Updated OS Research Articles

93PD - Afatinib (A) vs gefitinib (G) in patients with EGFR mutation-positive (EGFRm+) NSCLC: Updated OS data from the phase IIb trial LUX-Lung 7 (LL7)

93PD - Afatinib (A) vs gefitinib (G) in patients with EGFR mutation-positive (EGFRm+) NSCLC: Updated OS data from the phase IIb trial LUX-Lung 7 (LL7)

Atezolizumab as first-line therapy (1L) for advanced PD-L1-selected NSCLC patients: updated ORR, PFS, OS and exploratory biomarker results from the BIRCH study

Atezolizumab as first-line therapy (1L) for advanced PD-L1-selected NSCLC patients: updated ORR, PFS, OS and exploratory biomarker results from the BIRCH study

OA03.02 Atezolizumab as 1L Therapy for Advanced NSCLC in PD-L1–Selected Patients: Updated ORR, PFS and OS Data from the BIRCH Study

Atezolizumab, a humanized anti-PDL1 mAb, inhibits the PD-L1/PD-1 pathway to restore tumor-specific T-cell immunity, resulting in durable anti-tumor effects. BIRCH (NCT02031458) is a single-arm Phase II study of atezolizumab monotherapy in PD-L1–selected advanced NSCLC patients, across multiple therapy lines. Primary analyses (median follow-up, 8.5 months) demonstrated a meaningful ORR with durable response in chemotherapy-naive 1L and 2L+ PD-L1–selected patients. Here we report updated efficacy data in 1L patients. 1L eligibility criteria included PD-L1–selected, advanced-stage NSCLC with no CNS metastases or prior chemotherapy. PD-L1 was centrally evaluated (VENTANA SP142 IHC assay). Patients expressing PD-L1 on ≥5% of tumor cells (TC) or tumor-infiltrating immune cells (IC), ie, TC2/3 or IC2/3, were enrolled. Patients with EGFR mutation or ALK rearrangement must have had prior TKI treatment. Atezolizumab 1200mg was administered IV q3w until radiographic disease progression or unacceptable toxicity. The primary endpoint was independent review facility(IRF)-assessed ORR. Secondary endpoints included investigator(INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS. With a median follow-up of 14.6 months, median OS was not reached in TC3 or IC3 patients and was 20.1 months in TC2/3 or IC2/3 (ITT) patients; INV-assessed ORR was 32% and 24%, respectively (Table). Furthermore, ORR was 31% for mutant EGFR (n=13) vs 20% for wild-type EGFR patients (n=104), and 27% for mutant KRAS (n=33) vs 21% for wild-type KRAS patients (n=67). No new safety signals were observed. Updated efficacy (including IRF ORR), safety and exploratory biomarker analyses will be presented. With longer follow-up, atezolizumab continued to demonstrate promising efficacy in 1L NSCLC. These results indicate that atezolizumab has durable efficacy in the 1L setting, in EGFR and KRAS mutant and wild-type tumors, and support ongoing Phase III trials evaluating atezolizumab vs chemotherapy in 1L NSCLC.Tabled 1Endpoint (95% CI)TC3 or IC3a (n=65)TC2/3 or IC2/3b (n=139)INV ORR, %32% (21.2–45.1)24% (16.9–31.7)EGFR mutant/wild-type, %25%/29%31%/20%KRAS mutant/wild-type, %38%/27%27%/21%mDOR, mo13.1 (8.5–NE)13.1 (9.9–17.5)mOS, moNE (12.0–NE)20.1 (20.1–NE)12-mo OS rate, %61% (48.8–73.8)66% (57.9–74.5)mPFS, mo7.3 (4.9–12.0)7.3 (5.6–9.1)12-mo PFS rate, %36% (23.8–48.8)32% (24.0–40.7)NE, not estimable.a TC ≥50% or IC ≥10% PD-L1–expressing cells.b TC or IC ≥5% PD-L1–expressing cells. Open table in a new tab

783P - Atezolizumab (atezo) in platinum (plat)-treated locally advanced/metastatic urothelial carcinoma (mUC): Updated OS, safety and biomarkers from the Ph II IMvigor210 study

783P - Atezolizumab (atezo) in platinum (plat)-treated locally advanced/metastatic urothelial carcinoma (mUC): Updated OS, safety and biomarkers from the Ph II IMvigor210 study

A phase II therapeutic, open label, multi-center clinical trial of NPC-1C, a chimeric monoclonal antibody(mAb), in adults with chemotherapy refractory metastatic colorectal cancer (mCRC), initial results.

500 Background: NEO-102 is a novel chimeric mAb targeting a variant of MUC5AC with specificity to colorectal cancer. Its mechanism of action is through antibody dependent cellular cytotoxicity (ADCC). An earlier, phase I study, established the maximum tolerated dose at 3.0 mg/kg IV every 2 weeks with encouraging early signs of clinical activity. We report initial results of the subsequent phase II study. Methods: This is a single arm, open label multi-center clinical trial of NEO-102 in adults with mCRC pts who failed at least two lines of standard chemotherapy (C). An immunohistochemistry (IHC) based companion diagnostic assay was used to select eligible pts whose tumors express the target in > 20% of tumor cells. NEO-102 at 3.0 mg/kg IV was administered q 2 weeks until disease progression. The primary endpoint was OS. A minimum of 43 pts were needed assuming that treatment with NEO-102 will improve OS by 40% (7.0 months) using a one-sided significance level of 10% and 80% power for this study compared to historical control of 5 months. Additional objectives were to evaluate response rate as measured by RECIST criteria and analyze patient PBMCs for ADCC and immune cytokine profiling. Results: A total of 47 pts enrolled were evaluable. 26 pts were male and 35 pts were white. Twenty-four out of 47 pts (51%) remain alive as of September 2015 with an ongoing median OS of 7.0 months (Range 2-22 months). Of these heavily pre-treated pts, 42 were evaluable for response, 13 (31%) demonstrated stable disease by RECIST. Seven pts had more than 4 doses of treatment, maximum 13 doses. Grade 3 adverse events were anemia 1/47 (2%), hyperbilirubinemia 1/47 (2%), diarrhea 1/47 (2%), fatigue 1/47 (2%), headache 1/47 (2%), nausea 1/47 (2%) and vomiting 1/47 (2%). No grade 4 toxicities were reported. Conclusions: In the monotherapy phase 2 study of NEO 102 in patients with refractory mCRC preliminary results demonstrate excellent tolerability and encouraging OS. Updated OS and Progression Free Survival data will be presented at the ASCO 2016 GI Cancers symposium. Additional combination trials with NEO-102 and C are underway. Clinical trial information: NCT01040000.

3302 Safety and Activity of Combined Radiotherapy (RT) and Anti-PD-1 Antibodies (PD-1) in Patients (pts) with Metastatic Melanoma

Conclusions: Updated OS analysis confirmed improvement in OS favoring D+T over Vem with medians of 25.6 versus 18 months. Two-year OS rates and additional efficacy and safety analysis will be presented. Conflict of interest: Ownership: J Legos reported equity ownership with GSK. B Mookerjee reported equity ownership with GSK, Incyte Corporation, and AstraZeneca. Advisory Board: P Rutkowski participated in an Advisory Committee for Novartis, Roche, BMS, and MSD. R Dummer participated in an Ad Board with Roche, BMS, GSK, MSD, Novartis. V Chiarion-Sileni participated in an Advisory Committee for BMS, GSK, Roche, and Merck. I Krajsova participated in an Advisory Committee for BMS. Board of Directors: P Rutkowski was a member of the board of directors for Novartis, Roche, BMS, and MSD. V Chiarion-Sileni was a member of the board of directors for BMS, GSK, Roche, and Merck. I was a member of the board of directors for BMS. Corporatesponsored Research: M Lichinitser received research funding from GSK. R Dummer received research funding from Roche, BMS, GSK, MSD, Novartis. K Drucis received research funding from GSK. A Hauschild received research funding from Amgen, BMS, Celgene, Eisai, GSK, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, Roche Pharma. Other Substantive Relationships: C Robert acted as a consultant for GSK, Novartis, Merck, BMS, Amgen, and Roche. P Rutkowski received honoraria from Novartis, GSK, Roche, Amgen, Pfizer, BMS, MSD, and Bayer and participated in a speakers bureau for Novartis and Pfizer. L Mortier reports personal fees from GSK, during the conduct of the study. A Hauschild acted as a consultant for Amgen, BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, and Roche and received honoraria from Amgen, BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, and Roche. B Mookerjee and J Legos are employees of GSK. D Schadendorf acted as a consultant and received honoraria from, and participated in a speakers bureau for GSK, Novartis, Roche, Amgen, BMS, Boehringer Ingelheim, and Merck/MSD.

FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as initial treatment for metastatic colorectal cancer (TRIBE study): Updated survival results and final molecular subgroups analyses.

3510 Background: The phase III TRIBE study met its primary endpoint by demonstrating that first-line FOLFOXIRI plus bev significantly prolongs PFS, as compared to FOLFIRI plus bev (Loupakis et al, N Eng J Med 2014). At a median follow-up of 32.2 months a preliminary OS analysis indicated a borderline OS improvement with FOLFOXIRI plus bev (HR = 0.79, p = 0.054) with a consistent effect across RAS (KRAS and NRAS codons 12, 13, 61) and BRAFV600E molecular subgroups. Methods: 508 pts were randomized to either FOLFIRI plus bev (Arm A, N = 256) or FOLFOXIRI plus bev (Arm B, N = 252). On available samples from RAS and BRAF wild-type (wt) pts (N = 129), also KRAS and NRAS codons 59, 117 and 146 were analysed by means of Sequenom MassArray, identifying a new “all wt” population (N = 93). Results: At a median follow-up of 48.1 months, in the ITT population, updated median OS for Arm B vs Arm A was 29.8 vs 25.8 months (HR = 0.80, 95%CI, 0.65-0.98, p = 0.030). Estimated 5-years OS rate were: Arm B, 24.9% vs Arm A, 1...

Abstract P3-06-10: Hand-foot-syndrome (HFS) is a strong predictor for OS and PFS in HER2-negative metastatic breast cancer (mBC) treated with first-line capecitabine (CAP) + bevacizumab (BEV): Results of a subanalysis of the randomized phase III CECOG TURANDOT trial

Abstract Background: The randomized phase III TURANDOT trial performed by the Central European Cooperative Oncology Group (CECOG) compared first-line BEV + paclitaxel (PAC) vs BEV + CAP in HER2-negative mBC in a prospective randomized trial [Lang, Lancet Oncol 2013]. In this trial, HFS was the most common adverse drug reaction in the BEV + CAP arm. In the present subanalysis, we investigated whether the occurrence of HFS constituted a predictor for improved efficacy of BEV + CAP in the study population randomized to this treatment arm. Methods: In the TURANDOT trial, patients with HER2-negative mBC who had received no prior chemotherapy for mBC were randomized to either BEV-PAC (BEV 10 mg/kg d1 & 15 + PAC 90 mg/m2 d1, 8, & 15 q4w) or BEV-CAP (BEV 15 mg/kg d1 + CAP 1000 mg/m2 bid d1-14 q3w). Only patients who were randomized to the BEV-CAP arm and received at least one dose of CAP were included in the present analysis. Cox proportional hazard models with time-dependent covariate "HFS of any grade" and "HFS grade" were used to analyze the association between HFS and OS or PFS. In addition, landmark (LM) analyses were performed analyzing the impact of HFS occurrence within the first 3 treatment months on PFS and OS. Results: Baseline characteristics of patients with HFS (n=154) versus no HFS (n=123) were well balanced and showed no significant differences. Table 1 shows that with the occurrence of HFS, the hazard for progression or death was reduced by > 40%, while the risk reduction (RR) was >55% for OS. Moreover, with increasing HFS-grade an increasing RR was observed for OS. In patients with and without HFS in the first 3 months, the median PFS after the 3 months LM were 10 and 6.2 months (logrank test p=0.0026), respectively, and the corresponding OS rates at 2 years after the 3 months LM were 63% and 44% (log rank test, p=0.0842), respectively. Updated OS results will be presented at the conference. Cox Proportional Hazards Models for PFS and OS with HFS as Time-dependent CovariateUnivariateMultivariate*EndpointTime depent variableHazard ratio (95%Cl)p-valueHazard ratio (95%Cl)p-valuePFSHFS(Yes vs No)0.577(0.431,0.772)0.00020.558(0.409,0.760)0.0002HFS Grade 10.639(0.440,0.927)0.01840.536(0.350,0.821)0.0042HFS Grade 20.481(0.321,0.720)0.00040.487(0.320,0.741)0.0008HFS Grade 30.641(0.411,0.999)0.04950.740(0.466,1.178)0.2043OSHFS(Yes vs No)0.417 (0.273, 0.637)<.00010.436 (0.285, 0.666)0.0001HFS Grade 10.568 (0.334, 0.968)0.03750.548 (0.322, 0.934)0.0270HFS Grade 20.417 (0.227, 0.765)0.00480.448 (0.243, 0.824)0.0098HFS Grade 30.220 (0.093, 0.520)0.00060.247 (0.104, 0.586)0.0015* Significant baseline factors in multivariate models: ECOG (0 vs 1-2) in all models, ER/PR status (Any positive vs Other) in both OS models. Conclusion: HFS is a strong predictor for prolonged PFS and OS in mBC patients receiving BEV + CAP first-line treatment. Early occurrence of HFS and HFS severity might be used for treatment modifications and patient motivation. Detection of biomarkers for HFS could strengthen this approach. Citation Format: Zielinski C Christoph, Lang Istvan, Beslija Semir, Kahan Zsuzsanna, Moshe J Inbar, Stemmer M Salomon, Anghel Rodica, Vrbanec Damir, Messinger Diethelm, Brodowicz Thomas. Hand-foot-syndrome (HFS) is a strong predictor for OS and PFS in HER2-negative metastatic breast cancer (mBC) treated with first-line capecitabine (CAP) + bevacizumab (BEV): Results of a subanalysis of the randomized phase III CECOG TURANDOT trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-10.

763PD - Updated Overall Survival (Os) from the Phase 3 Trial, Ca184-043: Ipilimumab (Ipi) Vs Placebo (Pbo) in Patients with Post-Docetaxel Metastatic Castration-Resistant Prostate Cancer (Mcrpc)

ABSTRACT Aim: Ipi is a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor immune responses. The phase 3 trial, CA184-043, evaluated OS with radiotherapy (RT) followed by Ipi or Pbo in patients (pts) with advanced mCRPC. As reported previously, the primary endpoint was not met [HR (95% CI): 0.85 (0.72-1.00); P = 0.053] (Kwon ED, et al. Lancet Oncol. 2014; in press). Here, we report updated OS data with an additional year of follow-up from the primary analysis (2-yr minimum). Methods: 799 pts were randomized to receive a single dose of RT to bone metastases followed by either Ipi (N = 399) or Pbo (N = 400). Updated OS analysis was performed on the intention-to-treat (ITT) population. Prespecified and exploratory subset analyses based on Kaplan-Meier/Cox methodology were performed using known prognostic factors for OS in mCRPC. Results: Updated OS analysis (ITT population), with survival rates up to 3 yrs, was consistent with the primary analysis (Table). Also consistent with previous reports, prespecified subgroup analyses suggest greater activity in pts with lower disease burden [e.g., Ipi vs. Pbo, pts with (HR 1.17, 0.89–1.53) or without (0.74, 0.61–0.89) visceral metastases]. The safety profile with extended follow-up was similar to that reported previously, which included immune-related AEs (irAEs) (gastrointestinal, dermatologic, endocrine, and hepatic). Most irAEs were manageable with established Ipi treatment algorithms. Ipi + RT Pbo + RT Median OS (95% CI) 11.2 mo (9.6–12.6) 10.0 mo (8.4–11.2) HR (95% CI) 0.84 (0.72–0.98) Log-rank * P = 0.03 1-Year OS rate 47% 41% 2-Year OS rate 25% 17% 3-Year OS rate ** 12% 6% * Exploratory analysis (for descriptive purposes only). ** 27 pts (17 Ipi, 10 Pbo) included in the risk set at 36 mo. Conclusions: With an additional year of follow-up, the activity observed for Ipi + RT in post-docetaxel mCRPC pts is maintained. In addition, subgroup analyses suggest pts with lower disease burden may be more likely to benefit from Ipi treatment. Long-term OS and Ipi benefit in mCRPC pts with lower disease burden (i.e., no visceral metastases) will be evaluated in the ongoing phase 3 study, CA184-095. Disclosure: K. Fizazi: Advisory board: Bristol-Myers Squibb; C.G. Drake: Sponsored research: Aduro Biotech, Bristol-Myers Squibb, Janssen; consultant: Bristol-Myers Squibb, Compugen, Dendreon, Pfizer, Roche/Genentech, NexImmune; .D. Kwon: Advisory board: NCI GU Steering Committee. Dr. Kwon and Mayo Clinic have licensed technology related to immunotherapy to Bristol-Myers Squibb, MedImmune, Amplimune, and Medarex; A.J. van den Eertwegh: Advisory board: Bristol-Myers Squibb, Astellas, Janssen-Cilag B.V., Sanofi. Honoraria for presentations about ipilimumab/prostate cancer: Bristol-Myers Squibb, Sanofi, Janssen-Cilag; H.I. Scher: Ad board:Dendreon,Endo/Orion,Genentech,Novartis,OrthoBiotech,Aragon,BMS,Celgene,Exelixis,FoundationMedicine,Janssen,JJ Spons.research: Aragon,BMS,Exelixis,Janssen,Medivation; T.M. Beer: Corporate-sponsored research: Bristol-Myers Squibb; M.B. McHenry: Employee of Bristol-Myers Squibb and owns Bristol-Myers Squibb stock; D. Liu: Employee of Bristol-Myers Squibb; owns Bristol-Myers Squibb stock; W.R. Gerritsen: Advisory board: Aglaia Biomedical Ventures, Amgen, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck, and Sanofi; speaker's honoraria: Astellas, Bristol-Myers Squibb, and Janssen; C. Logothetis: Corporate-sponsored research: Johnson & Johnson; honoraria: Johnson & Johnson.All other authors have declared no conflicts of interest.

835P - Updated Os Analysis, Multivariate and Qtwist Analysis of a Randomized Sequential Open-Label Study (Switch) to Evaluate Efficacy and Safety of Sorafenib (So) / Sunitinib (Su) Versus Su/So in the Treatment of Metastatic Renal Cell Cancer (Mrcc)

ABSTRACT Aim: Results of the sequential randomized phase III SWITCH study comparing SO/SU and SU/SO have been reported previously (ASCO GU 2014, abstract 393) showing no significant difference in the primary endpoint total PFS (T-PFS, Hazard Ratio [HR] 1.01) nor the secondary endpoints overall survival (OS, HR 1.0) and 1st-line PFS (HR 1.19). We report here the results of an updated overall survival (OS) analysis, a multivariate analysis and QTWIST analysis (all post-hoc). NCT00732914. Methods: Pts with mRCC unsuitable for cytokines without prior systemic therapy, ECOG PS 0/1, MSKCC score low or intermediate, and ≥1 measurable lesion were randomized to receive open-label SO/SU (arm A) or SU/SO (arm B) in standard dosage. The updated OS analysis was performed with data cut-off 14 JAN 2014 (database closure) using 150 events. A multivariate logistic regression analysis was performed to identify patient factors to reach a second-line therapy. QTWIST analysed the number of days without certain grade 3/4 according to CTCAE v 3.0 (HFSR; fatigue, diarrhea, nausea, rash) from randomisation to disease progression or death. Results: The updated OS analyses revealed a median OS for SO/SU of 30 months (95%CI 23.3-34.7) and for SU/SO of 27.4 mos (22.3-35.9), HR 0.985 (one-sided 95%CI Conclusions: In this updated OS analysis there was no significant difference between the two sequential treatments concerning OS. In addition, the time without specific AEs of grade 3/4 (QTWIST) was not significantly different. A multivariate analysis showed that slowly progressing pts and those who started on sorafenib were more likely to reach 2nd line on study treatment. Disclosure: C. Eichelberg: Consultancy or advisory role: Bayer, Pfizer, Novartis, GSK Honoraria: Bayer, Pfizer, Novartis, GSK Research Funding: Bayer, Pfizer, Novartis, GSK, Wilex, Immatics; M. De Santis: Consultancy and Advisory Role: Bayer, Pfizer, Novartis; M. Staehler: Consultancy or Advisory Role: Bayer; A. Floercken: Honoraria: Pfizer, Bayer, GSK; M. Michel: Consultancy and Research Funding: Bayer. All other authors have declared no conflicts of interest.

691P - Regional Subanalysis of the Phase III Mpact Trial: Nab-Paclitaxel (Nab-P) Plus Gemcitabine (Gem) Vs Gem Alone for Patients (Pts) with Metastatic Pancreatic Cancer (Pc)

ABSTRACT Aim: nab-P + Gem demonstrated superior efficacy over Gem alone in the MPACT trial of patients with metastatic PC. An updated analysis confirmed the superior OS (primary endpoint) of nab-P + Gem vs Gem alone (8.7 vs 6.6 mo; HR 0.72; P Methods: Previously untreated pts with metastatic PC were randomized 1:1—stratified by performance status, region (Australia [AU], Eastern Europe [EE], Western Europe [WE], or North America [NA]), and the presence of liver metastases—to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on d 1, 8, and 15 of each 28-day cycle or Gem 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then d 1, 8, and 15 of each 28-day cycle (cycle ≥ 2). Results: The analysis included 861 pts. An updated OS analysis (data cutoff 9 May 2013) revealed that OS was longer for nab-P + Gem vs Gem alone in each region, although the difference was not statistically significant in all cases (table). Similar trends were observed for PFS and ORR. White blood cell growth factors were used at the following rates (nab-P + Gem vs Gem): NA, 28% vs 16%; EE, 16% vs 13%; AU, 16% vs 12%; WE, 37% vs 11%. The safety profile of each treatment arm was similar across the regions. Differences in the proportion of pts receiving post-progression therapies were noted for some regions (nab-P + Gem vs Gem): NA, 40% vs 42%; EE, 20% vs 31%; AU, 39% vs 41%; WE, 45% vs 55%. The rates of use were different across regions for 5-FU/capecitabine-based therapies (NA, 26% vs 31%; EE, 17% vs 26%; AU, 26% vs 22%; WE, 42% vs 47%) and FOLFIRINOX (NA, 6% vs 7%; EE, 0 vs 2%; AU, 2% vs 2%; WE, 3% vs 8%). nab-P + Gem Gem HR (95% CI) P Value n Median OS, mo n Median OS, mo North America 268 8.8 271 6.6 0.69 (0.57-0.82) Eastern Europe 64 7.7 62 5.9 0.84 (0.58-1.23) 0.372 Australia 61 9.4 59 6.7 0.59 (0.40-0.88) 0.010 Western Europe 38 10.7 38 6.9 0.82 (0.48-1.40) 0.471 Conclusions: nab-P + Gem was associated with improved survival compared with Gem alone in pts with metastatic PC, regardless of region. Variations in postprogression therapy use were noted across regions. Disclosure: R.K. Ramanathan: a consultant/advisor to Celgene, receives honoraria and research funding from them as well; D. Goldstein: is a consultant/advisor for Celgene and receives research funding from them; A. Romano: is a Celgene employee and owns stock; D. Penenberg: is a an employee of Celgene and owns stock; D.D. Von Hoff: is a consultant/advisor for Celgene and receives honoraria from them. He also receives research funding from TG Clinical Research. All other authors have declared no conflicts of interest.

Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas.

178^ Background: In the phase III MPACT trial, nab-paclitaxel (nab-P) + gemcitabine (G) was tolerable and demonstrated superiority to G alone for all efficacy endpoints in pts with metastatic pancreatic cancer (MPC). nab-P + G vs G alone met the study’s primary endpoint by demonstrating a significant improvement in overall survival (OS; median 8.5 vs 6.7 months; HR 0.72; 95% CI, 0.617 - 0.835; P < 0.001) and the secondary endpoints of progression-free survival (PFS; median 5.5 vs 3.7 months; HR 0.69; 95% CI, 0.581 - 0.821; P < 0.001) and overall response rate (ORR; 23% vs 7%; P < 0.001). The 1-year survival rates for nab-P + G vs G alone were 35% vs 22%. The OS data reported above were based on a database cutoff of September 17, 2012, at which time 80% of pts had died. Here, we report an updated OS analysis (post hoc) from MPACT. Methods: 861 pts with MPC and a Karnofsky performance status (KPS) ≥ 70 were randomized at 151 community and academic centers 1:1 to receive nab-P 125 mg/m2 + G 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle or G alone 1000 mg/m2weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of a 28-day cycle (cycle ≥ 2). The data for this survival analysis were collected through April 1, 2013. Results: As of the updated data cutoff, 380/431 (88%) pts in the nab-P + G arm and 394/430 (92%) pts in the G alone arm had died. OS was superior for nab-P + G vs G alone in the intent-to-treat population, and the longer follow-up allowed an estimate of the 3-year survival rates (Table). The treatment effect was consistent across all pt subgroups examined. Conclusions: This updated survival analysis revealed a sustained difference in OS over time between the 2 arms. MPACT is the first phase III study in MPC to report 3-year survival rates. These data confirm and extend the previous report of the primary endpoint and support the superior efficacy of nab-P + G over G alone. These results may encourage efforts to build upon this well tolerated backbone to further extend survival. Clinical trial information: NCT00844649. [Table: see text]

1155O - Updated Overall Survival (OS) Analysis from a Phase III Study of Sunitinib vs Placebo in Patients (PTS) with Advanced, Unresectable Pancreatic Neuroendocrine Tumor (NET)

ABSTRACT Background A phase III trial demonstrated that sunitinib improved progression-free survival (PFS) and OS vs placebo in pts with pancreatic NET (Raymond et al, NEJM 2011). Upon disease progression or trial closure, 69% of pts randomized to placebo crossed over to sunitinib, potentially confounding OS analysis. We now provide both updated OS data and updated estimates of the effect of sunitinib on OS after adjusting for crossover. Methods Pts were randomized 1:1 to sunitinib 37.5 mg/d or to placebo, each with best supportive care. The primary endpoint was PFS; OS was a secondary endpoint to be evaluated every 2 y for 5 y or until 95% of pts had died. OS data were analyzed using four different methods to adjust for crossover: 1) censoring of placebo-arm data at crossover, 2) Cox model analysis with treatment as a time-dependent covariate, 3) rank-preserving structural failure time (RPSFT) analysis (which models the absence of crossover while respecting the randomization), and 4) RPSFT analysis adjusted for time of crossover. Results 171 pts were randomized (sunitinib: 86; placebo: 85). Pts randomized to placebo crossed over to sunitinib at disease progression (38/85, 45%) or at trial closure (21/85, 25%). Median duration of follow-up was 34.1 months (95% CI: 31.1 - 35.5). By April 2011 (with 2 y of follow-up post trial closure), a total of 87 deaths (51%) had occurred (sunitinib: 40; placebo: 47). OS analysis results are provided in the table. Conclusions Updated OS based on the ITT analysis continued to favor sunitinib, although this result was not statistically significant for reasons that may include treatment crossover and limited statistical power. Four different methods of adjusting for crossover demonstrated improvements in OS with sunitinib treatment. Together, these analyses demonstrate a survival advantage and further support the clinical benefit of sunitinib for pts with pancreatic NET. OS analyses Hazard ratio a 95% CI P value ITT - no adjustment for crossover 0.713 0.468 - 1.088 0.115 Adjustment for crossover: Censoring at crossover 0.428 0.239–0.767 0.004 Time-dependent Cox model 0.492 0.285–0.851 0.010 RPSFT model 0.431 0.170–1.200 b 0.115 c RPSFT model adjusted for crossover time 0.568 0.184–1.086 b 0.115 c a Sunitinib vs placebo b From 20,000 bootstrap samples c The RPSFT method does not alter the P value obtained using the ITT method Disclosure S. Faivre: Honoraria: Pfizer and Novartis. Research funding: Pfizer and Novartis. P. Niccoli: Consultant or advisory role: Novartis. Honoraria: Novartis. Research funding: Pfizer. Y. Bang: Consultant or advisory role: Pfizer. Honoraria: Pfizer. Research funding: Pfizer. J.W. Valle: Consultant or advisory role: Pfizer. Honoraria: Pfizer. X. Huang: Employment: Pfizer. Stock ownership: Pfizer. S. Patyna: Employment: Pfizer. Stock ownership: Pfizer. R. Chao: Employment: Pfizer. Stock ownership: Pfizer. E. Raymond: Consultant or advisory role: Pfizer. Honoraria: Pfizer. Research funding: Pfizer. All other authors have declared no conflicts of interest.

Phase II study combining personalized dendritic cell (DC)-based therapy, AGS-003, with sunitinib in metastatic renal cell carcinoma (mRCC).

348 Background: AGS-003 is a personalized immunotherapy that employs autologous DCs co-electroporated with the subject’s amplified tumor mRNA and synthetic CD40L RNA. Based on previous results with single agent AGS‐003 and acceptance of TKIs as the standard of care for mRCC, AGS-003 was evaluated in combination with sunitinib as initial treatment for advanced RCC. Progression free survival (PFS) results for the combination have been previously presented and show improvement compared to historical data in unfavorable risk patients treated with sunitinib alone. Methods: AGS-003-006 is an open label phase II study that included subjects with newly diagnosed, metastatic clear cell RCC. Tumor was harvested by nephrectomy or metastasectomy for mRNA. Autologous monocytes were collected by leukapheresis for the production of DCs. Subjects subsequently received sunitinib (4wks on, 2wks off) combined with AGS-003 (every 3wks X 5 doses, then every 12wks) until progression. AGS-003 doses consisted of 1 X 107 cells administered by intradermal injection to a single lymph node basin. Response was evaluated per RECIST and subjects followed for PFS and OS. Immune responses were assessed at baseline and after five AGS-003 doses using multiparametric flow cytometry. Results: 25 subjects were enrolled; 21 received treatment. The median PFS from registration for subjects receiving at least one dose of AGS-003 was 11.9 months. For subjects with 1–2 MSKCC risk factors (intermediate risk), PFS = 14.9 months and for subjects with 3–4 MSKCC risk factors (poor risk), PFS = 6.0 months. Median OS from registration has not been reached. Median OS for poor risk subjects = 7.9 months. Median OS for intermediate risk subjects has yet to be reached, but will exceed 28.3+ months. Conclusions: AGS-003 is well tolerated with no immunotherapy-related SAEs or grade 3/4 AEs reported. Interim data indicate that AGS-003 in combination with sunitinib yields a median OS higher than that reported for sunitinib alone in unfavorable risk subjects. Updated OS and immune response correlates will be presented. These results support the ongoing, randomized phase III ADAPT study.

A phase II study of cisplatin plus S-1 in patients with carcinomas of unknown primary site.

e13620 Background: Carcinomas of unknown primary site (CUP) represent a group of heterogeneous tumors and accounts for about 5% of all cancer patients (pts). The prognosis of CUP is generally poor with a median overall survival time (OS) of 4 to 6 months, and no standard chemotherapy has been established. S-1 is a new oral fluoropyrimidine and shows broad efficacy for many carcinomas. Therefore, we conducted a phase II study of novel combination chemotherapy using cisplatin (CDDP) plus S-1 in pts with CUP to evaluate the efficacy and safety. Methods: The treatment schedule included CDDP given intravenously on day 8, and S-1 given orally twice a day on days 1-21, every 5 weeks. The primary endpoint was objective response rate, and secondary endpoints included safety, OS, and 1-year survival rate. Results: A total of 46 chemotherapy naïve pts were enrolled. Median age of pts was 63 years (range 31-84). There were twenty-five male. Twenty-three pts had adenocarcinoma, fourteen had squamous cell carcinoma, three had poorly differentiated carcinoma, and three had poorly differentiated adenocarcinoma. Eighteen pts presented with nodal metastasis only, and twenty-two with nodal and multiple organ metastasis. The median number of courses was four. The overall response rate and the disease control rate were 41.3% and 80.4%, respectively. (CR/PR/SD/PD/NE; 2/17/18/7/2) The median progression-free survival time and the overall survival time were 7.5 months and 17.4 months, respectively. The most common grade 3 or worse adverse events were hematologic and non-hematologic toxicities were generally mild. Neutropenia, thrombocytopenia, and febrile neutropenia occurred in 28.3%, 13%, and 2.2%, respectively. Conclusions: This study demonstrates the activity of CDDP plus S-1 combination chemotherapy in patients with CUP. Updated response rate, safety data, and OS data will be presented.

A phase I/IIa study of icotinib hydrochloride, a novel oral EGFR-TKI, to evaluate its safety, tolerance, and preliminary efficacy in advanced NSCLC patients in China.

7574 Background: To assess the safety, tolerance and efficacy of icotinib hydrochloride (BPI-2009H), a new selective EGFR TKI in Chinese patients (pts) with advanced NSCLC after failure of prior platinum-based chemotherapy. Methods: Sixty advanced NSCLC pts with PS 0/1 were enrolled in the open-label, single-center, phase I/IIa study during Dec 2007 to Jun 2009. Oral icotinib was administered once per 8 hours (Q8H) for a 28- continuous day cycle until disease progression or intolerable toxicity. Enrollment required age ≥ 18 and ≤ 70 yrs, ECOG performance status 0-1 and adequate organ functions. Tumor response was assessed according to RECIST. Progressive free survival (PFS) was calculated and a Cox regression model was used to identify factors that potentially affect PFS and DCR. Results: Adverse events (AEs) were generally mild (grade 1 and 2) and reversible. The most frequent AEs were rash (56.9%), diarrhea (15.5%), Dose-limiting toxicity (DLT) didn't occur even in the dosage group of 750 mg per day (250 mg Tid) ,thus the maximum-tolerated dose (MTD) was not reached yet. Among the 60 pts enrolled, 58 pts were eligible for clinical response assessment. The objective tumor response rate (ORR) and disease control rate (DCR) were 24.1% and 79.3%,and median PFS was 16 weeks (95%CI 9.3-22.8). Preliminary 1-year survival rate was 60% (30/50). PFS multivariate Cox regression analysis indicated that smoking, skin AE are key influencing factors. DCR multivariate logistic regression analysis indicated rash became the only significant influencing factor. PK analysis showed steady-state concentration exposured to icotinib 125 mg Q8H was obviously higher than it exposured to icotinib 100 mg Q8H. The T1/2 was around 6 hours and Tmax was around 2 hours in all six different dose levels. Conclusions: Oral icotinib was generally well tolerated, with manageable and reversible AEs, and showed positive clinical antitumor activities in patients with advanced NSCLC. No MTD was defined yet in this study. Updated results and OS of all pts will be presented. A head to head, double blinded, multicenter phase III study of icotinib to gefitinib is currently undergoing in China. No significant financial relationships to disclose.

Survival update from a multicenter, randomized, phase III trial of vitespen versus observation as adjuvant therapy for renal cell carcinoma in patients at high risk of recurrence

3009 Background: Vitespen (formerly HSPPC-96) is a novel, autologous, heat shock protein (gp96)-peptide complex vaccine. The survival registry is investigating long-term efficacy of vitespen in renal cell carcinoma (RCC) patients at high risk for recurrence postnephrectomy. Methods: Eligible patients were enrolled and active in Antigenics’ C-100–12 phase III protocol, with a last survival status of alive at study end. Patients randomized in C-100–12 (1:1, vitespen vs. observation) had AJCC stage I (T1b), II (≥5 cm; Fuhrman grade 3/4), stage III, or stage IV (M0) RCC, ≥25% clear cells, ECOG performance score 0/1 and ≥7 g viable tumor tissue for vaccine production. The registry's primary objective is to assess OS. Registry patients are contacted every 6 (no recurrence) or 3 (upon recurrence) m, for a total of 3 y from final C-100–12 data cutoff. Results: Upon C-100–12 termination, 513 of 728 patients were eligible for follow-up. Currently, 306/513 (60%) patients are in the registry database; 207 patients are being contacted. The cohort of 306 patients is well balanced by C-100–12 randomization arm: (59.8% vitespen, 59.5% observation). Formal statistical analyses are in process. Descriptively, updated OS data show a favorable trend in the vitespen arm vs. observation in all analysis sets, especially among patients with earlier-stage disease (stage I/II high grade; n = 118) or at intermediate risk for recurrence (stage I/II high grade, III T1, T2, T3a, low grade; n = 184 ), with 13/125 (10.4%) vs. 21/115 (18.3%), and 18/184 (9.8%) vs. 33/178 (18.5%) deaths reported in the vitespen and observation arms, respectively. Conclusions: The registry provides an opportunity to confirm whether the emerging survival advantage demonstrated at the data cutoff for the C-100–12 trial improves with prolonged follow-up. Formal statistical analyses are ongoing; data available to date show continuing signals of clinical benefit associated with vitespen treatment in patients with better prognostic factors. [Table: see text]

High-Dose Chemotherapy and Autologous Stem-Cell Transplantation for Primary CNS Lymphoma: Updated Results from a Pilot and Phase II Study

Introduction: High-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) demonstrated high efficacy in the treatment of newly-diagnosed primary CNS lymphoma (PCNSL) in younger patients (pts.). A 5-year overall survival probability (OS) of 69% could be demonstrated in 30 pts within a phase-II trial on HDT and ASCT with consolidating whole-brain-irradiation (WBRT) (Illerhaus et al. JCO 2006). A subsequent pilot trial on HDT and ASCT without WBRT showed a 5-year OS of 77% (Illerhaus et al. Haematologica 2008). Here we give an update of our two different treatment regimens and future perspectives.Patients and Methods: Thirty pts. ≤65 years were treated within the phase II trial, chemotherapy (CHT) consisted of 3 cycles of high-dose methotrexate (MTX, 8 g/m2), 1 cycle of AraC (2× 3 g/m2) plus thiotepa (TT, 40 mg/m2) followed by rG-CSF and stem-cell-mobilization. Conditioning regimen included BCNU (400 mg/m2) and TT (2×5 mg/kgBW) followed by ASCT. Hyperfractionated WBRT (45 Gy, 2×1Gy/d) was administered as consolidation. In our subsequent pilot trial 13 pts. (age 38–67 years) were treated without consolidating WBRT; CHT was intensified with 4 cycles MTX 8g/m2, 2 cycles AraC (2× 3 g/m2) and TT (40 mg/m2). Dose escalated HDT included BCNU (400 mg/m2) and TT (4×5 mg/kgBW) followed by ASCT. WBRT was reserved for pts. not responding to CHT.Results: Median follow-up of the 30 pts. treated within our phase II trial was extended to 95 months (mo), the updated 5-year OS of all pts. is 66.6% and 82,3% of the subgroup of pts. who underwent HDT and ASCT (n=23), respectively. Three additional deaths occurred due to relapse (n=2) after 45 and 71 mo and due to comorbidity (n=1) after 103 mo. Five of 30 pts. developed severe leukoencephalopathy during follow-up. With a median follow-up of 35 mo in the 13 pts. treated within the pilot-phase without consolidating WBRT 3-year OS of all pts. is 77%. No further relapse or non-relapse mortality occurred in this pilot-group during. Most recent follow-up data will be presented in detail.Conclusion: Sequential systemic application of high-dose cytostatic agents followed by HDT+ASCT is highly effective as initial therapy for pts. with PCNSL. The restriction of WBRT to refractory disease shows similar OS rates and a decrease in neurotoxicity. In an ongoing multicenter phase-II trial immunotherapy with rituximab is combined with HDT and ASCT to further increase remission rates. A future randomized trial should be focused on the efficacy of consolidation with HDT supported by ASCT.

Role of ultrasound (US) and US-guided fine needle aspiration cytology (US-FNAC) prior to sentinel lymph node biopsy (SLNB) in 500 melanoma patients: Reduction of need for SNLB by high US-FNAC SN positive identification rate

8512 Background: SN status as the important prognostic factor reflects the likelihood of metastatic melanoma and the MSLT-1 trial showed similar 5ys-survival rates of ∼85% both in the SN-staged group and in the watch&wait group. SN-staging far outperforms PET-scanning, since PET is only reliable for detection of metastatic lesions > 125 mm3. SN-staging is an invasive procedure and better screening methods are required to identify early disease in SNs. This ongoing study examines the role of US to demonstrate SN metastasis thus avoiding surgical SN- staging in a proportion of melanoma pts. Methods: In this prospective study 503 consecutive melanoma pts. underwent scintigraphy and then US-exam prior to scheduled SLNB. When US was suspicious for malignant deposits in the SN, pts underwent a FNAC. So far we determined outcome in 400 AJCC staged pts (median Br 2.7 mm). Interim FU-data are updated until 10/06 (mean/median FU 26/24 (1 - 64) mo. For pts with a positive SN we considered the pre-SN US/US-FNAC pos. if either US and/or FNAC were positive. If both were only suspicious, it was considered negative. Results: US identified the SN in 52/80 (86%). Specificity was 99% (317/320) with a PPV of 95% and NPV of 92%. SN identification rate by FNAC increased from 40% in stage pT1a/b to 79% in stage pT4a/b according to the higher probability for nodal disease in higher pT stages (4% in pT1ab vs 57% in pT4ab). FNAC became more sensitive with increasing tu load: SN with deposits of 0.50–1.99 mm were verified in 13/25 (52%), whereas with deposits > 2 mm in 13/16 (83%). 80/400 SNs were histologically malignant with 15/80 (22%) submicroscopic involvement (<0.1 mm), an identical percentage as in the Rotterdam series (van Akkooi, Ann Oncol 2006). Of the node pos. pts, 50% (40/80) already found positive on US guided FNAC could have avoided undergoing a SLNB and proceeded straight to TLND. Histolog. patterns of involvement in 68 SNs were examined: 26/68 showed subcapsular, 6/68 parenchymal and 20/68 combined. Updated DFS and OS will be reported. Conclusions: US of the SN and US-guided FNAC is highly accurate. In this prospective study 50% of the SN positive pts could have been spared the need to undergo a SLNB. No significant financial relationships to disclose.