droz Dit Busset Michele , Shaib Walid Labib
Published: September 2018

4017

Background: FGFR genetic aberrations have been implicated in the development and progression of a number of solid tumor types, including iCCA. Pts with unresectable advanced iCCA who relapse after first-line chemotherapy have limited treatment options with poor prognosis. Recently, FGFR2 fusions, observed in up to 20% of pts, have been recognized as a potential therapeutic target. ARQ 087 is a multi-kinase inhibitor with a potent pan-FGFR activity. Methods: 119 cancer pts were enrolled in the phase 1/2, open-label study of ARQ 087. Study design and results of the phase 1were reported previously. Assessments included response by RECIST v1.1 every 8 wks, safety (physical examination, vital signs, ECOG PS, laboratory tests), plasma concentrations of phosphate and FGF19, 21 and 23 (potential biomarkers). Results: As of 1Feb17, 35 iCCA pts with FGFR2 genetic aberrations were treated with ARQ 087 300 (n = 33) or 400 mg (n = 2) daily. FGFR2 status was identified by FISH or NGS, 29/35 pts were FGFR2 fusion positive (FISH n = 15/18; NGS n = 14/17). Pts were all white, female (60%) with ECOG PS 0 (69%) and median age 58 yrs (31-82). Median number of prior systemic therapies was 1(0-6). Drug-related AEs (all grades) were reported in 89% of pts; the most common (≥10%) included nausea (37%), dry mouth (29%), asthenia (26%), fatigue, vomiting (23%, each), abnormal LFTs, dysgeusia (20%, each), alopecia, diarrhea, vision blurred (14%, each), and conjunctivitis (11%). Grade 3/4 AEs occurring in ≥2 pts were asthenia and abnormal LFTs (6%, each). AEs were mostly (71%) of mild to moderate intensity, manageable and reversible. Median time on treatment was 183 days (95%CI: 166-289). 19 pts were on treatment for > 16 wks, nine are ongoing. 30 pts had at least one post-treatment radiographic assessment: 6 (20%) had PR (32-47% tumor reduction, all FGFR2 fusion positive), 17 SD (7 had tumor reduction between 10 to 25%), and 7 had PD. One pt died prior to scheduled assessment and assessment in 4 pts is pending. Conclusions: ARQ 087 demonstrated encouraging antitumor activity and manageable safety profile. Updated data, including safety, efficacy and biomarkers will be presented. Clinical trial information: NCT01752920.
VIKTORY trial: Report on AZD1775/paclitaxel in TP53 mutation (+) GC, selumetinib/paclitaxel in ras aberrant GC, AZD5363/paclitaxel in PIK3CA mt and biomarker negative, savolitinib/docetaxel in met (+), and vistusertib/paclitaxel in RICTOR(+) GC.
Authors: Lee Jeeyun , Kim Seung Tae , Mortimer Peter G. , Hollingsworth Simon J , Harrington Elizabeth A. , Shepherd Christopher , Kilgour Elaine , Park Se Hoon , Lee Hyuk , Oh Sung Yong , Kang Jung Hun , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kim Kyoung-Mee , Kang Won Ki
Published: September 2018

4024

Background: The VIKTORY trial is a biomarker-based umbrella trial in GC. Methods: See table below. Results: From June 2014 to Jan 2017, 432 metastatic gastric cancer patients were enrolled. 124 (28.7%) were treated on one of the associated study protocols. At January 2017, 25 pts were allocated to selumetinib/paclitaxel arm, 25 to AZD1775/paclitaxel arm, 16 to AZD5363/paclitaxel arm, 16 to vistusertib/paclitaxel arm, 4 to savolitinib monotherapy, 19 to savolitinib/docetaxel arm, 19 to phase I AZD6738/paclitaxel arm. Initial efficacy signals have been seen in several arms (selumetinib/paclitaxel, 6 of 21 evaluable patients in PR). Correlative analyses between molecular signatures and treatment response are ongoing and will be presented at the meeting. For vistusertib/paclitaxel in the biomarker negative arm, we found RICTOR amplification as a promising predictive biomarker for response. Two (of three) GC patients with RICTOR amplification achieved PR to vistusertib/paclitaxel. Conclusions: This is one of the first attempts to undertake a biomarker-driven trial in metastatic GC. 28.7% of the patients were guided to one of the parallel arms based on molecular screening outcomes. We were able to identify potential molecular targets in the biomarker-negative arm, for further assessment in new protocols. Clinical trial information: 02299648. [Table: see text]
Clinicopathological features of program death ligand-1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer.
Authors: Kawazoe Akihito , Shitara Kohei , Kuboki Yasutoshi , Bando Hideaki , Kojima Takashi , Yoshino Takayuki , Ohtsu Atsushi , Ochiai Atsushi , Togashi Yosuke , Nishikawa Hiroyoshi , Doi Toshihiko , Kuwata Takeshi
Published: September 2018

4040

Background: Recently, anti-programmed death 1 (PD-1) or its ligand (PD-L1) antibodies have shown promising activities in metastatic gastric cancer (MGC). However, little is known about detailed clinicopathological features of PD-L1 expression in patients (pts) with MGC. Methods: Pts with histologically confirmed MGC were eligible for this prospective observational study. PD-L1 expression on tumor cell (TC) or inflammatory cell (IC) and mismatch repair (MMR) were analyzed by immunohistochemistry (IHC). Epstein–Barr virus (EBV) was detected by in situ hybridization. The expressions of tyrosine kinase receptors (RTKs) such as HER2, EGFR and MET and cancer genome alterations were also evaluated by IHC or next generation sequencing. Results: A total of 237 pts were enrolled from September 2015 to December 2016. Samples of 199 (84.0%) pts were obtained from biopsy. PD-L1 expression on TC and IC was positive in 27 (11.4%) and 167 pts (70.5%), respectively. One hundred and seventy-one pts (72.2%) had positive PD-L1 expression on either TC or IC. MMR deficient (D-MMR) and EBV was detected in 14 (6.9%, n = 203) and 14 pts (5.9%, n = 237), respectively. PD-L1 expression on TC was more frequently observed in pts with D-MMR (P < 0.001) and KRAS mutation (P < 0.001), while that on IC was more frequently observed in pts with EBV+ (P = 0.045), lymph node metastasis (P = 0.001), and lung metastasis (P = 0.045). In contrast, pts with peritoneal metastasis were associated with less frequent PD-L1 expression in IC (P = 0.003). A significant association was not observed between PD-L1 expression and RTKs expression or presence of other gene alterations. D-MMR was significantly associated with intestinal type (P = 0.026) and absence of liver metastasis (P = 0.022). PD-L1 expression on either TC or IC was not prognostic factor (hazard ratio; 0.92, P = 0.741). Seven pts with D-MMR and seven pts with EBV+ MGC were enrolled in clinical trials of anti-PD-1/PD-L1 antibodies. Conclusions: PD-L1 expression in MGC was associated with some clinicopathological features. Impact of these characteristics on efficacy of anti-PD-1/PD-L1 antibody warrants further evaluation.
Phase II study of afatinib in recurrent and/or metastatic esophageal squamous cell carcinoma (R/M ESCC) (KCSG HN14-18).
Authors: Hong Min Hee , Lee Yun-Gyoo , Kim Hyo Song , Park Keon Uk , Kim Hoon-Gu , Ko Yoon Ho , Chung Ik-Joo , Min Young Joo , Kim Min Kyoung , Kim HyeRyun , Cho Byoung Chul
Published: September 2018

4051

Background: Afatinib, an irreversible pan-ErbB kinase inhibitor showed anti-tumor activity against esophageal cancer in phase I trial. In this multicenter, open-label, single arm phase II study, we aimed to evaluate the activity and safety of afatinib in R/M ESCC. Methods: Patients (pts) who had ECOG PS 0-2 and had progressed on platinum-based chemotherapy for R/M ESCC were enrolled. Pts were treated with afatinib 40mg/day until disease progression, unacceptable toxicity, or patient’s refusal. Primary endpoint was objective response rate (ORR) per RECIST 1.1. The estimated sample size was 49, using a two-stage minimax design to evaluate incremental response rate from 5 to 15%. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety profile. Additionally, we try to identify biomarker to predict efficacy of afatinib with target capture sequencing and gene expression profile as exploratory endpoints. Results: In a total of 49 enrolled pts (median age 60; range 44 -84), ORR and DCR were 14.3 % and 73.3%, respectively. With a median follow-up of 6.6 months, median PFS and OS was 3.4 months (95% CI 2.2-4.6) and 6.6 months (95% CI 5.2-8.0). Median treatment duration and duration of response were 2.8 months (range, 0.4-15.3) and 7.1 months (range, 2.5-13.9), respectively. Dose reduction and interruption occurred in 19 (38.8%) and 15 (30.6 %) pts. Treatment-related adverse events (TRAE) occurred in 33 pts (67.3%) with most common TRAEs being diarrhea (n=22, 44.9%) and acneiform rash (n=12, 24.5%). G3-4 TRAEs were rare, occurring in 7 pts (14.3 %). Conclusions: Afatinib demonstrated modest efficacy with manageable toxicity in platinum-resistant R/M ESCC patients. Given the modest response rate, identification of predictive biomarkers is essential for further clinical investigation of afatinib in R/M ESCC. Those biomarkers are being analyzed and will be presented in the conference (NCT02353936). Clinical trial information: NCT02353936. [Table: see text]
The impact of marital status on racial disparities in esophageal cancer care.
Authors: Paniagua Cruz Alan , Haug Karlie L. , Zhao Lili , Wadhera Priya , Reddy Rishinda
Published: September 2018

4056

Background: It is well known that racial disparities exist in cancer treatment and outcomes. The present study examined the impact of marital status as a surrogate for social support on esophageal cancer (EsC) care. Methods: We performed a secondary analysis of data collected from a state cancer registry. We included individuals with an EsC diagnosis between January 1, 2000 and December 31, 2013. A Chi-square test and Fisher’s exact test was used to analyze categorical variables and two-sample t-tests to compare continuous variables. Results: 8754 patients (Caucasian (C) or African American (AA) only) were included, with 88.4% C and 11.6% AA. Staging at diagnosis in C and AA patients revealed that 30.6% vs 28.6% had localized disease, followed by 33.8% vs 32.0% with regional, and 35.6% vs 40.0% with metastatic, respectively (p = .0155). Rates of chemotherapy (53.6% vs 53.5%) and radiation therapy (54.1% vs 56.2%) administration were found to be similar between C and AA patients. In contrast, surgery rates were significantly different between the two groups, with 29.7% of C undergoing surgical resection in comparison to only 12.0% of AA patients (p < .0001). When evaluating marital status, 63.3% of C were married, compared to 33.4% of AA patients (p < .0001). In the AA group, 20.1% of married patients underwent surgery in contrast to only 7.6% of single AAs (p < .0001). Similarly, in the C group, married patients underwent surgery at a rate of 34.5%, while single patients went to surgery at a rate of 22.2% (p < .0001). Surgery contraindication (CI) rates were found to be similar across all groups (5.6% married Cs, 5.2% married AAs, 6.6% single Cs, and 6.5% single AAs) along with surgery refusal rates (1.56% single Cs vs 2.68% married Cs (p = .052), and 1.04% single AAs vs 2.81% married AAs (p = .210)). Conclusions: African American patients receive chemotherapy and radiotherapy at comparable rates to Caucasian patients, but the rates of surgery are significantly lower. Being married was associated with an almost three-fold increase in surgery rates for AA patients, and cause a significant increase in Caucasians too.
Association of the addition of cetuximab to preoperative chemoradiotherapy (CRT) for locally advanced esophageal squamous cell carcinoma (SqCC) with rate of long term survival: Mature results of a prospective phase Ib/II trial.
Authors: Brenner Baruch , Purim Ofer , Gordon Noa , Goshen Lago Tal , Idelevich Efraim , Kashtan Hanoch , Menasherov Nikolai , Fenig Eyal , Sulkes Aaron , Kundel Yulia
Published: September 2018

4057

Background: Current treatment results in locally advanced esophageal cancer (LAEC) are far from being satisfying. This prospective phase IB/II study evaluated the safety and efficacy of the addition of cetuximab to standard preoperative CRT in this disease. Methods: Patients (pts) with potentially resectable LAEC (T2-4N0-1M0, T1-4N1M0 or T1-4N0-1M1A) received an induction cycle of cisplatin 100 mg/m2, day 1, and 5-FU 1000 mg/m2/day as a continuous infusion (CI), days 1–5, followed 4 weeks later by 50.4 Gy radiotherapy given concurrently with 2 cycles of cisplatin 75 mg/m2 and escalating doses of CI 5-FU, days 1–4 and 29-32. Pts received also 10 weekly infusions of cetuximab, 250 mg/m2, with a loading dose of 400 mg/m2, starting from the induction. The phase II part of the study started when the 5-FU dose during CRT was defined. Surgery was planned 6-8 weeks after CRT. Results: 64 pts were enrolled and 60 completed CRT. Median age was 65 years (range: 38-84 years) and 66% were males. The SqCC/adenocarcinoma ratio was 39%/61% (25/39). Pts had very advanced tumors: 95% T3-T4, 67% N1 and 19% M1A. The most common grade > 3 toxicities were leucopenia (45% of pts) and neutropenia (41%). There were two cases (3%) of fatal toxicities (neutropenic sepsis and sudden death). Among the 55 operated pts, R0 resection was achieved in 51 (93%). There were 8 cases (14.5%) of postoperative mortality, due to infection (3 pts), esophageal leak (2), bleeding (2) and pulmonary insufficiency (1). Pathological down-staging was noted in 72% of pts and pathological complete response (pCR) in 33%. 5y-local control, progression-free survival (PFS) and overall survival (OS) rates for all pts were 94%, 40%, 39%, respectively. Pts with SqCC had a significantly higher pCR rate (52% vs 15%, p = 0.007), 5y-PFS (67% vs. 21%, p = 0.008) and 5y-OS (64% vs. 20%, p = 0.019). Conclusions: This study suggests that the addition of cetuximab to standard preoperative CRT is safe. R0, pCR, local control and long term PFS and OS rates in pts with SqCC tumors are encouraging. Further evaluation of this approach in this population seems warranted.
Incidence rate and clinical-pathological features of hereditary diffuse gastric cancer patients in China.
Authors: Qiu Miaozhen , Xu Rui-hua , Zhou Yi-xin , Jin Ying , Wang Zi-Xian
Published: September 2018

4065

Background: Familial clustering is seen in 10 % of gastric cancer cases and approximately 1-3 % of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). Little is known about the incidence rate and clinical-pathologic features of HDGC in Chinese patients. Methods: We retrospectively collected gastric adenocarcinoma patients who were diagnosed in Sun Yat-sen University Cancer Center between January 2002 and December 2014. All the patients had detailed record of family history and Lauren classification. All of statistical analyses were performed using the Intercooled Stata 13.0 (Stata Corporation, College Station, TX). Results: 7431 patients were enrolled for analysis. The incidence rate of HDGC was 3.97% (295/7431). There were 124 (42.03%) male and 171 (57.97%) female patients. The median age was 35 (Mean ±SD: 35.23±7.50). The most common sites were gastric body (49.47%) and fundus (35.09%) . The distribution of AJCC 7thTNM stage was 47 (16.32%) stage I, 59 (20.49%) stage II, 88 (30.55%) stage III and 94 (32.64%) stage IV. Only 92 patients received the HER2 immunohistochemistry test. 4 (4.35%) patients were HER2 IHC +++ and 8 (8.70%) patients were ++. The median survival was 80 months for the whole population and 15 months for stage IV patients. Conclusions: The incidence rate of HDGC was 3.97% in China. About one third of the patients were diagnosed at stage IV. Early detection of HDGC was warranted in China.
Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses.
Authors: Kelley Robin Kate , Abou-Alfa Ghassan K. , Bendell Johanna C. , Kim Tae-You , Borad Mitesh J. , Yong Wei-Peng , Morse Michael , Kang Yoon-Koo , Rebelatto Marlon , Makowsky Mallory , Xiao Feng , Morris Shannon R. , Sangro Bruno
Published: September 2018

4073

Background: Durvalumab and tremelimumab, investigational monoclonal antibodies against PD-L1 and CTLA-4 immune checkpoints, respectively, have shown efficacy in monotherapy and offer promise in combination for patients (pts) with HCC. This is a phase I/II, open-label, randomized study of durvalumab combined with tremelimumab in unresectable HCC. Methods: Phase I part of this study is a safety run-in cohort treated at the recommended phase II doses of the durvalumab/tremelimumab combination (20 and 1 mg/kg IV Q4W respectively for 4 doses followed by 20 mg/kg Q4W durvalumab alone) in pts with unresectable HCC with or without concomitant HBV or HCV infection who progress on, are intolerant to, or have refused sorafenib therapy. Secondary objectives include evaluation of antitumor activity. Here we present results of a preplanned analysis from the completed phase I part of the study. Results: As of 10 January 2017, 40 pts have been enrolled (11 HBV+, 9 HCV+, 20 uninfected). 30% had no prior systemic therapy; 93% were Child Pugh Class A. 24 (60%) had ≥1 treatment-related AE; 20% had ≥1 grade ≥3 related AE. Most common (≥15%) treatment-related AEs: fatigue (20%), increased ALT (18%), pruritus (18%), and increased AST (15%). Most common grade ≥3 related AE was asymptomatic increased AST (10%). 24 pts have discontinued treatment: 3 due to treatment-related AEs (grade 3 pneumonitis, grade 3 colitis/diarrhea, asymptomatic grade 4 elevated AST and ALT), 16 due to progressive disease, 4 due to death unrelated to treatment (cardiac arrest, variceal bleed, progressive disease, probable HCC rupture), and 1 other (pt entered hospice care). 40 pts were evaluable for response at ≥16 weeks follow-up. Conclusions: No unexpected safety signals with durvalumab and tremelimumab were seen in this unresectable HCC population. Clinical activity observed predominantly in uninfected pts though interpretation limited by small subsets. Enrollment to the phase II portion of the study is ongoing. Clinical trial information: NCT02519348. [Table: see text]
A phase II study of sorafenib and yttrium-90 glass microspheres for advanced hepatocellular carcinoma, BCLC stage C.
Authors: Kaseb Ahmed Omar , Abdel-Wahab Reham , Murthy Ravi , Hassan Manal , Raghav Kanwal Pratap Singh , Xiao Lianchun , Morris Jeffrey , Avritscher Rony , Odisio Bruno C. , Ohaji Chimela , Wolff Robert A. , Yao James C. , Mahvash Armeen
Published: September 2018

4083

Background: Combined use of sorafenib and local therapy for treating unresectable hepatocellular carcinoma (HCC) is not well established. Notably, most common cause of death in HCC is liver failure, therefore we tested the promise of controlling the local tumors even in the setting of advanced/metastatic disease to improve survival. Our study aimed to assess the efficacy and safety of combined use of sorafenib and yttrium-90 resin microspheres (Y90 RMS) in unresectable HCC defined as Barcelona Clinic Liver Cancer class C. Methods: Between October 2013 and August 2016 we enrolled 40 advanced stage HCC patients, 38 patients were treated with sorafenib followed (after 4 weeks) with Y90 RMS at MD Anderson Cancer Center. Survival analysis was done to evaluate median overall survival (OS) and progression-free survival (PFS). We used modified Response Evaluation Criteria in Solid Tumors (RECIST) to assess response to treatment and the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 to evaluate the grading of treatment related toxicity. Results: The majority of our patients were males (74%), white (47%), 66% of patients had underlying liver cirrhosis, 26% had vascular invasion, and 26% had extrahepatic disease. The estimated median OS and 95% confidence interval (CI) in months was 18.46 (12.29 – NA) and the estimated PFS was 12.29 months (5.72 – 18.79). Stable disease (SD) was observed in 44.74% of patients, while 28.95% achieved partial response (PR). Grade III-IV adverse events included fatigue (n = 3), hyperbilirubinemia (n = 2), thrombocytopenia (n = 1), proteinuria (n = 1), hyponatremia (n = 1), elevated liver enzymes (n = 4), hypertension (n = 4), diarrhea (n = 1), nausea (n = 1) and vomiting (n = 2). Conclusions: This is the first prospective study to evaluate sorafenib followed by Y90 in HCC. Our study included patients with metastatic HCC and showed that combined use of sorafenib and Y90 was tolerable and was associated with longer OS and PFS compared to previous studies which evaluated sorafenib alone. However, future randomized phase III studies are warranted to assess sorafenib+/-Y90 in metastatc disease setting. Clinical trial information: NCT01900002.
Neoadjuvant FOLFIRINOX for patients with borderline resectable or locally advanced pancreatic cancer: Results of a decision analysis.
Authors: Choi Jin , Nipp Ryan David , Tramontano Angela , Ali Ayman , Zhan Tiannan , Kong Chung Yin , Pandharipande Pari , Dowling Emily , Ferrone Cristina , Hong Theodore S. , Schrag Deborah , Fernandez-del Castillo Carlos , Ryan David P. , Hur Chin
Published: September 2018

4117

Background: With the advent of more effective therapies for metastatic pancreatic ductal adenocarcinoma (PDAC), efforts to incorporate these agents, such as FOLFIRINOX, into the neoadjuvant setting are increasing. However, the efficacy and cost-effectiveness of using neoadjuvant FOLFIRINOX for patients with borderline resectable or locally advanced PDAC are unknown. We performed a decision analysis to assess the value of neoadjuvant FOLFIRINOX versus upfront surgery and adjuvant therapy. Methods: We developed a mathematical simulation model to evaluate the efficacy and cost-effectiveness of neoadjuvant FOLFIRINOX compared to upfront surgery and adjuvant therapy. We used published and institutional data as inputs to inform model development. Model outcomes included overall and disease-free survival, net benefits expressed as discounted quality-adjusted life-years (QALYs), costs in US dollars, and cost-effectiveness expressed as an incremental cost-effectiveness ratio. We used deterministic and probabilistic sensitivity analyses to explore the uncertainty of model assumptions. Results: Model estimated median overall survival (29 vs 23 months) and disease-free survival (14 vs 13 months) were better for neoadjuvant strategy compared with upfront surgery. Neoadjuvant strategy resulted in an additional 0.68 life-years gained, or 0.57 QALYs, at a cost of $59,000/QALY gained. Sensitivity analysis found that cancer recurrence rates affected model results the most. Our findings were otherwise robust with respect to changes in other model parameters, including chemotherapy toxicity, surgical complications and cancer mortality. Probabilistic sensitivity analyses showed that neoadjuvant strategy was cost-effective 80% of the time with a willingness-to-pay threshold of $100,000/QALY. Conclusions: Our model results demonstrate that neoadjuvant strategy is preferable to upfront surgery for patients with borderline resectable or locally advanced PDAC from both an efficacy and cost-effectiveness standpoint. Additional clinical data are needed to further define the long-term effectiveness of neoadjuvant FOLFIRINOX to confirm our results.
Molecular profiling of advanced pancreatic cancer (PC) patients from a phase I/II study using circulating tumor DNA.
Authors: Catenacci Daniel V.T. , Green Emma , Epstein Michael , Jones Greg , Morris Clive D. , O'Day Emily , Lomnicki S , Maranto Melissa , Karrison Theodore G. , Kindler Hedy L.
Published: September 2018

4124

Background: PC has a poor prognosis with a 5-year survival of 9%. Targeted therapies have yet to demonstrate improved outcomes in this disease. Circulating tumour DNA (ctDNA) may be used as a non-invasive method for the detection and quantification of genomic abnormalities. We performed a retrospective-prospective study to assess molecular alterations in the ctDNA of advanced PC patients. Methods: Plasma samples were banked from patients enrolled in the previously reported Phase Ib/II trial of gemcitabine with placebo or vismodegib (NCT01064622; Catenacci et al JCO 2015). Eligible patients had unresectable PC and no prior therapy for metastatic disease. Patient samples ( < 3ml) collected pre-treatment and at regular intervals and stored for ~6-8 years were analyzed using InVision (enhanced tagged-amplicon sequencing) for “hotspot” regions of 34 genes, including KRAS (exons 2 and 3), and select full gene coverage. Results: Of 113 patients enrolled in the trial, a cohort of 72 patients were included in this study. Baseline plasma ctDNA profiling detected any genomic event in 88% of patients (SNV/indels found at range of 0.07%-23% allele fraction (AF) with 20% detected at < 0.5% AF). Patients had between 1-5 mutations (median, 2): KRAS mutations were detected in 80% of patients tested, of which 86% had concurrent KRAS/TP53 mutation(s) and 16% with concurrent KRAS/TP53/CDK2NA. Of note, 2 cases presented with IDH1 point mutations (R132C, R132H). An ERBB2 amplification and a FGFR2 amplification were detected in 2 individuals. An update on the analyses will include serial ctDNA testing during treatment and correlation with outcomes. Conclusions: ctDNA analysis of this cohort of banked PC plasma samples described the landscape of genomic aberrations at baseline and over time, including rare but potentially important actionable events including ERBB2 and FGFR2 amplifications and IDH1 mutation. We demonstrate a sensitive method for re-analysing trial outcomes, despite limiting plasma volume and time lapse since samples were collected.
Subgroup analysis by prior lines of metastatic therapy (mtx) in NAPOLI-1: A global, randomized phase 3 study of liposomal irinotecan (nal-IRI) ± 5-fluorouracil and leucovorin (5-FU/LV), vs. 5-FU/LV in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) who have progressed following gemcitabine-based therapy.
Authors: Macarulla Teresa Mercade , Siveke Jens T. , Wang-Gillam Andrea , Li Chung-Pin , Bodoky Gyorgy , Dean Andrew Peter , Yanshen Shan , Jameson Gayle S. , Lee Kyung-Hun , Blanc Jean-Frédéric , Chiu Chang-Fang , Schwartsmann Gilberto , Braiteh Fadi S. , Cunningham David , Chen Li-Tzong , Von Hoff Daniel D. , Mamlouk Khalid Kevin , Bhargava Parul , de Jong Floris A. , Hubner Richard
Published: September 2018

4127

Background: In the NAPOLI-1 study, nal-IRI+5-FU/LV significantly increased median OS vs. 5-FU/LV control (6.1 vs. 4.2 mo; unstratified HR = 0.67 [0.49–0.92]; p = .012). This is a subgroup analysis by prior lines of mtx. Methods: Study methodology has been published (Wang-Gillam; Lancet 2016). This exploratory subgroup analysis compares outcomes in pts with 0–1 vs. ≥2 prior mtx lines, based on primary survival analysis data (cut-off February 2014) of the ITT population. Results: OS, PFS and CA19-9 response rates in pts with 0–1 (65.8% of pts) or ≥2 (34.2%) prior mtx lines are shown (see Table). Median OS for nal-IRI+5-FU/LV improved vs. 5-FU/LV by 2.1 mo to 6.2 mo (HR = 0.66; p = .03) in pts with 0–1 prior mtx lines and by 1.1 mo to 5.4 mo (HR = 0.68; p = .18) in pts with ≥2 prior mtx lines. The safety profile was similar between subgroups with nal-IRI+5-FU/LV (≥grade 3 drug-related AEs: 43 [55%] with 0–1 and 20 [51%] with ≥2 prior mtx lines). Conclusions: This post-hoc subgroup analysis shows significant increases for nal-IRI+5-FU/LV over 5-FU/LV in OS, PFS and CA19-9 response in pts with 0–1 prior mtx lines. Median OS benefit was less prominent in later lines, but conclusions are restricted by limited pt numbers. Clinical trial information: NCT01494506. [Table: see text]
Planned survival analysis from KEYNOTE-045: Phase 3, open-label study of pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC).
Authors: Bajorin Dean F. , De Wit Ronald , Vaughn David J. , Fradet Yves , Lee Jae-Lyun , Fong Lawrence , Vogelzang Nicholas J. , Climent Miguel Ángel , Petrylak Daniel Peter , Choueiri Toni K. , Necchi Andrea , Gerritsen Winald , Gurney Howard , Quinn David I , Culine Stephane , Sternberg Cora N. , Mai Yabing , Puhlmann Markus , Perini Rodolfo F. , Bellmunt Joaquim
Published: September 2018

4501

Background: Second-line chemotherapies (chemo) for advanced UC have limited clinical benefit (OS, 7-9 mo). Data from the open-label, phase 3 KEYNOTE-045 study (NCT02256436) showed significantly longer OS with pembro v chemo (median, 10.3 v 7.4 mo; hazard ratio [HR], 0.73; P = 0.002) in recurrent, advanced UC. Data from a planned survival analysis are presented. Methods: Pts had histologically or cytologically confirmed UC, progression after platinum, ECOG PS 0-2, measurable disease (RECIST v1.1), and ≤2 lines of systemic therapy. Pts were randomly assigned 1:1 to pembro 200 mg Q3W or investigator’s choice of paclitaxel 175 mg/m2 Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W. Primary efficacy end points were OS and PFS (RECIST v1.1, blinded central review). ORR (RECIST v1.1, blinded central review) was a secondary end point. Results: 542 pts were enrolled (pembro, 270; chemo, 272). Baseline characteristics were generally similar between arms. As of Jan 18, 2017, median follow-up was 18.5 mo (range, 14.2-26.5). Median OS was significantly longer with pembro v chemo (10.3 v 7.4 mo; HR, 0.70; P < 0.001), and significance was maintained regardless of PD-L1 expression as measured by combined positive score (HR: CPS < 1%, 0.84; CPS ≥1%, 0.59; CPS < 10%, 0.76; CPS ≥10%, 0.57). OS benefit with pembro v chemo was seen regardless of age, ECOG PS, prior therapy, liver metastases, histology, and choice of chemo. The 18-mo OS rate (95% CI) was 36.1% (30.1%-42.0%) with pembro v 20.5% (15.2%-25.8%) with chemo (KM estimate). PFS was not different between arms. ORR was higher with pembro v chemo (21.1% v 11.0%), and median (range) duration of response was longer (not reached [1.6+-20.7+ mo] v 4.4 mo [1.4+-20.3]). 69% (pembro) v 36% (chemo) of responses lasted ≥12 mo. Fewer pts experienced a treatment-related AE with pembro v chemo (any grade, 61.3% v 90.2%; grade ≥3, 16.5% v 49.8%). Conclusions: The OS benefit and superior safety profile of pembro over chemo are maintained with longer follow-up. Combined, these results support the potential of pembro as a new standard of care for patients with UC who previously received platinum. Clinical trial information: NCT02256436.
Phase II study of alternate sunitinib schedule in patients with metastatic renal cell carinoma.
Authors: Jonasch Eric , Slack Rebecca , Geynisman Daniel M. , Milowsky Matthew I. , Rathmell Kimryn , Stovall Summer , Juarez Donna , Plimack Elizabeth R. , Tannir Nizar M. , Rini Brian I.
Published: September 2018

4513

Background: Sunitinib is an antiangiogenic agent indicated for the treatment of metastatic renal cell carcinoma (mRCC). Sunitinib is given in a 4 week on, 2 week off (4/2) schedule. Significant toxicities are observed in patients in the 3rd and 4th weeks of therapy. We hypothesized that a 2 week on, 1 week off (2/1) schedule would provide improved toxicity without compromising efficacy. Methods: A multicenter, single arm study was performed, with patients initiating sunitinib 50mg on a 2/1 schedule. Schedule and dose alterations were performed if grade > 3 toxicities were observed. The primary objective was to determine the percentage of patients who experienced grade > 3 fatigue, diarrhea, or HFS. The sample size of 60 patients was selected to ensure the upper bound of a 95% confidence would fall below standard schedule rate of 25%-30% if sample rate was 10%-15%, respectively. Secondary outcomes included response rate (RR), progression free survival (PFS) and dose reductions. Results: Between August 2014 and April 2016, 60 patients were enrolled, and 59 treated. Patients had a median age of 65.5 years (ranging from 45-92). 24% of patients (14/59) had grade 3 or higher fatigue, diarrhea, or HFS (95% CI: 13.6%, 36.6%). This is similar to the average of the 4 week on, 2 week off schedule of 25%-30%, and the lower bound of the confidence interval is in the center of our target rate of 10%-15%. Among events at least possibly related to study drug, patients were most likely to experience the expected events of diarrhea (75% with 5 grade 3 events), fatigue (71% with 6 grade 3 events), and HFS (54% with 3 grade 3 events). 22 (37%) patients responded (25.0%, 50.9%). Among patients with secondary endpoint data available, median PFS was 19.3 months (95% CI: 8.2, NR) and 33/56 (59%) of patients underwent dose reduction. Conclusions: Sunitinib administered in a 2/1 schedule in this study did not result in a lower rate of grade 3 or higher fatigue, diarrhea or HFS when compared to historical data from trials employing a 4/2 schedule. However, efficacy data showed robust response rate and a prolonged PFS, suggestive of long-term tolerability in patients receiving sunitinib on a 2/1 schedule. Evaluation of toxicity kinetics and patient quality of life is ongoing. Clinical trial information: NCT02060370.
Multiregion sequencing of penile cancer to reveal distinct patterns of heterogeneous actionable mutations.
Authors: Rodney Simon , Tanic Miljana , Barrett James , Amy Webster Philomena , de Winter Patricia , Tan Wei Shen , Khetrapal Pramit , Dong Liqin , Rezaee Sheida , Freeman Alex , Nigam Raj , Malone Peter , Muneer Asif , Beck Stephan , Feber Andrew , Kelly John D
Published: September 2018

4518

Background: Penile cancer is a rare but mutilating disease. Due to its rarity few studies have investigated the molecular oncogenic changes. There is a huge need to improve the poor outcome of metastatic disease by advancing the standard practice of platinum based therapies. Treatment based on actionable mutations and the potential of immunotherapies may improve clinical outcomes. We present the first analysis of intra-tumour heterogeneity within penile cancer. Methods: Tissue samples, greater than 80% purity, were collected from four spatially distinct tumor regions together with matched normal and metastatic tissue. Deep whole exome sequencing was performed on the resulting 48 samples from eight patients. Mutations were called by using Mutect2 and annotated with Annovar. Copy number changes were estimated using Sequenza and phylogenetic trees created using pyclone. Results: A mean of 650 single nucleotide variants and insertion/deletion events were discovered per tumor sample. Extensive intra-tumor heterogeneity was found with a wide range of different predicted subclonal architectures. Two distinct patterns were noted: either the acquisition of mutations by the lymph node metastasis was an early event with a lower mutational load, or it was a later event with a high mutational load. In the two instances where patients were negative for human papillomavirus infection, the lymph node metastasis evolved at a later date. However in 5/6 cases of HPV infection, an early subclone developed which potentially led to the lymph node metastasis. Driver mutations in p53, cMET or FAT1 were found to be truncal early events in 80% of cases. Actionable mutations in PIK3CA and EGFR were found to be subclonal in two further samples. Conclusions: There is extensive intra- and inter-tumour heterogeneity within penile cancer. The main truncal drivers in penile cancer are cMET, FAT1 and p53. Samples infected with human papillomavirus appeared to have a distinct signature in terms of both copy number changes and clonal architecture. Actionable mutations PIK3CA and EGFR were found to be subclonal in origin. This may have profound effects on the clinical utility of targetable treatments such as tyrosine kinase inhibitors.
Phase II trial of pembrolizumab in patients (pts) with incurable platinum refractory germ cell tumors (GCT).
Authors: Adra Nabil , Althouse Sandra K. , Ammakkanavar Natraj Reddy , Radovich Milan , Albany Costantine , Vaughn David J. , Einhorn Lawrence H. , Hanna Nasser H.
Published: September 2018

4520

Background: Despite remarkable results with salvage standard-dose (SDCT) or high-dose chemotherapy (HDCT), about 15% of pts with relapsed GCT are incurable. Immune therapy with Pembrolizumab is a novel approach for salvage in pts with metastatic GCT. Methods: Single arm phase 2 trial investigating pembrolizumab 200mg IV Q3weeks until disease progression in pts with relapsed GCT and no curable options. Pts age≥18 with metastatic GCT who progressed after first line cisplatin-based chemotherapy and after at least 1 salvage regimen (HDCT or SDCT) were eligible. Centrally assessed PD-L1 on tumor infiltrating immune cells using PD-L1 (22C3) assay was scored as 0, 1, 2, 3 along with PD-L1 expression score (H-score) incorporating intensity of staining. Pts were eligible irrespective of PD-L1 expression status. The primary endpoint was overall response rate using immune-related response criteria. Simon’s 2-stage design required response in ≥ 1/12 pts to proceed to stage 2 enrolling 8 more pts for a total of 20. Results: 12 male pts were enrolled. Median age 38 (range, 27-55). All pts had non-seminoma. Primary tumor site was testis in 11 pts and mediastinum in 1. Median AFP 615 (range, 1-32,760) and hCG 4 (range, 0.6-37,096). 5 pts had late relapse ( > 2years). Median number of previous chemotherapy regimens was 3 (range, 1-6). 6 pts received prior HDCT. 2 pts had positive PD-L1 staining (H-score 90 and 170). Median number of deliverable pembrolizumab doses was 2 (range, 1-8). There were 5 grade 3 adverse events, with 3 events possibly related to study treatment (chest pain, hyperglycemia, abdominal pain). No partial or complete responses were observed. 2 pts achieved stable disease for 12 and 9 weeks respectively; 10 pts had progression of disease as their best response. The 2 pts with stable disease had continued rising AFP level despite radiographic stability; both had negative PD-L1 staining. Conclusions: This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Although 2 pts had stable disease, each had rising tumor markers suggesting continued treatment resistance. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT. Clinical trial information: NCT02499952.
Molecular profiling of small cell bladder cancer (SCBC) to reveal gene expression determinants of an aggressive phenotype.
Authors: Koshkin Vadim S. , Reynolds Jordan , Elson Paul , Magi-Galluzzi Cristina , McKenney Jesse , Smith Karen Streator , Shadrach Bonnie , Isse Kumiko , Saunders Laura R. , Hu Ming , Tendulkar Rahul D. , Stephenson Andrew J. , Fergany Amr Farouk , Abazeed Mohamed , Rini Brian I. , Garcia Jorge A. , Lee Byron , Mian Omar Y , Grivas Petros
Published: September 2018

4529

Background: SCBC is rare and its underlying biology poorly understood. Molecular profiling can shed light on the biology and identify treatment targets and biomarkers. Methods: A retrospective review of 63 patients (pts) with biopsy-confirmed SCBC at Cleveland Clinic (1994-2015) was performed. Percentage of small cell component (SC%) was defined by independent pathology review. DLL3 and PD-L1 protein expression were measured by IHC in 53 pts. Gene expression analysis was done in 38 primary SCBC tumor samples, 1 metastatic sample, and 5 normal bladder tissue samples (44 total) from the same cohort using HTG EdgeSeq OBP Assay with probes for 2568 genes. Analysis was performed via the RNAseq workflow (Partek Genomics Suite). Results: Among 63 identified pts, median age was 71 (39-90), 83% were men, median SC% was 100% (range 5-100%), median follow-up was 16.6 months and estimated median overall survival (OS) was 22.8 months. Unsupervised hierarchical clustering of gene expression patterns from 44 samples produced 4 distinct clusters. Pts with tumors in cluster 1 (that also included normal samples) did not have metastasis at diagnosis or distant recurrence, both of which were over-represented in the other 3 clusters. Kaplan-Meier analysis revealed a trend towards longer OS in cluster 1 patients (log rank p = 0.065). Higher gene expression of PRC1, NCAM1 (CD56) and DLL3 correlated with higher SC%, as did lower gene expression of ERBB2, PD-L1 and HPGD (p < 0.01). PD-L1 protein expression (≥1% cells) was noted in 30% of pts but did not correlate with outcome, SC%, DLL3 protein expression, or PD-L1 gene expression. DLL3 protein expression (≥1% cells) was noted in 68% of pts and DLL3 > 10% correlated with decreased OS (p = .03). Higher DLL3 protein expression correlated with DLL3 gene expression (Spearman r = 0.70, p < .01) and with SC% (r = .33, p = .01). Conclusions: This is the first study to reveal distinct gene expression patterns that define aggressive behavior, metastatic potential and outcomes in SCBC. The prognostic value of differential gene expression networks and the presence of underlying genomic and epigenetic alterations is the subject of ongoing prospective validation in a larger cohort.
Incidence of secondary malignancies (SM) in patients (pts) with germ cell tumors (GCT) who received high-dose chemotherapy (HDCT): A retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) database.
Authors: Secondino Simona , Necchi Andrea , Rosti Giovanni , Badoglio Manuela , Raggi Daniele , Giannatempo Patrizia , Lanza Francesco , Pedrazzoli Paolo
Published: September 2018

4549

Background: Little is still known about the incidence of SM in young adult pts with GCT after HDCT, owing to the rarity of the disease, and the need for registries with long term follow-up (FUP) data. In Europe, the EBMT may provide a suitable platform for such retrospective analyses. Methods: Criteria for patient selection included diagnosis of GCT, adult male gender, ≥2yr of FUP after the administration of HDCT. Summary statistics were used to describe pt characteristics and outcomes. χ2 tests were used to compare groups according to the length of FUP. Kaplan-Meier estimates were used to estimate overall survival (OS). Univariable Cox regression analyses examined clinical factors potentially associated with OS. Survival times were calculated from the HDCT administration date. To estimate the probability of developing SM, the cumulative incidence of SM was calculated for all pts. Results: From 1981 to 2014, 9,153 autografts, accounting for 5,100 pts, have been registered. Of them, 1,855 had ≥2yr of FUP. Among the latter, a total of 56 cases of SM were identified (3.0%). 28 (50%) had solid SM, 22 (39.3%) hematologic (hem) SM (5 had uncoded SM). Median age at first HDCT was 34 years (IQR: 30-42), median age at development of SM was 42 (37-51). 26 pts (46.4%) received single HDCT cycle, 22 (39.3%) multiple HDCT cycles (8 unknown). 31 pts had ≥5 yr FUP, 25 pts 2-5 yr FUP. The median latency of SM was 3.3yrs (IQR: 1.8-6.1) for hem SM and 5.6yrs (IQR: 1.2-10.8) for solid SM. Median FUP was 6.4yrs. Univariably, the type of SM (solid vs. hem) was significantly associated with OS. Hem vs solid SM: HR: 2.17 (95%CI: 1.19-4.97, p = 0.020). Median OS of pts who developed solid SM was 13.3yrs compared to 4.1yrs of those with hem SM. The retrospective nature of the data is the major limitation. Conclusions: In the largest European database of SM in GCT pts, we observed different trends for SM development according to the SM type. This information may be important for FUP guidelines of these pts. Dataset implementation is ongoing and we will compare the SM incidence from EBMT database with SM rates in the general EU population.
Genomic comparison of matched primary and metastatic germ cell tumors (GCT).
Authors: Audenet Francois , Donoghue Mark , Pietzak Eugene J. , Isharwal Sumit , Cheng Michael L. , Iyer Gopa , Funt Samuel , Bajorin Dean F. , Al-Ahmadie Hikmat , Reuter Victor E. , Eng Jana , Reichel Jonathan B , Arcila Maria E. , Tsui Dana , Shady Maha , Berger Michael F. , Bosl George J. , Sheinfeld Joel , Solit David B. , Feldman Darren R.
Published: September 2018

4556

Background: Tumor genomic analysis may be useful in patients with GCT as a means of identifying potentially actionable genomic alterations or mutations such as TP53 that confer resistance to chemotherapy. As GCTs often exhibit significant morphologic heterogeneity, we evaluated the level of concordance between genomic alterations in matched primary and metastatic GCT samples. Methods: GCT patients enrolled on an institutional prospective sequencing protocol with available primary and metastatic tumor tissue were eligible. Each tumor was subjected to MSK-IMPACT, an exon capture sequencing assay, which detects copy number alterations (CNAs) and mutations in 410 cancer-related genes. For each primary-metastasis pair, concordance and clonality was assessed using the FACETS algorithm. Results: Matched primary-metastasis tumor pairs were available for 36 patients (78% nonseminoma, 22% seminoma, median age 33.5 years). All patients received chemotherapy, with 25 (69%) receiving treatment prior to analysis of the metastatic samples. The frequency of genetic alterations was low with a median of 3 mutations (1-7), 7 amplifications (1-26) and 1 deletion (1-9) detected per sample, with no significant difference in mutational/CNA burden between primaries and metastases. Of 109 unique mutations across patients, only 44 (40%) were concordant between the primary and matched metastasis, including 5 of 9 hotspot mutations. For CNAs, 184 (81%) of 226 were concordant. Only 24 of 109 (22%) mutations were clonal (defined as predicted to be present in all cancer cells) in either the primary or metastatic matched samples; of these, only 4 were clonal in both the primary and metastatic samples, including 2 hotspots. However, 4 of 5 alterations in TP53/MDM2 were shared by both the primary and metastasis pairs. In a separate exploratory cohort, 4 TP53 mutations were identified in 3 primary tumors and 1 metastasis, and all 4 mutations were also detected by cell-free DNA profiling. Conclusions: Genomic concordance, particularly for mutations, is poor between primary and metastatic GCT samples. Cell-free DNA analysis may help overcome this limitation by identifying alterations in progressive tumors without need for a new biopsy.