H.Y. Lim

Brivanib in Patients With Advanced Hepatocellular Carcinoma Who Were Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the Randomized Phase III BRISK-PS Study

PURPOSEnBrivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib.nnnPATIENTS AND METHODSnIn all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety.nnnRESULTSnMedian OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%).nnnCONCLUSIONnIn patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.

Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma

BACKGROUNDnRetrospective and molecular biologic data suggest that sunitinib may be effective in patients with non-clear cell renal cell carcinoma (nccRCC).nnnPATIENTS AND METHODSnEligibility criteria included advanced nccRCC except for collecting duct carcinoma and sarcomatoid carcinoma without identifiable renal cell carcinoma subtypes. Patients were treated with 50 mg/day oral sunitinib for 4 weeks, followed by 2 weeks of rest. The primary end point was overall response rate (RR).nnnRESULTSnThirty-one eligible patients were enrolled. Twenty-four patients (77%) had prior nephrectomy. By Memorial Sloan-Kettering Cancer Center criteria, 8 patients (26%) had poor risk and 14 (45%) had intermediate risk. Twenty-two patients had papillary renal cell carcinoma (RCC), and three had chromophobe RCC. Eleven patients had partial response with a RR of 36% (95% confidence interval (CI) 19% to 52%) and an additional 17 patients (55%) had stable disease. Median duration of response was 12.7 months (95% CI 6.3-19.1 months), and median progression-free survival was 6.4 months (95% CI 4.2-8.6 months). At a median follow-up duration of 18.7 months (95% CI 13.7-23.7 months), 13 patients (42%) had died, resulting in an estimated median survival of 25.6 months (95% CI 8.4-42.9 months). Toxicity profiles were commensurate with prior reports.nnnCONCLUSIONSnSunitinib has promising activity in patients with nccRCC (NCT01219751).BACKGROUNDnRetrospective and molecular biologic data suggest that sunitinib may be effective in patients with non-clear cell renal cell carcinoma (nccRCC).nnnPATIENTS AND METHODSnEligibility criteria included advanced nccRCC except for collecting duct carcinoma and sarcomatoid carcinoma without identifiable renal cell carcinoma subtypes. Patients were treated with 50 mg/day oral sunitinib for 4 weeks, followed by 2 weeks of rest. The primary end point was overall response rate (RR).nnnRESULTSnThirty-one eligible patients were enrolled. Twenty-four patients (77%) had prior nephrectomy. By Memorial Sloan-Kettering Cancer Center criteria, 8 patients (26%) had poor risk and 14 (45%) had intermediate risk. Twenty-two patients had papillary renal cell carcinoma (RCC), and three had chromophobe RCC. Eleven patients had partial response with a RR of 36% (95% confidence interval (CI) 19% to 52%) and an additional 17 patients (55%) had stable disease. Median duration of response was 12.7 months (95% CI 6.3-19.1 months), and median progression-free survival was 6.4 months (95% CI 4.2-8.6 months). At a median follow-up duration of 18.7 months (95% CI 13.7-23.7 months), 13 patients (42%) had died, resulting in an estimated median survival of 25.6 months (95% CI 8.4-42.9 months). Toxicity profiles were commensurate with prior reports.nnnCONCLUSIONSnSunitinib has promising activity in patients with nccRCC (NCT01219751).

Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma

BACKGROUNDnThe efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC).nnnPATIENTS AND METHODSnPatients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS).nnnRESULTSnThe estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival.nnnCONCLUSIONSnAxitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC.nnnTRIAL REGISTRATIONnClinicalTrials.gov, NCT01210495.

Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients

Abstract Background To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and methods We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples. Results Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; Pu2009=u20090.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (Pu2009=u20090.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications. Conclusions The present study showed that HER2+u2009GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.

Rapamycin-insensitive companion of mTOR (RICTOR) Amplification Defines a Subset of Advanced Gastric Cancer and is Sensitive to AZD2014-mediated mTORC1/2 Inhibition.

BackgroundnTargeting oncogenic genomic aberrations is an established therapeutic strategy in multiple tumor types. Molecular classification has uncovered a number of novel targets, and rapamycin-insensitive companion of mTOR (RICTOR) amplification has been identified in lung cancer. Further investigation assessing the therapeutic potential of RICTOR amplification as a novel target across advanced cancers is needed.nnnPatients and methodsnTumor samples from 640 patients with metastatic solid tumors, primarily gastrointestinal and lung cancers were prospectively subjected to a next-generation sequencing (NGS) assay to identify molecular targets. Samples with NGS-detected RICTOR amplification were confirmed with FISH. A RICTOR-amplified patient-derived cell (PDC) line was generated and used to investigate the effectiveness of selective AKT, mTORC1, and mTORC1/2 inhibition.nnnResultsnNGS identified 13 (2%) of 640 patients with RICTOR-amplified tumors (6 gastric, 3 NSCLC, 1 SCLC, 1 CRC, 1 sarcoma, 1 MUO). Of the 13 patients, seven patients had RICTOR protein overexpression by IHC. The prevalence of RICTOR amplification in gastric cancer by NGS was 3.8% (6/160). FISH testing confirmed amplification (RICTOR/controlu2009>2) in 5/13 (38%) of samples, including four gastric cancers and one lung cancer. Treatment of a RICTOR amplified PDC with a selective AKT (AZD5363), selective mTORC1 (everolimus), dual mTORC1/2 (AZD2014), and the multi-target kinase inhibitor pazopanib demonstrated preferential sensitivity to the mTORC1/2 inhibitor (AZD2014). Knockdown of RICTOR reversed PDC sensitivity to AZD2014, validating the importance of RICTOR amplification to the PDC line.nnnConclusionsnRICTOR amplification is a rare but therapeutically relevant genomic alteration across solid tumors. Our results support further pre-clinical and clinical investigation with AZD2014 in RICTOR amplified gastric cancer and highlights the importance of genomic profiling.

Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma

BackgroundnArginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase-conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy.nnnMethods and patientsnPatients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2xa0:xa01 to ADI-PEG 20 18u2009mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6u2009months increase in median OS (one-sided αu2009=u20090.025). Secondary end points included progression-free survival, safety, and arginine correlatives.nnnResultsnA total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8u2009months for ADI-PEG 20 versus 7.4 for placebo (Pu2009=u20090.88, HRu2009=u20091.02) and median progression-free survival 2.6u2009months versus 2.6 (Pu2009=u20090.07, HRu2009=u20091.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 hadu2009≥grade 3 anaphylactic reaction. Death rate within 30u2009days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16u2009weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion.nnnConclusionnADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.nnnClinical Trial numbernwww.clinicaltrials.gov (NCT 01287585).

719PTUMOUR SHRINKAGE AT 6 WEEKS PREDICTS FAVORABLE CLINICAL OUTCOMES IN A PHASE III STUDY OF GEMCITABINE AND OXALIPLATIN WITH OR WITHOUT ERLOTINIB FOR ADVANCED BILIARY TRACT CANCER

Background: The aim of this study was to determine whether early tumor shrinkage (ETS) at 6 weeks after treatment correlates with progression-free survival (PFS) and overall survival (OS) in advanced biliary tract cancer (BTC) patients receiving gemcitabine plus oxaliplatin (GEMOX), with or without erlotinib. Methods: This was a multicenter, open label, randomized, phase III trial of 103 BTC patients (ClinicalTrials.gov Identifier; NCT01149122, and Rigistration date; January, 7, 2010), comparing GEMOX with GEMOX plus erlotinib. Tumor shrinkage was expressed as a relative decrease compared to baseline and was dichotomized according to a previously reported cutoff value of 10 %. Results: Fifty-four patients (52.4 %) received GEMOX and 49 patients (47.6 %) received GEMOX plus erlotinib. The latter achieved a better overall response rate (RR) (40.8 % vs. 18.6 %, p= 0.02) and showed ETS more frequently (63.2 % vs. 40.7 %, p= 0.03). ETS was significantly correlated with the overall RR (correlation coefficient, 0.53; p< 0.01). The median PFS and OS did not differ according to erlotinib administration. However, the median PFS (7.3 vs. 2.1 months, p< 0.01) and OS (10.7 vs. 5.8 months, p< 0.01) were significantly longer amongst patients with ETS at 6 weeks after treatment, irrespective of erlotinib administration. In patients with wild-type KRAS who were treated with GEMOX plus erlotinib, ETS was a significant prognostic factor for PFS (p< 0.01). Conclusions: ETS might predict PFS and OS in BTC patients treated with GEMOX with or without erlotinib. Additionally, ETS may be an indication for adding erlotinib to chemotherapy for BTC patients wild-type KRAS. These findings need to be prospectively validated.

744TiPMET-POSITIVE ADVANCED HEPATOCELLULAR CARCINOMA AND CHILD-PUGH CLASS A LIVER FUNCTION IN ASIAN PATIENTS: A RANDOMIZED, MULTICENTER, PHASE IB/II TRIAL OF THE ORAL C-MET INHIBITOR MSC2156119J VS SORAFENIB

ABSTRACT Background: Advanced hepatocellular carcinoma (HCC) is associated with a poor prognosis. Sorafenib is the recommended treatment for HCC patients (pts); however, it is not widely used in Asia due to affordability and unsatisfactory efficacy. The highly selective c-Met inhibitor MSC2156119J showed promising antitumor activity in a phase I trial (Falchook et al. J Clin Oncol 2013:31[Suppl]:2506) with a recommended phase II dose (RP2D) of 500u2003mg/d. This phase Ib/II, open-label, multicenter trial assesses the efficacy of MSC2156119J monotherapy in first-line treatment vs sorafenib in Met-positive (Met+) advanced HCC pts (NCT01988493). Trial design: Primary objectives include confirmation of the RP2D of 500u2003mg MSC2156119J in HCC pts (phase Ib) and evaluation of MSC2156119J monotherapy efficacy vs sorafenib, as determined by time to progression (TTP) per independent read (phase II). Secondary objectives are preliminary antitumor activity of MSC2156119J, pharmacokinetics (phase Ib), tolerability, safety, and antitumor activity of MSC2156119J vs sorafenib (phase II: overall survival, objective response, disease control, time to symptomatic progression, progression-free survival, and TTP per investigator read). Main eligibility criteria include: Asian adults with confirmed advanced HCC of BCLC Stage C, Child-Pugh Class A liver function, ECOG status 0–2 (only phase II: Met + , defined as moderate or strong protein overexpression determined by immunohistochemistry, measurable disease according to RECIST v1.1, and eligible for sorafenib treatment), life expectancy >3 mo, no prior systemic anticancer treatment or treatment targeting the HGF/c-Met pathway (phase II only), no neoplasm other than HCC, and no impaired cardiac function, history of liver transplant, or gastrointestinal disease. The Phase Ib part is a “3 + 3” dose-escalation design (300 or 500u2003mg MSC2156119J p.o./d; 21-d cycle) enrolling up to 18 pts. The phase II part is planned to randomize 140 pts (1:1) who receive MSC2156119J at the RP2D p.o./d or 400u2003mg sorafenib p.o./twice daily (21-d cycle). Enrollment began on Jan 9, 2014. Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting. All rights reserved. Disclosure: L. Xu: Employee of Merck Serono Pharmaceutical RD H. Zheng: Stock ownership: Merck/EMD Serono Employee of EMD Serono, Boston, MA; F. Bladt: Employee of Merck KGaA, Darmstadt, Germany. All other authors have declared no conflicts of interest.

722PMOLECULAR SUBGROUP ANALYSIS OF CLINICAL OUTCOMES IN A PHASE 3 STUDY OF GEMCITABINE AND OXALIPLATIN WITH OR WITHOUT ERLOTINIB IN ADVANCED BILIARY TRACT CANCER

ABSTRACT Aim: We previously reported that the addition of erlotinib to gemcitabine and oxaliplatin (GEMOX) resulted in greater antitumor activity and might be a treatment option for patients with biliary tract cancers. Molecular subgroup analysis of treatment outcomes in patients who had tumor specimens available for analysis was undertaken. Methods: EGFR, KRAS, and PIK3CA mutations were evaluated using peptide nucleic acid-locked nucleic acid (PNA–LNA) PCR clamp reactions. Survival and response rates were analyzed according to the mutational status. Results: 64 patients (48.1%) were available for mutational analysis in the chemotherapy alone group and 61 (45.1%) in the chemotherapy plus erlotinib group. 1.6% (2/116) harboured an EGFR mutation (2 patients; exon 20), 9.6% (12/121) harboured a KRAS mutation (12 patients; exon 2), and 9.6% (12/118) a PIK3CA mutation (10 patients; exon 9 and 2 patients; exon 20). The addition of erlotinib to GEMOX in patients with KRAS wild type disease (n = 109) resulted in significant improvements in overall response compared with GEMOX alone (30.2% vs. 12.5%, p = 0.024). In 95 patients with both wild type KRAS and PIK3CA, there was evidence of a benefit associated with the addition of erlotinib to GEMOX with respect to response rate (RR) as compared with GEMOX alone (p = 0.04). Conclusions: This study demonstrates that KRAS mutational status might be considered a predictive biomarker for the response to erlotinib in biliary tract cancers (BTCs). Additionally, the mutation status of PIK3CA may be a determinant for adding erlotinib to chemotherapy in KRAS wild type BTCs. Disclosure: All authors have declared no conflicts of interest.

726PNATURAL HISTORY OF UNTREATED PATIENTS WHO HAD METASTATIC BILIARY TRACT CANCER (BTC) WITH GOOD PERFORMANCE STATUS (PS)

ABSTRACT Aim: Although chemotherapy is widely recommended for patients with metastatic biliary tract cancer (BTC), the natural course of these patients, especially those with good performance status (PS) who are indicated for chemotherapy, is not known. Methods: We retrospectively reviewed patients with metastatic or locally advanced BTC who were examined between January 2005 and September 2013 at six cancer centers. Patients were eligible if they had good PS (Eastern Cooperative Oncology Group score 0-2) and no history of any treatment for cancer. The primary objective was to evaluate the survival time of patients with advanced BTC with good PS who were untreated. Results: Of the 1,677 screened patients, 204 met the inclusion criteria. The median age was 70.1 years and median overall survival (OS) was 7.1 months. OS by disease location was 4.7 months for intrahepatic, 9.7 months for extrahepatic, 4.4 months for gallbladder, and 11.2 months for ampulla of Vater cancer. In subgroup analysis, OS of locally advanced BTC was 13.8 months and that of patients with normal CEA/CA 19-9 was 10.6 months. In multivariate analysis, variables that were associated with poor prognosis were disease extent (metastatic disease) [HR 2.19 (95% CI 1.39-3.45 p = 0.001)], high baseline CEA level (defined as > 4.0u2003ng/mL) [HR 1.51 (95% CI 1.06-2.17 p = 0.024)], and high baseline CA 19-9 level (defined as > 100 U/mL) [HR 1.93 (95% CI 1.33-2.91 p = 0.001)]. Conclusions: Metastatic BTC with good PS showed modest survival without any treatment for primary cancer. Furthermore, subgroup analysis showed that patients with normal CA19-9 or CEA level or locally advanced status had favorable survival. Further studies comparing the outcome of chemotherapy with that of best supportive care in patients with unresectable BTC are warranted. Disclosure: All authors have declared no conflicts of interest.