Neoadjuvant approaches to the establishment of adjuvant therapeutic efficacy with IFN, anti-ctla4 and

Transcription

1 Neoadjuvant approaches to the establishment of adjuvant therapeutic efficacy with IFN, anti-ctla4 and combinations Ahmad A. Tarhini, MD, PhD Assistant Professor of Medicine, Clinical i l and Translational l Science University of Pittsburgh School of Medicine University of Pittsburgh Cancer Institute I have the following relevant financial relationships to disclose: BMS (research funding) ( g) Merck (research funding) Prometheus (research funding, consultant) Genentech (consultant) 1

2 Outline Briefly Current State of Melanoma Adjuvant Therapy HDI E1697 EORTC18991 EORTC 18071, US Intergroup E1609 Neoadjuvant Approaches Establishing Future Adjuvant Therapy HDI ; UPCI Ipilimumab; UPCI Combinations HDI + Ipilimumab UPCI E3611 Other SLN; UPCI year Survival Rates for Melanoma by Stage 1.0 Survival Function Stage I (n=18,370) Stage II (n=9,269) Stage III (n=3,307) Stage IV (n=7,972) Survival Time in Years Balch, C. M. et al. MELANOMA STAGING AND PROGNOSIS 2009 The Best Opportunity to Cure Melanoma Presently Lies in the Adjuvant Setting 2

3 Cooperative group/pi Eligibility n Treatment agent/dosage/duration NCCTG Creagan T3-4, N1 262 ECOG 1684 Kirkwood Impact on DFS IFNα2a 20 MU/m2/D IM TIW x3 mos + - T4, N1 287 IFNα2b 20 MU/m2/D IVx1 mo 10 MU/m2 SC TIW for 11 mos OS + + at yrs E1690 Intergroup Kirkwood T4, N1 642 IFNα2b 20 MU/m2/D IVx1 mo 10 MU/m2 SC TIWx11 mos vs 3 MU/D SC TIWx2 yrs + - at yrs WHO #16 Cascinelli EORTC Kleeberg E1694 Intergroup Kirkwood N IFNα2a 3 MU/D SC TIWx3 yrs - - T3-4, N1 830 IFNα2b 1 MU/D SC QODx1 yr vs IFNg 0.2 mg/d SC QODx1yr - - T4, N1 880 IFNα2b 20 MU/m2/D IVx1 mo 10 MU/m2 SC TIWx11 mos vs GMK vaccine x 96 wks + + at yrs ECOG 2696 Kirkwood T4, N1, M1 107 GMK + IFN or -->IFN vs GMK + - at yrs UKCCR Aim-High T4, N1 674 IFNα2a 3 MU/D SC QODx2 yrs Hancock - - EORTC Eggermont T4, N IFNα2b 10MU/d then10 MU TIW x1 or 5 MU TIW x 2 years EORTC Eggermont French Grob Austrian Pehamberger TxN T2-T4 ( 1.5mm), N0 489 T2-T4 ( 1.5mm), N0 311 Peg-IFN alfa-2b SC 6 µg/kg/week (8 weeks) then 3 µg/kg/week (5 years) vs Observation + - IFNα2a 3 MU SC TIW x 18 mo vs Obs + - IFNα2a 3 MU SC QD x 3 wks then TIW x 1 yr vs Obs + - E1684, E1690, and E1694: Durable and Significant Impact upon Relapse-free * and Overall Survival** Proportion Alive and Relapse Free P E1684: IFN vs Observation** HR=1.38 P 2 =0.02 Proportion Alive and Relapse Free E1690: IFN vs Observation* HR=1.24 P 2 = Time (Years) Time Interval (Years) Observ. 89/140 12/51 3/39 0/35 1/32 1/29 0/15 0/3 IFN 73/146 14/68 3/53 1/50 2/48 2/44 0/31 0/10 (No. events/no. at risk) ortion Alive and Relapse Free Prop R E1694: IFN vs GMK** Time (Years) Time Interval (Years) Observ. 105/212 16/94 5/72 2/44 0/13 IFN 98/215 15/108 5/85 2/53 0/20 (No. events/no. at risk) HR=1.33 P 2 = Time (Years) Time Interval (Years) IFN 118/436 28/257 8/123 3/47 0/3 GMK 153/439 40/240 6/113 3/40 0/0 (No. events/no. at risk) Kirkwood. Clin Cancer Res. 2004;10:1670; Ives et al.,

4 3 Meta-analyses of all trials of IFN also confirm RFS, OS impact Meta-analysis #RCT RFS OS Comment Ives, JCO Wheatley, ASCO Mocellin, JNCI /+ Did not include E OR=0.87, 95% CI= , p= HR = 0.82, 95% CI = ; P < OR=0.9, 95% CI= , p= HR = 0.89, 95% CI= ; P =.002 benefit with IFN dose OS translates into absolute benefit of 3% (CI 1%-5%) at 5 yrs 18% risk reduction in DFS 11% risk reduction in OS Goals of Therapy: Reduce Toxicity Is one year of IFN necessary? Dose, route, and duration of IFN therapy All trials of IFN with durable RFS and OS impact utilized IV induction at 20MU/m 2 (C max >10,000u/ml) Is one month of IV IFN 2b necessary and sufficient? i Intergroup E1697 Neoadjuvant Trial UPCI

5 E A randomized study of four weeks of high-dose interferon alpha-2b in stage T3-T4 or N1 (microscopic) melanoma Hypothesis: Induction IV IFN is necessary and sufficient to achieve durable adjuvant benefit in intermediate-risk melanoma patients STRATIFICATION Arm A: R Pathologic Lymph Node Status Known Unkown Lymph Node Staging Procedure Sentinel Lymph Node Procedure Elective Lymph Node Dissection No Lymphadenectomy Breslow Depth mm mm > 4 mm Ulceration of Primary Lesion Yes No Disease Stage Lymph Node Positive Lymph Node Negative A N D O M I Z E Observation Arm B: 4 week high-dose IFN alfa-2b (Intron A) 20 MU/m 2 /d qd IV for 5 consecutive days out of 7 (M-F) every week times 4 weeks Pittsburgh Skin Cancer SPORE Project 1: Analysis of genetic and proteomic predictors of IFN benefit E1697: 3 rd Interim Analysis, October, 2010 Total Accrual: 1150 cases (1420 planned) Open December 22, 1998 and October 26, 2010 Primary endpoint RFS (time to recurrence or death w/o recurrence) Cure rate model for RFS: Improvement in cure rate from 65% to 72.5% and median RFS 1.5 to yrs for not cured Secondary endpoint OS Cure rate model for OS: Improvement in cure rate from 75% to 82.5% and median OS 2.5 to yrs for not cured Early stopping boundaries for efficacy have not been crossed at the third interim analysis Futility analysis indicated low conditional power 5

6 E1697: 3 rd Interim Analysis RFS (N=838) Median RFS HDI 6.8 yrs, 95% CI (5.1, 9.0) (n=425) Observati 7.3 yrs, 95%CI (5.3, 9.8) on (n=413) Efficacy p-value from stratified analysis log-rank test = no significant difference Futility analysis HR=1.01, 95% RCI (0.71, 1.43) Conditional Power: 3% E1697: 3 rd Interim Analysis OS (N=1091) HDI (n=556) Observati on (n=535) Efficacy analysis 5-yr OS rate 0.82, 95% CI (0.78, 0.86) 0.85, 95%CI (0.81, 0.89) p-value from stratified log-rank test = no significant difference Futility analysis HR=1.19, 95% RCI (0.78, 1.83) Conditional Power: <1% 6

7 E1697 Current Assessment No benefit from one month of IFN in intermediate-risk melanoma Patients with IIB/IIIA disease should consider one year of standard therapy (E1684, E1690, E1694) Analysis of mortality & salvage therapy?crossover to IFN from observation (as in E1690) Anti-CTLA4 Abs, BRAF kinase inhibitors Biomarkers predictive of therapeutic benefit more crucial than ever EORTC 18991: PEGYLATED IFN-a2b vs. OBSERVATION IN RESECTED STAGE III (TxN1-2M0) MELANOMA Patients (n=1,256): Resected TxN1-2M0 melanoma, within 7 weeks of lymphadenectomy Randomization Stratified by: Microscopic (N1) vs. palpable (N2) 1 vs. 2-4 vs. 5+ nodes Breslow Ulceration Gender and site Observation Peg-IFN alfa-2b Induction (8 weeks) 6 µg/kg/week Maintenance (5 years or distant metastasis) 3 µg/kg/week Dose reduction to 3, 2, 1 to maintain performance status Primary Endpoints: Relapse-free survival (RFS) Distant metastasis-free survival (DMFS) Eggermont AM, et al. Lancet 2008; 372:

8 RFS benefit of adjuvant peginterferon maintenance sustained at 7.6 years follow-up No change in DMFS or OS observed from 2007 to 2011 EORTC Update in ASCO 2011: Outcome at 7.6 yrs F-up RFS benefit still significant at 7.6 years but has eroded No change in DMFS or OS Outcome (ITT) HR (95% CI) P Value HR (95% CI)* P Value RFS 0.82 ( ) ( ).05 DMFS 0.88 ( ) ( ).33 OS 0.98 ( ) ( ).57 EORTC 18991: Outcome in N1 Population in 2011 Stage III N1 disease showed significant benefit in RFS and DMFS in 2007 Improvements still seen in 2011, but no longer statistically significant Outcome in N1 Population HR P Value HR (99% CI)* P Value RFS DMFS OS ( ) 0.86 ( ) 0.86 ( )

9 EORTC 18991: Outcome in N2 Population in 2011 Patients with stage III N2 showed no benefit in any endpoint Outcome in 2007 Evaluation 2011 Evaluation N2 HR P Value HR (99% CI)* P Value RFS ( ) DMFS ( ) OS ( ) EORTC 18991: Primary Tumor Ulceration Primary tumor ulceration found associated with improved OS: significant in 2007 but not in 2011 OS Outcome in 2011 Based on Primary Tumor Ulceration HR (99% CI) P Value Ulcerated 0.81 ( ) Not ulcerated 1.05 ( )

10 EORTC 18991: Stage III N1, Ulcerated Disease Stage III N1 and ulcerated primary tumors showed significant benefit for all endpoints, including OS Median OS pegifn vs. observation: > 9 vs. 3.7 years Outcome in 2011 in Patients With Stage III N1, Ulcerated Primary HR (99% CI) RFS 0.72 ( ) DMFS 0.65 ( ) 1 04) OS 0.59 ( ) P Value EORTC plans to compare pegifn with observation in patients with ulcerated primary tumors > 1 mm Adverse Event Summary and Treatment Compliance Grade 3/4 Adverse Event, % Peginterferon (n = 627) Observation (n = 629) Any Events occurring in > 5% of patients (Grade 3/4) Fatigue 14/1 1/0 Liver toxicity 10/< 1 1/< 1 Depression 6/< 1 < 1/< 1 Treatment compliance Median induction duration: 8 weeks Median maintenance duration: 14.9 months ~ similar to HDI 31% pts discontinued treatment owing to AEs & 23% remained on treatment in Yrs 4-5 this proportion of discontinuation is >10% reported in E

11 Adjuvant Modalities for Melanoma Evaluated to Date IFN alfa-2b, 2a; Peg IFN alfa-2b Only HDI has confirmed significant durable OS & RFS benefit (ITT) at >20 years (E1684/90/94) IL-2 Vaccines MAGE A3 GM-CSF Anti-CTLA4 blocking mabs Never tested, too toxic Canvaxin detrimental in Ph III trial Pending Neither GMCSF nor peptide vaccination achieved objectives of significant improvement in OS or DFS - Suggests effects of GMCSF on DFS and OS are largest among Stage IV subjects Pending EORTC US Intergroup E1609 Intergroup E1609 Adjuvant Phase III trial: Ipilimumab vs. HDI: Activated May 25 th Ipilimumab 10 mg/kg g S U R G E R Y Patients with resectable IIIB, IIIC M1a, M1b N=1000 HDI Endpoints OS RFS QOL Immunological correlates of RFS, OS serial blood serum and lymphocytes baseline tissue blocks 11

12 Intergroup E1609 Adjuvant Phase III trial: Ipilimumab vs. HDI Ipilimumab 10 mg/kg g S U R G E R Y Patients with resectable IIIB, IIIC M1a, M1b N=1500 Ipilimumab 3 mg/kg HDI Endpoints OS RFS QOL Immunological correlates of RFS, OS serial blood serum and lymphocytes baseline tissue blocks Neoadjuvant Evidence for Role of IV Induction HDI in Stage IIIB Melanoma Schema: UPCI Stage IIIB, IIIC melanoma (Tx, N2b, or N3, M0) IFN- 2b induction therapy (20 MU/m 2 /d IV 5d/wk, 4 wks) IFN maintenance therapy (10 MU/m 2 /d tiw, 48 wks) Excisional biopsy (sample 1) Radical regional lymphadenectomy (sample 2) Moschos et al., JCO

13 Results 20 patients enrolled median age 59 59, range 40-78; 40 78; 13 males 11 with bulky recurrent nodal disease 15 completed 4 weeks of HDI Objective Response at 4 weeks: Clinical: 1 complete, 10 partial Pathologic: 3 complete, 2 with only microscopic residual disease CD3 et et pt CD11c et et Before IFN pt After IFN 13

14 HDI Down-Regulates pstat3 Tyr705 And STAT3 Expression in Tumor Cells Post treatment IHC H&E Pretreatment Blue = pstat3tyr705 Red = STAT3 Wang et al., Clin Cancer Res 2007 HDI Down-Regulates pstat3 Tyr705 and STAT3 in Regional Lymph Node Metastases of Melanoma 0-20 pstat3 STAT3 P =.002 P = Mean ((post-pre)/pre % n=7 0 pre post pstat3 pre post STAT3 Wang et al., Clin Cancer Res

15 Conclusions of Neoadjuvant High- Dose IFN-α2b Trial UPCI Clinical responses seen at day 29 Molecular impact upon STAT3 pstat3/stat3, IFNAR2 pstat1, pstat1/3 ratio, and TAP2 Immunologic impact upon CD3 T cell, DC response to tumor CD3 T cell and CD11c dendritic cell populations in tumor Neoadjuvant Ipilimumab in N1b,2b, N2c, N3 Melanoma UPCI Tx, N2b, N2c or N3, M0 Ipilimumab 10 mg/kg every 21 days x 2 Ipilimumab 10 mg/kg every 21 days x 2 Enrollment Excisional biopsy (sample 1) Radical regional lymphadenectomy (sample 2) Tarhini et al., ASCO

16 Patient Demographics and Baseline Disease Characteristics (N=27 patients) Variable No. of Patients (%) Age, years 52 (40-87) Median (Range) Cutaneous/unknown primary 23 Mucosal 4 Gender Female Male Performance Status Prior HDI 10 AJCC stage IIIB 5 IIIC Tarhini et al., ASCO 2011 Treatment Details (N=27) Cycle No. pts treated No. pts off PD as Reason Toxicity as treatment for D/C Reason for D/C Other Reason for D/C 1 27* ** NA NA NA NA *2 patients recently received cycle 1 and are planned to proceed with cycle 2 **3 patients recently received cycle 2 and are planned to proceed with cycle 3 Tarhini et al., ASCO

17 Adverse events (worst grade) considered possibly, probably or definitely related to Ipilimumab (N=25) Type All Grades Grade 1 Grade 2 Grade 3 No. Patients % No. Pts. % No. Pts. % No. Pts. % Immune mediated Adrenal Insufficiency Diarrhea/Colitis Hepatitis AST/ALT/AP/GGT Hyper/pothyroidism Hypophysitis (low ACTH) Skin rash Constitutional Fatigue Fever Pruritus Gastrointestinal Nausea Vomiting Amylase/Lipase Neuro-Psychiatric 0 0 Depression/Anxiety Other Infusion reaction Tarhini et al., ASCO 2011 PFS and OS (N=22; for 5 patients surgery is pending) Median F-up 8.0 (range ) months Prob. of 6 & 12 month PFS: 0.89, 95% CI (0.63, 0.97) & 0.57, 95% CI (0.26, 0.79) Prob. of 6 & 12 month OS: 0.94, 95% CI (0.65, 0.99) & 0.94, 95% CI (0.65, 0.99) Tarhini et al., ASCO

18 Circulating T-reg and MDSC (N=17 pts) (Change: baseline to 6 weeks) Significant increase in circulating T-reg cells CD4+CD25hi+CD39+; p= CD4+CD25hi+ Foxp3+; p=0.009 In parallel, significant decrease in circulating MDSC (1) monocytic: lin1neg/hla-drneg/ CD33+/CD11b+; p=0.038 (2) other monocytic: HLA-DR+ / low/cd14+; p< (3) lymphoid: Lin1neg/HLA-DR-/CD33+/CD11b+; p=0.067 Tarhini et al., ASCO 2011 Change in Circulating MDSC and T-reg (N=17 pts) Tarhini et al., ASCO

19 Forest Plot of Type I CD4 and CD8 Ag-specific T Cell Immunity Tarhini et al., ASCO 2011 Conclusion Preliminary results neoadjuvant ipilimumab is clinically promising and immunologically modulates host immune responses Apparent in CD4+CD25hi+ FOXP3+ and CD4+CD25hi+ CD39+ T-reg but associated with in overall CD4+ T-cells suggesting that direct inhibition by ipilimumab of CTLA4 suppressive effects on T effector cells leading to their expansion and prolonged activation is likely l more important t than it s effect on T-reg Ipilimumab leads to sig in all MDSC at week 6 This may have a role in the reduction of immune suppression observed with ipilimumab therapy Evidence of spontaneous in vivo cross presentation resulting in type I CD4 and CD8 antigen specific T cell immunity Ongoing studies plan to fully characterize the cytokine profile in saved peptide pool stimulated supernatant TIL studies in 4 patients show evidence of antigen-specific T-cell responses, T cell activation (CD69), induction/potentiation of T cell memory (CD45RO+), enhanced T cell cytotoxicity Ongoing Tarhini et al., ASCO

20 IFN augmentation of cell numbers and effector polarization of host response to tumor IFNs inhibit tumor proliferation, angiogenesis, and STAT3 Rationale for IFN/Treme IFN- Th0 DC1 IL-12 IL-18 IFN-γ Cell-mediated antitumor immunity Th1 IL-10 TGF-β MDSC,Tr/Th3 IL-4 IL-5 IL-10 DC2 Th2 Humoral antitumor immunity idc Tarhini et.al. ASCO 2010 IFN augmentation of cell numbers and effector polarization of host response to tumor IFNs inhibit tumor proliferation, angiogenesis, and STAT3 Rationale for IFN/Treme IFN- Th0 DC1 IL-12 IL-18 IFN-γ Cell-mediated antitumor immunity Th1 IL-10 TGF-β Anti- CTLA4 MDSC,Tr/Th3 IL-4 IL-5 IL-10 DC2 Th2 Humoral antitumor immunity idc Tarhini et.al. ASCO

21 UPCI IFN-Treme: Study Schema Inoperable stage III/IV melanoma Prior therapy allowed Treated brain metastasis N = 37 Tremelimumab (15 mg/kg) IV on day -3 (Friday) Q90D + IFN-α2b 20 MU/m2 IV on days 0,1,2,3,4 a week (M F) for 4 weeks IFN-α2b 10 MU/m2 SC 3 days a week (MWF) for 8 weeks Up to 1 year (4 courses) Tarhini et.al. ASCO 2010 Summary of Clinical Efficacy with IFN/Treme IFN/Treme Study Size (number of patients) 37* Rate (%) 9/35 (26%) Response Durability 6, 6, 12+, 14+, 18+, 20, 28+, 30, 37+ (mo) SD Rate (%) 14/35 (40%) Durability (mo) DCR (%) 23/35 (66%) PFS (median, mo) 6.4 OS (median, mo) 21 *Two patients were non-evaluable for response (no response data available) *One unconfirmed responder PD surgery NED (16+) *One PD TMZ/Decitabine x2wks PD NED 21

22 PFS IFN-Treme Proportion Surviving Median 6.4 months (95% CI= ) Months Since Start of Therapy OS IFN-Treme Proportion Surviving Median 21mon (95% CI =9.5, Inf) Months Since Start of Therapy Gender PS Visceral Disease IFN-Treme - One Year Survival Rate Observed vs Predicted (Korn-Kirkwood Model) Total As of 2/16/ Year Observed Rate Pred. Rate* Male 0 N % 35% Male 0 Y % 22% Male 1 N % 17% Male 1 Y % 10% Female 0 N % Female 0 Y % 33% Female 1 N % 27% Female 1 Y % 16% One Year Survival Rate Predicted by Korn Model = 21% * Predicted rates assume the study was open to patients with brain metastasis 37 Patients Analyzed - 23 Alive at one year - 14 Dead at one year Observed 1 Year Survival Rate = 62% 95% Confidence Interval = 46% - 78% One tailed hypothesis test: observed rate better than predicted (21%) -> p <

23 IFN-Treme: Change in T-reg and MDSC at Baseline and During Treatment... Randomized Neoadjuvant IFN-Ipilimumab Trial in N1b,2b, N2c, N3 Melanoma UPCI (N=30) Tx, N2b, N2c or N3, M0 IFN-Ipilimumab (3 vs. 10 mg/kg) Induction IFN-Ipilimumab (3 vs. 10 mg/kg) Maintenance Excisional biopsy (sample 1) Radical regional lymphadenectomy (sample 2) 23

24 E3611 Phase II trial: Ipilimumab + HDI versus Ipilimumab (N=220) Ipilimumab 10 mg/kg g R A N D O M I Z E unresectable III/IV Melanoma Up to 1 prior regimen HDI + Ipilimumab 10 mg/kg Endpoints OS (1-yr OS 45% 57%; median OS yr) RFS Immunological correlates of RFS, OS serial blood serum and lymphocytes baseline tissue blocks University of Pittsburgh Cancer Institute Melanoma program-sln protocols A UPCI Sentinel Node and Non-Sentinel Lymph Nodes Procurement for Molecular Profiling Analysis B PCI Pilot Analysis of the Effects of IFN α2b upon the Molecular Profile of Regional Lymph Nodes in Melanoma Patients with and without Tumor-Involved Sentinel Lymph Nodes 1) Two protocols running concurrently 2) Protocols do not compete with each other for accrual (on the basis of Breslow depth) 3) Protocol A : patients will be enrolled in order to acquire the requisite 25 SLN positive patients 4) Protocol B/PILOT study: 60 patients total will be accrued (12 per treatment group) 24

25 UPCI SLN Protocol B - Immune Intervention Molecular Profiling Analysis of the Effect of IFN a2b on the regional nodal status of SLNs Patients with primary < 2 mm in Breslow depth, recently biopsied (within 6 weeks), and not widely resected Randomize treatment groups 12 pts a 12 pts 12 pts 12 pts 12 pts b c d e HDI INDUCTION Regional HDI MAINTANANCE PEG INDUCTION Regional PEG MAINTANANCE No intervention IFNa2b IV at 20 mu/m2 5d/week x2 Day -14 to day -9 Day -7 to day -2 IFNa2b sc peri-lesionally (PL) at 10 miu/m2 QOD/week x2 PEG IFNa2b sc at 6ug/kg at site that is not regional Day -14 Day -7 PEG-IFNa2b sc PL at 3ug/kg Day -14 Day -7 Control SLN collection- targeted molecular and IHC analyses (Treg, DC, STAT, Angiogenesis Markers) Day 0 = day of SLN surgery Perilesionally (PL) = injection as close to the primary site as possible, in the region that is presumed to be drained by the node to be dissected UPCI SLN Protocol B-Immune Intervention Pilot Analysis of the Effects of IFN α2b upon the Molecular Profile of Regional Lymph Nodes in Melanoma Patients with and without Tumor-Involved Sentinel Lymph Nodes Primary objective: Gene-profiling analysis of regional node tissue, to molecularly characterize the effect of IFN α2b and PEG-IFNα2b on the SLN Endpoint: mrna expression by gene array The tissue collected for this protocol will be analyzed by various The tissue collected for this protocol will be analyzed by various techniques for transcript profiling (gene/microrna arrays) 25

26 Acknowledgments John M Kirkwood Univ. of Pitt. Melanoma Center Team Especially our patients and family members 26