ΤΟΥ ΚΑΡΚΙΝΟΥ ΤΟΥ ΠΝΕΥΜΟΝΑ. Δημήτρης Μαυρουδής Παθολόγος - Ογκολόγος Πανεπιστημιακό Νοσοκομείο Ηρακλείου

Transcription

1 ΕΛΙΞΕΙΣ ΣΤΗΝ ΑΝΟΣΟΘΕΡΑΠΕΙ ΤΟΥ ΚΑΡΚΙΝΟΥ ΤΟΥ ΠΝΕΥΜΟΝΑ Δημήτρης Μαυρουδής Παθολόγος - Ογκολόγος Πανεπιστημιακό Νοσοκομείο Ηρακλείου

2 LUNG CANCER INCIDENCE

3 LUNG CANCER MORTALITY

4 LUNG CANCER Non-small Cell Lung Cancer (NSCLC) Small Cell Lung Cancer (SCLC) 80% of cases Operable in early stages ChemoTx + radiotx in advanced stages 20% of cases Inoperable ChemoTx + radiotx

5 NSCLC survival by stage Stage TNM subset 5 year survival 0 In situ carcinoma IA T1N0M0 61 IB T2N0M0 38 IIA T1N1M0 34 IIB T2N1M0 24 T3N0M0 22 IIIA T3N1M0 9 T1N2M0 13 T2N2M0 13 T3N2M0 13 IIIB T4N0M0 T4N1M0 7 T4N2M0 T1N3M0 T2N3M0 T3N3M0 3 T4N3M0 IV Any T Any N M1 1

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7 Therapeutic Cancer Vaccines

8 Vaccines at the most advanced stage of clinical development in NSCLC

9 LUCANIX IN NSCLC Vaccine four irradiated NSCLC cell lines transfected with TGF-β2 antisense Study phase II dose variable 75 pts with stage II, III, IV NSCLC monthly or every other month up to 16 doses Results 15% partial response rate in 61 pts with stage IIIB/IV improved survival in 11 pts with cellular and humoral response J Clin Oncol. 2006;24: J.Clin Oncol. 2009;27(15S)

10 LUCANIX current status STOP trial ongoing randomized phase III 700 pts with stage IIIA, IIIB, IV lucanix vs placebo after 1 st line chemotx primary endpoint overall survival

11 CIMAvax in NSCLC Vaccine EGFR a validated target in NSCLC human recombinant EGF immunoadjuvant Study randomized phase II 80 pts with stage IIIIB, IV after 1 st line chemotx CIMAvax vs best supportive care Results 64% pts reduced serum EGF levels with vaccine trend for improved survival in vaccinated pts (n=37; p=0.09) improved survival in pts <60 years (n=22; p=0.01) J Clin Oncol. 2008;26:1452-8

12 CIMAvax current status Licensed in Cuba Approved for clinical development in the US Phase II/III trial - ongoing in Malaysia - IIIB, IV NSCLC - after 1 st line chemotx - primary endpoint overall survival

13 MAGE-A3 vaccine in NSCLC Vaccine MAGE-A3 expressed in 35-50% of NSCLC but not normal cells MAGE-A3 recombinant protein ASO2B immunoadjuvant Study randomized phase II in MAGE-A3 expressing NSCLC 182 pts with resected stage IB, II post-op MAGE-A3 vaccine vs placebo (2:1 ratio) Results DFI, DFS, OS were in favor of vaccine J.Clin Oncol. 2007;25(18S)

14 MAGE-A3 vaccine in NSCLC

15 MAGRIT Phase III Trial 2270 patients Primary endpoint DFS

16 TG4010 vaccine in NSCLC Vaccine MUC1 is an abnormally glycosylated transmembrane protein recombinant viral vector expressing MUC1 and IL-2 Study controlled phase IIB in MUC1-expressing NSCLC 148 pts with stage IIIB wet, IV allocated to parallel groups (1:1 ratio) TG4010+chemoTx vs chemotx alone primary endpoint was 6-month PFS Results 43% vs 35% in favor of TG4010+chemoTx (p=0.3) Lancet Oncol 2011;12:

17 TG4010 vaccine in NSCLC

18 TG4010 vaccine in NSCLC

19 BLP25 (Stimuvax) vaccine in NSCLC Vaccine liposome-based (enhanced uptake by APCs) extracellular domain of MUC1 MPL as immunoadjuvant Study randomized phase IIB 171 pts with stage IIIB, IV responding or stable after 1 st line chemotx BLP25+best supportive care vs best supportive care Results median OS 30 vs 13 months in favor of BLP25 (p=0.16) greatest OS benefit in stage IIIB disease J Thorac Oncol 2007;2(suppl 4):S332-3

20 BLP25 (Stimuvax) current status START trial randomized phase III 1300 pts with stage III response or stable after chemoradiation BLP+BSC vs placebo+bsc primary endpoint is overall survival

21 Dominant & Cryptic Peptides

22 Vx-001 Vaccine in NSCLC Vx-001 is composed of two peptides of nine aminoacids administered separately The native cryptic TERT 572 (RLFFYRKSV) derived from TERT and presented on the tumor cell surface in association with HLA-A2 The optimized cryptic TERT 572Y (YLFFYRKSV) variant which is strongly immunogenic Vx-001 is administered subcutaneously, emulsified with the Montanide ISA51 adjuvant Vx-001/TERT 572Y Vx-001/TERT 572 Vx-001/TERT 572 Vaccination Immuno- Monitoring Wk 0 Wk 3 Wk 6 Wk 9 Wk 12 Wk 15 Every 3 months until disease progression

23 NSCLC Patient Demographics Demographics Patients (n=38) % Median age (years) 60 Sex Male Female 4 11 Histology AD SCC LCC 4 10 Unknown 4 10 Response to prior therapy Disease Control (PR/SD) Progressive Disease (PD) Disease stage III IV Lines of previous treatments > J Clin Oncol 25: , 2007

24 Immune Response In Vaccinated NSCLC Patients p=0.013 p=0.004 Specific T cells/10 5 CD8 cells Prevac 2nd vac Postvac 7/26 17/27 12/16

25 Vx-001 Induced Partial Response in NSCLC Patient (1) Prevaccination 5 months later 7 months later Response duration: 20+ months

26 Vx-001 Induced Partial Response in NSCLC Patient (2) Prevaccination 4 months later 8 months later Response duration: 10 months

27 Overall Survival of Vaccinated NSCLC Patients Correlation With Immune Response p= months Immune responders 6.9 months Non Immune responders

28 Overall Survival of Vaccinated NSCLC Patients Correlation With Early Developed Immune Response Log rank test p=0.08 Early Immune Responders (N=19) 29.6 months Non Early Immune Responders (N=11) 7 months

29 A multicenter, randomized, double-blind, placebo-controlled Phase IIb Efficacy Study of Vx-001 to maintain disease control after first line treatment in NSCLC Primary endpoint: Survival Rate at 12 months Target population: HLA-A*0201 positive patients with TERT positive NSCLC; recurrent stage I-III or stage IV with disease control (1) after firstline treatment Protocol schedule: SCREENING HLA-A*0201+ NSCLC TERT+ recurrent stage I-III or stage IV Selected Patients PS 0-1 Disease control * R A N D O M I S A T I O N Vx-001 emulsified with the adjuvant: Two injections of the optimised peptide at week 0 & week 3 Four injections of the native peptide every 3 weeks up to week 15 and then one injection every 3 months until disease progression Stratified by OR vs SD, squamous vs non-squamous, stage IV vs recurrent I-III Placebo emulsified with the adjuvant: Same schedule as Vx-001 (1) Disease control: CR, PR or SD after 6 cycles of first-line treatment

30 Conclusions No therapeutic cancer vaccine has been approved yet for NSCLC NSCLC vaccines are showing promise Demonstration of immune responses in the majority of patients Encouraging phase II efficacy data Results of ongoing Phase III studies eagerly awaited