DISCLOSURE SLIDE. ARGOS: research funding, scientific advisory board

Transcription

1 INTERIM ANALYSIS OF THE PHASE 3 ADAPT TRIAL EVALUATING ROCAPULDENCEL-T (AGS-003), AN INDIVIDUALIZED IMMUNOTHERAPY FOR THE TREATMENT OF NEWLY-DIAGNOSED PATIENTS WITH METASTATIC RENAL CELL CARCINOMA (MRCC) Robert Figlin, MD R Figlin, N Tannir, S Tykodi, D Chen, V Master, B Lane, M DeBendette, W Tian, T Monesmith, S Leland, J Abbey, C Nicolette, and C Wood for the ADAPT study team. esmo.org

2 DISCLOSURE SLIDE ARGOS: research funding, scientific advisory board 2

3 Metastatic RCC Represents a Significant Unmet Medical Need Metastatic clear cell RCC (mrcc) is largely incurable and has a poor prognosis Approximately 1/3 of mrcc patients have metastatic disease at the time of diagnosis and have the worst prognoses These poor and intermediate risk patients exhibit disease progression within ~5-8 months and survive for ~2 years with a 5 year survival rate of 5-15% when treated with modern targeted therapies 3

4 Rocapuldencel-T Mechanism Of Action Rocapuldencel-T consists of autologous dendritic cells programmed with amplified RNA from patient s primary tumor Designed to overcome immunosuppression and induce broadly reactive, long-lasting anti-tumor memory T cells Electroporation with autologous total amplified tumor mrna programs DCs with a large number of tumor antigens, including private neoantigens RNA-encoded CD40L protein allows DCs to produce IL-12, necessary to overcome immunosuppression and required for memory T cell differentiation 4

5 Phase 3 ADAPT Trial Design n = 462 2:1 6 WEEKS Sunitinib Control Arm: Standard Therapy Alone 1 Rocapuldencel-T + Standard Therapy 1 Newly diagnosed renal cell carcinoma (clear cell histology) with metastatic disease Randomized, open label front line study Stratified by Heng risk factors (77% Intermediate Risk and 23% Poor Risk) Dosing: Weeks 6, 9, 12, 15, 18, 24 and quarterly thereafter Primary endpoint: OS (log rank test) Secondary endpoints: PFS, response rate and disease control rate (RECIST) Exploratory endpoint: Immune responses 107 clinical sites in North America, Europe and Israel (1) Other therapies may be substituted for sunitinib for intolerance or progression 5

6 ITT Population Characteristics No significant differences in baseline characteristics between the combination arm and the control arm Median follow-up is 20 months (range: months) Median number of doses of rocapuldencel-t is 8 (48 weeks) Generally comparable subsequent and sequential standard-of-care treatments in each arm 6

7 ITT Population: Baseline Characteristics Baseline characteristics are consistent across both arms Combination Arm Control Arm ITT Population n=307 n=155 Median Age 60.0 yr 61.0 yr Gender, Male % % Race White % % Non-White % 4 2.6% Time from Initial Dx 2.67 mo 2.63 mo Metastatic Disease Yes % % Measurable % % Non-measurable % % No 2 0.7% 0 0% Heng Risk Factors Intermediate Risk % % Poor Risk % % Karnofsky Performance Status 100% % % 90% % % 80% % % 70% % 7 4.5% 60% 1 0.3% 1 0% 7

8 Patient Disposition at Interim Analysis 1 Total Subjects Randomized n=462 Combination Arm n=307 Control Arm n=155 Combo Subjects Who Died n=149 Control Subjects Who Died n=69 Combo Subjects Alive n=158 Control Subjects Alive n=86 ITT population (all randomized patients) includes 39 patients who never received rocapuldencel-t Successful manufacture for over 96% of patients 67 patients were receiving rocapuldencel-t in the combination arm at time of interim analysis (1) The data cut-off date for the interim analysis was February 3,

9 Primary Endpoint Interim Analysis - Overall Survival Interim Analysis Combination Arm Control Arm ITT Population n=307 n=155 Percentage Censored Subjects 51% 55% Median Overall Survival (months) % Confidence Interval (CI) 23.0, , - Hazard Ratio (95% CI) - Unadjusted 1.10, (0.83, 1.46) Hazard Ratio (95% CI) Adjusted , (0.79, 1.40) At Interim Analysis: More than half the subjects in both treatment groups were censored for survival Approximately 98% of the censored subjects remained alive at interim analysis (1) Median overall survival estimated by Kaplan-Meier methodology (2) Adjusted for randomization stratification factors - number of Heng risk factors and metastatic disease status (measurable vs. non-measurable) 9

10 Key Secondary Endpoint Interim Analyses Progression Free Survival Combination Arm Control Arm ITT Population n=307 n=155 Median Progression Free Survival (months) % CI 5.8, , 9.3 Hazard Ratio % CI 0.92, 1.44 (1) Progression determined by investigator and not by independent radiographic review 10

11 Key Secondary Endpoint Interim Analyses Objective Response Rate Combination Arm Control Arm ITT Population n=307 n=155 Best Overall Response, n (%) Complete Response (CR) 9 (2.9%) 3 (1.9) Partial Response (PR) 122 (39.7%) 58 (37.4%) Stable Disease (SD) 121 (39.4%) 57 (36.8%) Progressive Disease (PD) 30 (9.8%) 10 (6.5%) Not Evaluable (NE) 25 (8.1%) 27 (17.4%) Objective Response Rate (CR + PR) n (%) (95% Confidence Interval) Disease Control Rate (CR + PR + SD), n (%) (95% Confidence Interval) 131 (42.7%) (37.1, 48.4) 253 (82.4%) (77.7, 86.5) 61 (39.4%) (31.6, 47.5) 118 (76.1%) (68.6, 82.6) 11

12 Summary of Adverse Events - Safety Population Combination Arm Control Arm Subjects Who Received Any Amount of Study Medication (n=299) n, % (n=141) n, % Pre-Treatment Period Any Adverse Events 10 (3.3%) 2 (1.4%) Any Serious Adverse Events 1 (0.3%) 0 (0.0%) Any Grade 3/4/5 AEs 1 (0.3%) 0 (0.0%) Randomized Treatment Period Any Adverse Events 296 (99.0%) 139 (98.6%) Rocapuldencel-T Related AEs 174 (58.2%) - Standard of Care Related AEs 285 (95.3%) 134 (95.0%) Any Grade 3/4/5 AEs 214 (71.6%) 98 (69.5%) Rocapuldencel-T Related Grade 3/4/5 AEs 6 (2.0%) - Standard of Care Related Grade 3/4/5 AEs 144 (48.2%) 74 (52.5%) Deaths 19 (6.4%) 7 (5.0%) 12

13 Rationale For Continuing ADAPT and Longer Term Survival Follow-up Potential for delayed treatment effect (tail-of-curve) Rocapuldencel-T induces long-term memory immune responses >50% of subjects censored in both treatment groups at interim analysis 98% of censored subjects remained alive Interim analyses may not fully capture the potential benefit of an active immunotherapy due to insufficient long-term follow-up 1 Limited survival follow-up at time of interim analysis: median of 20 months Longer follow-up may provide useful information to identify a potential beneficial effect of rocapuldencel-t Censoring may impact assessment of both median survival and potential tail-of-curve effect (1) TT Chen Statistical Issues and Challenges in Immuno-oncology; Journal for ImmunoTherapy of Cancer, 2013 Oct 21;1:18 13

14 Survival Probability Phase 2 Trial of Rocapuldencel-T Showed Survival Curve Inflection Point at ~18 Months* Overall Survival (months) *Amin A. Journal for ImmunoTherapy of Cancer :14 14

15 Overall Survival by Time of Randomization 1 1 st 33% randomized st 66% randomized All 100% randomized N Combination Arm Control Arm Delta Median OS Median OS % Censored N % Censored Months (Months) (Months) (23.3, -) 30.4 (24.8,-) 27.7 (23.0, 35.9) (17.2, -) 32.4 (21.7, -) 32.4 (22.5, -) Hazard Ratio 0.88 (0.56, 1.36) 0.98 (0.70, 1.37) 1.10 (0.83, 1.46) Benefit in median overall survival (combination arm vs. control arm) seen in subjects with longest survival follow-up Suggests interim analysis of median overall survival may be premature (1) Median overall survival estimated by Kaplan-Meier methodology based upon data cut-off as of February 3,

16 Survival Probability Kaplan-Meier Analysis of Overall Survival in Tertile 1 Hazard Ratio 0.88 Combination Arm (n=102) mos= 30.1 mo Standard-of-Care Treatment Arm (n=52) mos= 22.2 mo Overall Survival (months) 16

17 Survival Probability Kaplan-Meier Analysis of Overall Survival with Tumor Response Rocapuldencel-T Arm: OS Correlates with Tumor Response CR/PR Progressive disease Stable disease Not evaluable 17 Overall Survival (months)

18 Duration of Response (PR/CR) is Longer in Combination Arm And Suggests a Flattening of the Progression Curve More patients experience objective tumor response in combination vs. control (42% vs. 39%) Patients in the combination arm had more durable tumor response (median 8.4 vs 6.3 months) Percent of Patients Remaining Progression-Free After Initial Response (by KM estimate) 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Combination Arm (n=131) Control Arm (n=61) > 1 2 > 1 8 > 2 4 > 3 0 > 3 6 Months from Initial Response (CR/PR) * * None of the patients remaining progression free had reached 36 months 18

19 Survival Probability Greater Increase in Antigen-Specific Memory T Cells* above Baseline after 7 Doses Associated with Improved Survival Increase of antigen-specific memory T cells correlates with OS after 7 doses (Spearman s Rho=0.33, p<0.0021) 7 th dose administered at week 36 and analysis conducted at week 48 Median increase =6085 cells/ml <Median: N=41 (73% censored) Median: N=42 (81% censored) Top one-third: N=27 (93% censored) Overall Survival (months) *Memory T cells defined as CD8+CD28+CD45RA- cells reactive with antigens encoded by autologous tumor RNA Analysis includes 83 patients who received at least 7 doses out of the 117 patients analyzed for immune response. 19

20 Survival Probability Antigen-Specific Memory T Cells are Present at Baseline But Do Not Correlate with OS OS vs IM at Baseline (N=127, 65% censored): Above the Median vs Below the Median Median #Cells/ml=5338 Greater number of baseline antigen-specific memory T cells NOT associated with greater OS Overall Survival (months) 20

21 Summary Analysis of the immune response data shows a clear correlation with the MoA of rocapuldencel-t and survival outcomes At the time of the interim analysis, the median OS favors the control arm, but the data is immature Median follow-up of 20 months and >50% of patients still censored Longest mos seen for SoC in any study of patients with intermediate and poor risk Study remains open following discussion of the data with the FDA regarding potential tailof-the-curve effect IL-12, Tregs and other biomarker analyses are ongoing to identify a prospective biomarker to be used in the future development of rocapuldencel-t Next data update planned at 290 events expected in 1H

22 Acknowledgements We would like to thank all of our investigators, nurses, study coordinators, operations staff and most importantly, our participating patients and their families at sites in the following countries: Canada (9) Czech Republic (6) Hungary (3) Israel (9) Italy (3) Spain (9) United Kingdom (6) United States (110)