RINDOPEPIMUT (CDX-110) IN GLIOBLASTOMA

Transcription

1 RINDOPEPIMUT (CDX-110) IN GLIOBLASTOMA MULTIFORM GEINO 2014 Dra Estela Pineda Madrid Hospital Clínic Barcelona

2 EGFRvIII in glioblastoma multiform The most common mutation of EGFR in GBM Expressed in 30% of GBM, but not in normal tissue An early genetic alteration - gene rearrangement Only in GBMs with EGFR amplification and overexpression Radioresistance Associated with Classical subtype Wong et al. PNAS Nagane et al. Can Res Wikstrand et al. Cancer Res Frederick et al. Cancer Res Kuan et al. End Rel Cancer Del Vecchio et al. Oncogene 2013.

3 EGFRvIII in GBM A truncated receptor. Tumor specific protein. In-frame deletion of exons 2-7 constitutively active protein with unique amino acid sequence at the fusion junction. Epitope is in the extracellular domain; accessible to antibodies and highly immunogenic: encodes a constitutively active tyrosine kinase that enhances tumorigenicity and migration Loss of EGFR s extracellular domain, involved in dimerization and ligand binding. Ligand-independent and constitutive phosphorilation of the receptor. Wong et al. PNAS Wikstrand et al. Cancer Res Babu et al. Core Evidence 2012.

4 EGFRvIII Lowenstein ASCO Kindly provided by Sampson.

5 EGFRvIII: classical subtype Verhaak et al. Cancer Cell 2010.

6 EGFRvIII in GBM Poor long term survival Promote proliferation of EGFRvIII negative glioma cells via paracrine (IL-6) and via autocrine (EGFR-EGFRvIII crosstalk - STAT-3) Promote angiogenesis and tumor growth via IL-8 and NF-κB Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells Marker of glioma stem cell population (self-renewal, tumor intiating ability) Heimberger et al. Clin Can Res Pelloski et al. JCO Weller et al. IJC Inda et al. Genes Develop Fan et al. Cancer Cell Bonavia et al. Oncogene Al-Nedawi et al. Nature Cell Biol Emlet et al. Cancer Research 2014.

7 EGFRvIII in GBM: poor long term survival 0.96 vs 0.98 vs 1.07 years n= vs 2.02 vs 1.21 years n=198 n=89 p< / 38 n=89 44 / / 32 Few long-term survivors (2 years) 21% vs 5% Heimberger et al. Clin Can Res Pelloski et al. JCO EGFRvIII negative EGFRvIII positive n=472 n=177

8 EGFRvIII in GBM: poor long term survival 0.96 vs 0.98 vs 1.07 years n= vs 2.02 vs 1.21 years n=198 n=89 p< / 38 n=89 44 / / 32 Few long-term survivors (2 years) 21% vs 5% Heimberger et al. Clin Can Res Pelloski et al. JCO EGFRvIII negative EGFRvIII positive n=472 n=177

9 EGFRvIII in GBM: poor long term survival N=184 Weller et al. IJC N=85

10 EGFRvIII in GBM: poor long term survival Reardon et al. SNO 2014.

11 EGFRvIII: IL-6) Inda et al. Genes Develop promote proliferation of EGFR wt population (cytokines,

12 EGFRvIII: IL-6) Inda et al. Genes Develop promote proliferation of EGFR wt population (cytokines,

13 Cooperation between EGFR and EGFRvIII Fan et al. Cancer Cell 2013.

14 Cooperation between EGFR and EGFRvIII Fan et al. Cancer Cell 2013.

15 Zadeh etl al. Cancer Cell Fan et al. Cancer Cell 2013.

16 EGFRvIII: promote glioma angiogenesis and pathway) EGFRvIII is associated with significantly higher expression levels of IL-8. EGFRvIII regulates its expression through the transcription factors: NF-κB, AP-1 and C/EBP. GBM clinical samples (left) and GBM tumor spheres (right) determined by realtime PCR. *p<0.05 Bonavia et al. Oncogene growth (NF-κB, IL-8

17 EGFRvIII: intercellular transfer of Al-Nedawi et al. Nature Cell Biol EGFRvIII by microvesicles

18 EGFRvIII: marker of Cancer stem cell EGFRvIII is highly coexpressed with CD133 (n=28; 81% 13/16). + + EGFRvIII /CD133 or 0%). Emlet et al. Cancer Research the population with the highest degree of self-renewal and tumor-initiating ability (83% vs 33%, 28%

19 EGFRvIII: marker of Cancer stem cell EGFRvIII is highly coexpressed with CD133 (n=28; 81% 13/16). + + EGFRvIII /CD133 or 0%). Emlet et al. Cancer Research the population with the highest degree of self-renewal and tumor-initiating ability (83% vs 33%, 28%

20 Diagnosis of EGFRvIII Immunohistochemistry RT-PCR Aldape et al. J Neuropathol Exper Neurol Yoshimoto et al. Clin Cancer Res Weller et al. IJC 2014.

21 Diagnosis of EGFRvIII Weller et al. IJC 2014.

22 Rindopepimut (CDX-110) targeted therapy anti-egfrviii Lowenstein ASCO Kindly provided by Sampson.

23 Rindopepimut: Preclinical studies Effective antitumor activity in vitro and in vivo models. Increased median survival in mice with EGFRvIII expressing intracerebral tumors Humoral immune responses ADCC Antitumoral activity: ADCC, CD8+ T and NK cells Heimberger et al. Clin Cancer Res Sampson et al. PNAS Heimberger et al. Neurosurg 2002.

24 Rindopepimut: Clinical studies VICTORI phase n Population Primary end-point I 15 Newly diagnosed GBM Safety and immunogenicity Sampson 09 ACTIVATE DCs Rindopepimut x3 II 18 Samspon 10 Newly diagnosed GBM 6-month PFS EGFRvIII ACT II II 22 Sampson 11 Newly diagnosed GBM Immune response: two EGFRvIII different regimens of TMZ ACT III II 65 Lai SNO 2011 Newly diagnosed GBM PFS 5.5 months from EGFRvIII vaccination ReACT II Reardon 72 Recurrent GBM EGFRvIII 73 (BVZ naïve; BVZ refractory) 700 Newly diagnosed GBM 6-month PFS SNO 2014 ACT IV Ongoing III EGFRvIII Overall survival

25 VICTORI: design Phase I trial (Duke) n=15 n=12 Newly diagnosed GBM with gross total resection, KPS 80% and completed radiation. Primary end-point : safety and immunogenicity DCs 500 ug Rindopepimut x3 Sampson et al. Mol Cancer Ther Lowenstein ASCO 2014.

26 VICTORI: results Minimal toxicity grade 2. No dose-limiting toxicity. Immune response DTH PEPvIII DTH KLH Proliferation (PEPvIII) Proliferation (KLH) 56% (5/9) 100% (9/9) 83% (10/12) 92% (11/12) Most patients developed EGFRvIII-specific immune responses. EGFRvIII mutation: a safe and immunogenic tumor-specific target for immunotherapy Sampson et al. Mol Cancer Ther 2009 TTP OS OS 24m 10.2 m 22.8 m 50%

27 ACTIVATE: design Phase II multicenter study (MDACC, Duke) n=18 ( ) Newly diagnosed GBM EGFRvIII + (IHC) with gross total resection and KPS 80%, completed chemoradiation without progression. PEPvIII-KLH vaccine until PD. The primary end-point: 6-month PFS (matched cohort) Sampson et al. JCO 2010.

28 ACTIVATE: PFS and OS EGFRvIII Mathced vaccine control group (n=18) (n=17) PFS 6m 94 % 59 % PFS % 24 % m PFS 24 HR % 6% p=0.041 m PFS 14.2 m 6.3 m OS 26 m 15 m OS12 m 94% 71 % OS 24 m 53 % 6% Sampson et al. JCO (1-4.8) HR 5.1 ( ) p=0.0013

29 ACTIVATE: immune response Humoral response 43% (6/14) DTH (delayed-type hypersensitivity) response 18% (3/17) Humoral and cellular immune responses associated with OS IHC analysis 11 recurrent tumors Loss of EGFRvIII expression in 82% (9/11) EGFRvIII Ab (n=6) NO EGFRvIII Ab (n=8) Adverse events: Minimal toxicity OS OS 47.7 m 22.8 m DTH + (n=3) DTH (n=14) 50 m 23.1 m p=0.025 Injection site reactions gr2 p=0.03 One severe allergic reaction One leukoencephalopathy gr1 Sampson et al. JCO 2010.

30 ACT II: trial design Phase II multicenter trial (MDACC, Duke) n=22 ( ) Newly diagnosed GBM EGFRvIII + (IHC) with gross total resection and KPS 80% completed chemoradiation without progression Standard-dose TMZ (n=12) + PEPvIII-KLH vaccine. Intensified dose TMZ (n=10) + PEPvIII-KLH vaccine. The primary endpoint: to determine differences in immune response between two different TMZ regimens used in conjunction with an experimental PEPvIIIKLH vaccine Sampson et al. Neuro-Oncology 2011.

31 ACT II: immune response EGFRvIII-specific immune responses in all patients. DI TMZ regimen produced humoral (p=0.037) and delayed-type hypersensitivity responses (p=0.036) of greater magnitude. IHC analysis from 12 of 17 recurrent tumors. Loss of EGFRvIII expression in 91.6% (11/12) Sampson et al. Neuro-Oncology 2011.

32 ACT II: immune response Sampson et al. Neuro-Oncology 2011.

33 ACT II: adverse events

34 ACT II: PFS and OS Overall n=22 Historical controls n=17 Overall n=22 Historical controls n=17 PFS 15.2 m 6.3 m PFS 1y 63.6 % 23.5 % HR 0.35 (0.14- OS 23.6 m 15 m OS 1y 100 % 70.6 % OS 2y 44.4 % 5.9 % 0.87) PFS 2y 20.1 % Sampson et al. Neuro-Oncology % p=0.024 MGMT methylation 41% (7/17) HR 0.23 ( ) p=0.019

35 ACT III: design N=65 multicenter 31 centers Newly diagnosed GBM EGFRvIII positive Completed CRT and KPS 80% Lai et al. SNO 2011.

36 ACT III: long-term safety Lai et al. SNO 2011.

37 Lai et al. SNO 2011.

38 Lai et al. SNO 2011.

39 ACT III: PFS Lai et al. SNO 2011.

40 ACT III: OS Lai et al. SNO 2011.

41 Lai et al. SNO 2011.

42 Rindopepimut: long-term follow-up from phase II trials in newly diagnosed GBM Matched cohort 3 year rate Reardon et al. SNO 2013 RTOG % GGN 17%

43 Lowenstein ASCO Kindly provided by Sampson.

44 ReACT: design Reardon et al. SNO 2014.

45 ReACT: patient characteristics Reardon et al. SNO 2014.

46 ReACT: safety Reardon et al. SNO 2014.

47 Reardon et al. SNO 2014.

48 Reardon et al. SNO 2014.

49 ReACT: PFS and OS BVZ naïve recurrent GBM

50 Reardon et al. SNO 2014.

51 Reardon et all. SNO 2014.

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53 Reardon et al. SNO 2014.

54 Bevacizumab in recent phase II randomized trials PFS-6m OS AVAREG BVZ 26% 7.3 m BELOB BVZ 16% 8m 11% 8.8 m 27% 12 m ReACT Rindop-BVZ BVZ

55 Razis et al. SNO patients, 23 sites, 6 countries 24 newly diagnosed GBM (88% TMZ) 40 recurrent GBM (73% BVZ)

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57 Rindopepimut compassionate use: immunity and safety Razis et al. SNO 2014.

58 Rindopepimut compassionate use: OS and PFS Razis et al. SNO 2014.

59 ACT IV Phase III trial international, randomized, double-blind. Newly diagnosed GBM EGFRvIII+ resected. N=440. Chemoradiation completed. Concomitant with temozolamide. ITT population - gross total resection n=374 (<2 cm2 residual disease) Incomplete resection: safety and exploratory efficacy analyses Stratification factors: * PS 2 MGMT * DXM 2 mg RPA * 6-12 cycles TMZ geographic region

60 ACT IV: study objectives Primary end-point: Overall survival (patients with gross total resection) Secondary end-points: PFS Safety and tolerability Health related quality of life and symptom severity Objective response rate RANO Correlative studies: EGFRvIII specific immune response Elimination of EGFRvIII expression End enrollment (n=700): november 2014

61 Take home messages EGFRvIII in 25-30% GBM: poor long term survival. Enhanced tumorigenicity (proliferation and angiogenesis). Marker of stem cell. Specific oncogenic protein. Rindopepimut (CDX-110) PEP3-KLH: oncospecific immune treatment Minimal toxicity, very well tolerance Humoral immune response >80% Immune response: predictive biomarker Newly diagnosed GBM (phase I, 3 phases II) concomitant with TMZ: Promising results on PFS (12 months) and OS (24 months) OS 3y (30%) Bias: selected population of better prognosis Probably increase of long term survivors Phase III ACT IV: pending results Phase II in recurrent GBM concomitant with BVZ Promising results on PFS 6m (27%) and OS (12 m) Phase III?

62 Thank you for your attention