NOVITA IN TEMA DI CARCINOMA GASTRICO ROSA BERENATO

Transcription

1 NOVITA IN TEMA DI CARCINOMA GASTRICO ROSA BERENATO ONCOLOGIA MEDICA 1 FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI MILANO

2 PROGRESS AGAINST METASTATIC GC OS in first-line palliative setting Little progress against mgc: Median overall survival in most first-line large studies is 9 11 months

3 STATUS OF TARGETED AGENTS IN GC What do we have so far? Trastuzumab + cisplatin + capecitabine/5fu in HER2+ GC as first-line Ramucirumab +/- Paclitaxel in second-line Bang YJ, et al. Lancet 2010 Wilke H, et al. Lancet Oncol 2014 Fuchs C, et al. Lancet 2014

4 HOW CAN WE MOVE FORWARD? Targeting HER-2 Targeting Angiogenesis Immune Checkpoint Inhibitors

5 HOW CAN WE MOVE FORWARD? Targeting HER-2 Targeting Angiogenesis Immune Checkpoint Inhibitors

6 1 LINE CHEMO PLUS TRASTUZUMAB Incremental survival gains: trastuzumab beats cytotoxics! ToGa HER ,8 4,2 ToGA 11,1 2,7 V325 8,6 OS, months 0,6 Bang YJ, et al. Lancet 2010

7 HOW TO MOVE ON AFTER ToGA TRIAL? Dual HER2 blockade? 2 Line anti-her2 Therapy? Resistance mechanisms?

8 JACOB STUDY DESIGN Metastatic HER-2+ gastric/gej cancer (n=780) R A N D O M I Z E (1:1) Pertuzumab (840 mg) Trastuzumab (8 6 mg/kg) CDDP + 5-FU/cape Placebo Trastuzumab (8 6 mg/kg) CDDP + 5-FU/cape Treatment until disease progression or unacceptable toxicity Secondary endpoints: PFS, ORR, PRO, Safety, PK, IG Multicenter, randomized, double-blind, placebo-controlled phase III study Primary endpoint: overall surival superiority Secondary endpoint: PFS, ORR, duration-of-response, clinical benefit rate, safety, cardiac safety

9 GATSBY STUDY DESIGN Adaptative phase II/III study Primary endpoint: overall surival Secondary endpoint: PFS, ORR, duration-of-response, PRO, safety, and PK Presented By Yoon-Koo Kang at 2016 ASCO GI

10 GATSBY STUDY: OVERALL SURVIVAL Presented By Yoon-Koo Kang at 2016 ASCO GI

11 TyTAN STUDY: RESULTS OS: ITT population PSF ITT population

12 LOSS OF HER2 AS ACQUIRED RESISTANCE MECHANISM HER2 status changes according to definition of HER2 positivity (IHC + ISH) and HER2 overexpression (IHC only) HER2 positivity HER2 over-expression Concordance Loss Concordance Loss N % N % N % N % Baseline HER2 IHC score All p value* HER2 IHC in baseline (A, B) and postprogression samples (C, D) in a patient receiving trastuzumab in association to CDDP + 5FU followed by trastuzumab maintenance until disease progression Pietrantonio F, Berenato R, et al. Submitted

13 TyTAN STUDY: HER2 STATUS AND RESULTS PFS HER2 3+ OS HER2 3+

14 TRASTUZUMAB RESISTENCE: FGFR3 An FGFR3 autocrine loop sustains acquired resistance to trastuzumab in gastric cancer patients. Piro G, et al. Clin Cancer Res 2016

15 TRASTUZUMAB RESITANCE : ONGOING TRIALS Molecules Trial number Conditions Combined agents Phase Afatinib NCT Her2 positive mgc 1 L CDDP + 5FU II Afatinib NCT Her2 positive / Trastuzumab-refractory Afatinib NCT Her2 positive / Trastuzumab-refractory Paclitaxel Trastuzumab II II Poziotinib NCT Her2 positive mgc 1 L Paclitaxel + Trastuzumab I, II Dacomitinib NCT Her2 positive / Trastuzumab-refractory None II Pertuzumab NCT Her2 positive mgc 1 L CDDP + 5FU III

16 HOW CAN WE MOVE FORWARD? Targeting HER-2 Targeting Angiogenesis Immune Checkpoint Inhibitors

17 ANTI-VEGFR2 TARGETED THERAPY Study Treatment arms Line mos OS HR RAINBOW (phase III) REGARD (phase III) Chinese (phase III) INTEGRATE (phase II) Ramucirumab + paclitaxel Placebo + paclitaxel Ramucirumab Placebo Apatinib Placebo Regorafenib Placebo 2 L L L L (p 0.017) (p 0.047) 1.8 HR= 0.70 (p 0.014) 1.3 HR=0.74 p Primary endpoint PFS 58% cross-over No biomarker for antiangiogenic tx is currently available Wilke H, et al. Lancet Oncol 2014 Fuchs CS, et al. Lancet 2014 Li J, et al. J Clin Oncol 2016 Pavlakis N, et al. J Clin Oncol 2016

18 RAINFALL STUDY DESIGN Metastatic HER-2- gastric/gej cancer (n=616) R A N D O M I Z E (1:1) Ramucirumab 8mg/kg gg1,8 CDDP + 5-FU/cape Placebo CDDP + 5-FU/cape Treatment until disease progression or unacceptable toxicity Multicenter, randomized, double-blind, placebo-controlled phase III study Primary endpoint: progression-free survival superiority Secondary endpoint: OS, TTP ORR, duration-of-response, clinical benefit rate, safety, biomarkers

19 Progression-Free Survival (%) RAMUCIRUMAB IN FIRST LINE Exploratory Analysis - PFS by tumor location Esophageal HR 1.10 (0.61, 1.97) P =.746 median 5.8 vs 5.8 mos Gastric/GEJ HR RAM FOLFOX (0.29, 0.97) Placebo + FOLFOX P =.036 median 9.3 vs 7.6 mos Time (months) Overall Survival Esophageal: HR 1.29 (0.75, 2.19); 10.5 vs 11.5 m Gastric/GEJ: HR 0.94 (0.55, 1.61); 14.6 vs 12.5 m RAM + FOLFOX Placebo + FOLFOX Presented by Yoon at ASCO2014

20 ARMANI STUDY DESIGN Assessment of Ramucirumab plus paclitaxel as switch MANteInance versus continuation of first-line chemotherapy in patients with advanced HER-2 negative gastric or gastroesophageal junction cancers Metastatic gastric/gej HER-2 neg N=280 FIRST-LINE STANDARD FOLFOX or CAPOX X 3 months S c R e e n I n g If no PD RANDOM MAINTENANCE Paclitaxel Ramucirumab FOLFOX or CAPOX X 3 months Then single agent fluoropyrimidine PD TOX Multicenter, randomized, open-label, phase III no-profit study (35 centers in Italy) Primary endpoint: superiority of progression-free survival Secondary endpoint: OS, TTF, ORR, duration-of-response, safety, QoL (PRO) Exploratory endpoints: tissue biomarkers, PGX, circulating biomarkers

21 HOW CAN WE MOVE FORWARD? Targeting HER-2 Targeting Angiogenesis Immune Checkpoint Inhibitors

22 PEMBROLIZUMAB- ANTI-PD1 Keynote-012 (n= 39) Decrease in target lesions 53% Objective response 23% Muro K, et al. Lancet Oncol 2016

23 IPILIMUMAB IN GC A randomized, open-label, two-arm, phase II trial comparing the efficacy of sequential ipilimumab versus best supportive care following first-line chemotherapy in patients with unresectable, locally advanced/metastatic gastric or gastroesophagel junction adenocarcinoma Immune-Related Progression Free Survival (irpfs) Overall Survival (OS) irpfs was the primary endpoint of the study Median irpfs (95% CI), months: -Ipilimumab: BSC: 4.90 (HR = 1.44; p = 0.097) Moehler M, et al. ASCO 2016; abs 4011

24 CHECKMATE 032 STUDY DESIGN Janjigian Y, et al. ASCO 2016; abs 4010

25 CHECKMATE 032 RESULTS Janjigian Y, et al. ASCO 2016; abs 4010

26 CHECKMATE 032 Janjigian Y, et al. ASCO 2016; abs 4010

27 PD-1 BLOCKADE IN H-MSI This is the first step to validation of MSI as predictive biomarker of benefit from PD-1 blockade Le DT et al, NEJM 2015

28 NEW MOLECULAR SUBTYPES TGCA Epstein Barr virus (EBV)- positive Microsatellite instability (MSI) Genomically stable (GS) Chromosomal instability (CIN) 9% 22% 20% 50% PIK3CA mutation Hypermutation Diffuse histology Intestinal histology PD-L1/2 overexpression Gastric-CIMP CDH1, RHOA mutations TP53 mutation EBV-CIMP MLH1 silencing CLDN18 ARHGAP fusion RTK-RAS activation CDKN2A silencing Mitotic pathways Cell adhesion VEGF-A amplification Immune cell signaling Bass et al. Nature 2014

29 AFTER ASCO: EVEN MORE TRIALS FOR GC Anti-CTLA4 or Anti PD1 or Anti-PDL1 Perioperative First-Line Second-Line Third-Line + Refractory to standard Ipilimumab (BMS) Anti-CTLA4 Phase III Nivo Ipi vs CTX Phase II Ipi vs Standard of care Nivolumab (BMS) Anti-PD1 Phase III Nivo Ipi vs CTX ONO-473 Phase III Nivo vs Taxanes ONO Phase II Nivo Pembrolizumab (MSD) Anti-PD1 KEYNOTE-062 Phase III Pembro vs Pembro + Cis + 5Fu vs Cis + 5FU KEYNOTE-181 Phase III Pembro vs Standard of care KEYNOTE-061 Phase III Pembro vs Pacltaxel KEYNOTE-180 Phase II Pembro Durvalumab (AZ) Anti-PDL1 Phase II Maintenance Her2-: Durva vs Cape vs observation Her+: Tratuzumab +/- Durva NCT (Ph I/II): Durva vs Treme vs Durva + treme NCT (PhI): Durva + Ramucirumab Atezolizumab (roche) Anti-PDL1 Phase II Perioperative FOLFOX/FLOT +/- Atezo Phase I Her2-: CT + Atezo + Bev Phase I Atezo + Bev +/- CT vs Atezo + CT Avelumab (Pfizer) Anti-PDL1 JAVELIN GASTRIC 100 Phase III Maintenance after FOLFOX JAVELIN GASTRIC 300 Phase III Avelumab

30 IMAB362 ANTIBODY IN GC - FAST Chimeric IgG1 antibody Highly specific for CLDN18.2 Modes of action: Antibody-dependent cellular cytotoxicity (ADCC) Complement-dependent cytotoxicity (CDC) In combination with chemo: enhances T-cell infiltration and induces proinfiammatory cytokines Presented By Salah-Eddin Al-Batran at 2016 ASCO Annual Meeting

31 International, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without IMAB362, a first-in-class anti-cldn18.2 antibody, as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophagel junction adenocarcinoma PFS in all patients FAST STUDY: RESULTS PFS in high expressor patients* *CLDN18.2 in IHC 2+/3+ in >70% tumor cells Presented By Salah-Eddin Al-Batran at 2016 ASCO Annual Meeting

32 HOW CAN WE MOVE FORWARD? Better patients selection in clinical trials Better understanding of tumor biology and heterogeneity