Presidential Symposium 3

Transcription

1 Presidential Symposium 3 Chair(s) Session Type Details A. Cervantes (Valencia, Spain)F. Ciardiello (Napoli, Italy) Presidential Symposium ESMO 2016 Congress, , 16:30-18:10, Copenhagen LBA6_PR - Full-dose neoadjuvant anthracycline + ifosfamide chemotherapy is associated with a relapse free survival (RFS) and overall survival (OS) benefit in localized high-risk adult soft tissue sarcomas (STS) of the extremities and trunk wall: Interim analysis of a prospective randomized trial A. Gronchi (Milano, Italy)S. Ferrari (Bologna, Italy)V. Quagliuolo (Rozzano, Italy)J. Martin Broto (Sevilla, Spain) A. Lopez-Pousa (Barcelona, Spain)G. Grignani (Candiolo, Italy)V. Ferraresi (Roma, Italy)J. Blay (Lyon, France) P. Rutkowski (Warsaw, Poland)F. D. Merlo (Genova, Italy)E. Marchesi (Bologna, Italy) P. Ledesma (Palma de Mallorca, Spain)A. Dei Tos (Treviso, Italy)S. Bague Rosell (Barcelona, Spain) J. Coindre (Bordeaux, France)C. Morosi (Milano, Italy)S. Stacchiotti (Milano, Italy)P. Picci (Bologna, Italy) P. Bruzzi (Genova, Italy)P. G. Casali (Milano, Italy) Background An Italian Sarcoma Group randomized trial versus no chemotherapy was indicative of an OS benefit with 5 cycles of adjuvant full-dose epirubicin + ifosfamide in localized high-risk STS (JCO 2001;19:1238). A subsequent randomized trial showed no difference between 3 vs 5 cycles of the same neo-adjuvant regimen (JCO 2012;30:850). This multicenter European randomized trial compared epirubicin 120 mg/sqm + ifosfamide 9 g/sqm versus an histology-driven regimen: gemcitabine + docetaxel in undifferentiated pleomorphic sarcoma (UPS); trabectedin in high-grade myxoid liposarcoma; high-dose prolonged-infusion ifosfamide in synovial sarcoma (SS); etoposide + ifosfamide in malignant peripheral nerve sheath tumors (MPNST); gemcitabine + dacarbazine in leiomyosarcoma (LMS). Patients had localized high-risk STS (grade = 3; size >5 cm; deep site) of extremities or trunk wall. Primary end-point was RFS. With an expected accrual of 350 randomized patients, the trial was powered to show a 1/3 reduction in the hazard risk of relapse in favor of histology-driven therapy (with 80% power at the 5% [1-sided] significance level). Yearly futility analyses were conducted. From May 2011 to May 2016, 287 patients were randomized (97 = UPS; 65 = myxoid liposarcoma; 70 = SS; 27 = MPNST; 28 = LMS). At the third futility analysis, with a median follow-up of 12.3 months, the RFS probability at 46 months was 0.62 and 0.38 (log rank p = 0.004; figure 1) and OS probability at 46 months was 0.89 and 0.64 (log rank p = 0.033; figure 2), in the standard and in the histology-driven arm, respectively. In agreement with the Independent Reviewing Committee, the study was closed in advance. The analysis is being updated and subgroup analyses will be reported. This trial provides randomized evidence that a neo-adjuvant chemotherapy with 3 full-dose courses of an anthracycline plus ifosfamide full-dose regimen can be associated with an absolute benefit averaging 20% for both RFS and OS over a different

2 chemotherapy regimen, in a population of STS patients selected by a risk of relapse averaging 60-70%. NCT ; EUDRACT Italian Sarcoma Group Eurosarc FP All authors have declared no conflicts of interest. Invited discussant LBA6 _PR A. Le Cesne LBA9_PR - Final overall survival (OS) from the AFFINITY phase 3 trial of custirsen and cabazitaxel/prednisone in men with previously treated metastatic castration-resistant prostate cancer (mcrpc) K. Fizazi (Villejuif, France)S. J. Hotte (Hamilton, Canada)F. Saad (Montreal, Canada) B. Alekseev (Moscow, Russian Federation)V. B. Matveev (Moscow, Russian Federation)A. Flechon (Lyon, France) G. Gravis (Marseille, France)F. Joly (Caen, France)K. N. Chi (Vancouver, Canada)Z. Malik (Wirral, United Kingdom) P. Stewart (Bothell, United States of America)C. Jacobs (Bothell, United States of America) T. M. Beer (Portland, United States of America) Background Treatment failure is the major barrier to extending survival in patients (pts) with advanced cancer. Clusterin (CLU) is a cytoprotective protein upregulated by chemotherapy in cancer cells. Custirsen (C) inhibits CLU production in vivo. This international phase 3 study (AFFINITY; Clinicaltrials.gov NCT ) evaluated C in combination with cabazitaxel/prednisone (Cbz/P) in pts with mcrpc. Co-primary objectives were to evaluate overall survival (OS) in pts receiving Cbz/P/C compared to pts receiving Cbz/P alone for all randomized (ITT) pts and a poor prognosis subgroup. Pts with progressive disease after docetaxel, adequate organ function, and Karnofsky score 70% were randomized to Cbz/P/C or Cbz/P. Treatment consisted of 21-day cycles of 25 mg/m2 IV Cbz on day 1 with 10 mg oral P daily with or without 640 mg IV C on days 1, 8, and 15 (plus 3 prior loading doses) until disease progression, unacceptable toxicity, or 10 cycles. Overall type I error probability (alpha) was one-sided 0.025, allocated as 0.01 and for ITT and poor prognosis final analyses, respectively, with 85% power. Hypothesized HR for ITT was 0.75 at 547 events. Hypothesized HR for poor prognosis was 0.69 assuming 299 events. 635 men were randomized: median age 68 yrs, Karnofsky score 80% in 50%. Demographics and exposure to Cbz/P were similar for both arms. In ITT population (n = 635), median OS was 14.2 mo on Cbz/P/C and 13.4 mo on Cbz/P (two-sided p = 0.529; HR 0.946, 95% CI ). 62% of pts (n = 392) met criteria for poor prognosis; OS was 11.1 mo on Cbz/P/C (n = 195) and 10.9 mo on Cbz/P (n = 197) in this subset (p =

3 0.470; HR 0.918, 95% CI ). 28.9% of pts on Cbz/P/C and 25% on Cbz/P discontinued due to progressive disease, and 21.9% and 18.9% due to adverse events (AEs). Arms were comparable in Grade 3 AEs (75.9% vs 66.3%) and SAEs (49.2% vs 42.3%). The most frequently reported Gr3 AEs were neutropenia, anemia, fatigue, asthenia, bone pain, and febrile neutropenia. In this phase 3 study, no survival benefit was seen in pts receiving Cbz/P/C compared to Cbz/P in both ITT population and poor prognosis subset. NCT OncoGenex Pharmaceuticals, Inc. OncoGenex Pharmaceuticals, Inc. K. Fizazi: The author declares participation on advisory boards and honoraria from Orion, Bayer, Sanofi, Amgen, Genentech, Janssen, Astellas, and Takeda. F. Saad: Grants from OncoGenex during the conduct of the study; grants and personal fees from Sanofi, grants and personal fees from Astellas, grants and personal fees from Janssen, grants and personal fees from Amgen outside the submitted work. A. Flechon: Honoraria: Astellas, Janssen-Cilag, Sanofi, Ipsen Travel: Astellas, Janssen, Sanofi, MSD, Pfizer, Novartis, Bayer, Astra Zeneca. F. Joly: Outside the submitted work: Grant received: Astellas Board, scientific expertise, and congress: Roche, Novartis Board, scientific expertise: Sanofi, Astra Zeneca Congress: Amgen. P. Stewart: OncoGenex: Employee, stock ownership. C. Jacobs: OncoGenex: Employee, executive leadership, stock ownership. All other authors have declared no conflicts of interest. Invited discussant LBA9_PR R. De Wit LBA30_PR - CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mrcc) of poor and intermediate risk groups: from ALLIANCE A trial T. K. Choueiri (Boston, United States of America)S. Halabi (Durham, United States of America) B. Sanford (Durham, United States of America)O. Hahn (Chicago, United States of America) M. Michaelson (Boston, United States of America)M. Walsh (Boston, United States of America) T. Olencki (Columbus, United States of America)J. Picus (St Louis, United States of America) E. J. Small (San Francisco, United States of America)S. Dakhil (Wichita, United States of America) D. George (Durham, United States of America)M. J. Morris (New York, NY, United States of America) Background Cabozantinib (Cabo) is an oral, potent inhibitor of MET, AXL and VEGFR2 that increases progression free-survival (PFS) and overall survival (OS) in mrcc patients (pts) after VEGF-targeted therapy. This randomized phase II multicenter trial compared the PFS of Cabo to Sunitinib (Sun) as front-line targeted therapy in pts with mrcc.

4 Eligible pts had untreated clear-cell mrcc, ECOG performance status 0-2, and were intermediate or poor risk, per the International mrcc Database Consortium Criteria (IMDC, Heng JCO 2009). Pts were randomized 1:1 to Cabo (60 mg QD) or Sun (50 mg QD, 4 weeks on/2 weeks off). Pts were stratified by IMDC risk groups (intermediate vs. poor risk) and bone metastasis (yes, no). With 123 events (progression or deaths), the log-rank statistic has 85% power to detect a hazard ratio of 0.67 for PFS assuming a one-sided type I error of From July 2013 to April 2015, 157 pts were randomized (79 to Cabo and 78 to Sun). Median follow up was 20.8 months (mo). 13 (16.46%) pts remained on therapy in the Cabo arm vs. 2 (2.56%) pts in the Sun arm. 80.9% of pts were IMDC intermediate risk and 36.3% had bone metastases and were equally distributed across arms. Median PFS was significantly increased at 8.2 mo (95% CI = ) for Cabo vs. 5.6 mo (95% CI = ) for Sun, with 31% reduction in rate of progression or death (adjusted HR 0.69, 95% CI 0.48 to 0.98, one-sided P = 0.012). ORR was 46% (95% CI 34-57%) for Cabo vs. 18% (95% CI 10-28%) for Sun. Median OS was 26.4 mo. for Cabo vs mo for Sun (adjusted HR 0.87, 95% CI ). All-causality grade 3 or higher adverse events were 70.5% for Cabo and for 72.2% for Sun, and included diarrhea (Cabo 10%, Sun 11%), fatigue (Cabo 6%, Sun 15%), hypertension (Cabo 28%, Sun 22%), palmar-plantar erythrodysesthesia (Cabo 8%, Sun 4%) and hematological (Cabo 2.6%, Sun 22.2%). In each arm, 16 pts ended treatment due to toxicity. Cabozantinib demonstrated a significant benefit in PFS and ORR over standard sunitinib in untreated intermediate and poor risk mrcc pts. NCT Alliance/CTEP Exelixis T.K. Choueiri: Institutional funds from Exelixis and Pfizer. Advisory board compensation from Pfizer. All other authors have declared no conflicts of interest. Invited discussant LBA30_PR B. Escudier LBA11_PR - Phase III trial of sunitinib (SU) vs placebo (PBO) as adjuvant treatment for high-risk renal cell carcinoma (RCC) after nephrectomy (S-TRAC) A. Ravaud (Bordeaux, France)R. J. Motzer (New York, United States of America) H. S. Pandha (Surrey, United Kingdom)M. Staehler (Munich, Germany)D. George (Durham, United States of America) A. J. Pantuck (Los Angeles, United States of America)A. Patel (London, United Kingdom)Y. Chang (Taipei, Taiwan) B. Escudier (Villejuif, France)F. Donskov (Aarhus C, Denmark)A. Magheli (Berlin, Germany)G. Carteni (Naples, Italy) B. Laguerre (Rennes, France)P. Tomczak (Poznań, Poland)J. Breza (Bratislava, Slovak Republic) P. Gerletti (Milan, Italy)X. Lin (San Diego, United States of America)M. Lechuga (Milan, Italy) J. Martini (San Diego, United States of America)J. Patard (Le Kremlin Bicetre, France)

5 Background This randomized, double-blind phase 3 trial examined the efficacy and safety of SU vs PBO in post-nephrectomy patients (pts) with locoregional RCC at high risk (per modified UISS criteria) of tumor recurrence. Treatment-naïve pts (n = 615) with locoregional RCC ( T3 and/or N1 2) received 50 mg/d SU or PBO in a 4-wks-on/2-wks-off schedule for 1 yr until disease recurrence, occurrence of secondary malignancy, significant toxicity, or consent withdrawal. One dose reduction to 37.5 mg/d was allowed. Baseline imaging was centrally reviewed to exclude pts with suspicion of metastases. Primary endpoint was disease-free survival (DFS) assessed by central review. Secondary endpoints included investigator-assessed DFS, overall survival (OS), safety, and pt-reported outcomes. Baseline characteristics were balanced between the SU (n = 309) and PBO (n = 306) arms. Median (m) number of cycles and relative dose intensity (SU) were 9 and 88.4%, respectively. Fewer DFS events were seen with SU (113; 36.6%) vs PBO (144; 47.1%). The trial met its primary endpoint: DFS by central review was significantly longer for SU vs PBO (HR, 0.761; P = 0.030), and these results were supported by secondary DFS analyses in all randomized pts and a higher-risk subgroup (Table 1). OS data were immature at data cutoff (mos not reached in either arm). Grade 3 adverse events (AEs) were more frequent with SU (62.1%) vs PBO (21.1%), but serious AE incidence was similar (21.9% vs 17.1%); no death occurred due to treatment toxicity. DFS analyses Central Review SU PBO HR (95% CI) SU vs. PBO P mdfs (95% CI) (yr) All randomized 6.8 (5.8 NR) 5.6 ( ) ( ) Higher-risk* 6.2 (4.9 NR) 4.0 ( ) ( ) Investigator review All randomized 6.5 ( ) 4.5 ( ) ( ) Higher-risk* 5.9 ( ) 3.9 ( ) ( ) * T3, N0 or NX, M0, Fuhrman's grade 2, ECOG PS 1 and T4 and/or N1 2 SU prolonged DFS in pts with locoregional RCC at high risk for recurrence. Given the increase in DFS and the manageable safety profile, SU represents a potential new treatment option as adjuvant therapy in RCC. NCT (Release date: July 2016) Pfizer, Inc. Pfizer, Inc. A. Ravaud: Member of advisory boards in RCC for Pfizer, Novartis, GSK, Roche, and

6 BMS, and received institutional support grants from Pfizer and Novartis, and housing and transportation for meetings and speeches by Pfizer, Novartis, and BMS. R.J. Motzer: received personal fees and other from Pfizer, Eisai, Novartis, and Exelixis, and other from Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, and Acceleron. M. Staehler: received honoraria, consulting fees, and research grants from Pfizer, Bayer, Novartis, Roche, Bristol Myers Squibb, Aveo, GSK, and Exelixis, and consulting fees from Eisai. D. George: reports honoraria & consulting: Dendreon, Sanofi, Novartis, Bayer; consulting: Medivation, Merck, Genentech; grants: Genentech/Roche, Novartis, Janssen, Astellas, Celldex, Acerta; grants & consulting: Exelixis, Pfizer, Sanofi, Innocrin Pharma, BMS. A.J. Pantuck, A. Patel: received consulting fees from Pfizer. B. Escudier: Received consulting fees from Bayer, Pfizer, and Novartis, and honoraria from Bayer, Roche, Pfizer, Genentech, Novartis, and Aveo. F. Donskov: Received research funding from Pfizer, Novartis, and GSK. A. Magheli: Received compensations for speeches from Janssen, Bayer, Astellas, and Pfizer. B. Laguerre: Received honoraria from Pfizer. P. Gerletti, X. Lin, M. Lechuga, J-F. Martini: Is an employee of and owns stock in Pfizer Inc. J-J. Patard: received consulting fees from Pfizer and GSK. All other authors have declared no conflicts of interest. Invited discussant LBA11_PR A. Bex