Durable Response Rate in High Grade Glioma: an Emerging Endpoint for Immunotherapeutics. Timothy Cloughesy, MD University of California, Los Angeles

Transcription

1 Durable Response Rate in High Grade Glioma: an Emerging Endpoint for Immunotherapeutics Timothy Cloughesy, MD University of California, Los Angeles

2 Disclosure 2

3 FDA Endpoints for the Approval of Cancer Drugs and Biologics 1 Patient-centered: Overall survival (OS) Patient reported outcomes (PRO) Tumor-centered: used as surrogates for patient-centered endpoints Disease-free survival (DFS) Objective Response Rate (ORR) Complete Response (CR) Progression-Free Survival (PFS) or Time to Progression (TTP) 1 FDA guidance for industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics

4 Advantages and Disadvantages of Approval Endpoints Endpoint Advantages Disadvantages 4 OS DFS ORR CR PFS or TTP Universally accepted direct measure of benefit Easily and precisely measured Smaller sample size and shorter follow-up necessary compared with survival studies Can be assessed in single-arm studies Assessed earlier and in smaller studies Effect attributable to drug, not natural history Can be assessed in single-arm studies Durable complete responses can represent clinical benefit Assessed earlier and in smaller studies Smaller sample size and shorter follow-up necessary Measurement of stable disease included Not affected by crossover or subsequent therapies Generally based on objective and quantitative assessment May involve larger studies May be affected by crossover therapy and sequential therapy Includes non-cancer deaths Not statistically validated as surrogate for survival in all settings Not precisely measured; subject to assessment bias, particularly in open-label studies Definitions vary among studies Not a direct measure of benefit Not a comprehensive measure of drug activity Only a subset of patients who benefit Not a direct measure of benefit in all cases Not a comprehensive measure of drug activity Small subset of patients with benefit Not statistically validated as surrogate for survival in all settings Not precisely measured; subject to assessment bias Definitions vary among studies Frequent radiological or other assessments Involves balanced timing of assessments among treatment arms FDA guidance for industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 2007

5 FDA Approval Endpoints for Recurrent Brain Cancer Treatment Indication Endpoint Data Year Carmustine implant 1 rgbm OS6 56% (Gliadel) vs 36% (placebo) 1996 Temozolomide 2 raa ORR 22% 1996 Bevacizumab 3 rgbm ORR 25.9% 2009 Optune 4 rgbm mos 6.3 (Optune) vs 6.4 (chemotherapy) Gliadel Wafer package insert; 2 TEMODAR product insert; 3 AVASTIN package insert; 4 Optune FDA Summary of Safety and Effectiveness Data 5

6 Novel MOA s Drive Innovation in Oncology Endpoints Rituximab, first therapeutic monoclonal antibody approved (1997) Normal lymph node size complicated assessment of tumor shrinkage using standard response criteria Novel response criteria supported FDA approval (Lymphoma Expert Confirmation of Response (LEXCOR) criteria) Checkpoint inhibitors paved the way to evaluate modifications to RECIST (2009) Delayed response or pseudo-progression may occur Modifications to standard criteria enables more accurate assessment of response Ibrutinib, Bruton s tyrosine kinase inhibitor, for chronic lymphocytic leukemia (2014) Lymphocytosis complicated interpretation Lugano Classification response criteria was adopted to consider additional clinical data Viral gene therapy, Imlygic, approved on Durable Response Rate (DRR) as 1 endpoint (2015) Long tail of mos obscure clinical impact DRR helped identify clinically meaningful drug activity, which allowed subset analysis and approval 6

7 Durable Response Rate (DRR): An Emerging Endpoint for Immunotherapeutics Definition: The percentage of patients with CR or PR observed continuously for 24 weeks or longer ORR DRR association with clinical benefit 1 Duration of response (DoR) 24 weeks 1 Kaufman et al, J. for ImmunoTherapy of Cancer,

8 DoR/DRR Commonly Used For Novel Immunotherapeutics Therapy Indication Primary endpoint Secondary endpoint Imlygic Melanoma Durable response rate (DRR) Yervoy (Ipilimumab) Melanoma OS OS median time to response DRR best ORR at week 24 Opdivo (Nivolumab) Keytruda (pembrolizumab) Hodgkin Lymphoma Objective response rate (ORR) Duration of response (DoR) HCC ORR DoR Melanoma OS, PFS DoR, ORR Hodgkin lymphoma ORR DoR, OS, PFS MSI-H/dMMR cancers ORR DoR, OS, PFS MSI-H = microsatellite instability-high; dmmr = mismatch repair deficient; HCC: hepatocellular carcinoma 8

9 Toca 511 (vocimagene amiretrorepvec) Retroviral replicating vector that carries a prodrug activator enzyme Regulatory genes Structural RRV genes CD gene Regulatory genes Tumor selectivity and replication in cancers cells is driven by: Defects in the innate immune system of cancer cells Virus enters some normal cells, but is rapidly eliminated by innate and acquired immunity Virus spreads through tumor without triggering immune system Virus only infects dividing cells Optimized CD (cytosine deaminase) 5-FC (Toca FC) Antifungal Prodrug 5-FU Anticancer Drug 5-FU has a very short half-life with direct cell killing localized to cancer microenvironment RRV= Retroviral replicating vector 9

10 Toca 511 & Toca FC: Toca 511 spreads then converts Toca FC to 5-FU for tumor killing and immune activation Novel 5-FU delivery kills tumor cells and activates immune system against cancer STEP 1 - Toca 511 & CD CD CD Proposed MOA: Tumor killing and anticancer immune activation CD Tumor STEP 2 - Toca FC 5-FU 5-FU 5-FU 10 Brain and tumor samples from Tocagen clinical trial patients CD = cytosine deaminase (yeast) Toca FC = extended release 5-FC

11 Three phase 1 ascending dose trials* in recurrent high grade glioma setting evaluating delivery approaches (n=127) Resection Injection into cavity wall after removal of tumor Intratumoral Direct injection into tumor Intravenous Injection IV prior to resection and into cavity wall at resection NCT (n = 56) NCT (n = 54) NCT (n = 17) *All three trials finished enrollment 11

12 Phase 1 ascending dose trial of safety & tolerability of Toca 511 & Toca FC in rhgg Toca 511 administered into the resection cavity wall Eligibility GBM or AA Planned resection 80% yrs old Single or contiguous tumor KPS 70 Adequate lab values No prior bevacizumab for recurrence Tumor 5 cm S U R G E R Y Toca 511 once From 1.4 X 10 7 to 4.8 X 10 9 TU (half-log increases) Multi-center Adaptive 3+3 design Cyclic Toca FC From 135 to 220 mg/kg/day Dose Escalation Objective: Safety, tolerability, and MTD Adapted from M.A. Vogelbaum, MD PhD, SNO, Nov. 21 st,

13 All responders are now in complete response and alive All responses are in higher dose cohort and durable Response Category 1 All Patients N=53 2 n (%) Higher Doses and Ph3 Entry Criteria Subset 3 N=23, (%) Objective response rate 6 (11.3); All CR 4 5 (21.7); All CR 5 Median duration of response Durable response rate (CR or PR 24 weeks) Not reached (median follow-up: 35.1 months Not reached (median follow-up: 35.7 months) 6 (11.3); All CR 5 (21.7); All CR Stable disease 10 (18.9) 5 (21.7) 13 Progressive disease 37 (69.8) 13 (56.6) Clinical Benefit Rate (CR, PR, and SD at 8 weeks) 16 (30.2) 10 (43.5) 1 Includes MRI by independent radiology review and clinical data 2 From 56 safety evaluable patients, 53 patients who received Toca 511 & Toca FC are efficacy evaluable and of these 2 were not evaluable for response 3 Higher doses (cohorts 4-7a) and meet Ph3 entry criteria of 1 st and 2 nd recurrence, no prior Avastin in raa or rgbm, tumor not > 5cm 4 Includes 4 IDH wildtype and 2 IDH mutant patients 5 Two patients converted from PR to CR status since last data cutoff Data cutoff date August 15 th, 2017

14 A positive association of durable response with overall survival Best response & survival post progression All Responses are Durable Complete Responses & Associated with Long Term Survival Toca Overall Survival and the Best Response 1 st /2 nd Recurrence, No prior bevacizumab, <=5cm, Higher Dose Cohorts (N=23) AA, IDH1 mt AA, IDH1 mt GBM, IDH1 wt GBM, IDH1 wt GBM, IDH1 wt GBM, NA 14 Adapted from Cloughesy et al. AACR-NCI-EORTC Conference, 2017.

15 Complete response in a patient with progressive GBM, IDH1 wt PR at 19 months, CR at 30 months*, alive > 33 months *Independent Radiology Review, Macdonald criteria 15 Toca FC cycle is every 6 weeks

16 Pivotal Phase 3 Trial Design Robustly Designed Trial, 187 Patients Already Enrolled Primary Endpoint: Overall Survival Secondary Endpoints Include Durable Response Rate Stratify by IDH1 mutation status KPS (70-80 vs ) and region Surgery And Randomization N=380 * Administered at time of surgery ** Begins 6 weeks post-surgery 1:1 randomization Toca 511* Toca FC** Chemotherapy** (lomustine or temozolomide) or bevacizumab Eligibility GBM or AA First and 2 nd recurrence Tumor 5cm ClinicalTrials.gov Identifier: NCT Biomarker monitoring includes blood (lymphocytes, immune activation markers, cytokines) and tumor (TILS and immune-suppressive myeloid cells)

17 Conclusions Traditional clinical endpoints may have limitations for novel therapies such as immunotherapies Durable response rate (DRR) is an emerging clinical endpoint for immunotherapeutics In a subset of patients from Phase 1 resection study, Toca 511 & Toca FC treatment shows: 5 complete responses (3 rgbm with IDH1 wt, 2 raa with IDH1 mt) Median duration of response has not been reached after a median follow-up of 35.7 months Suggests a positive association between durable response and overall survival Phase 3 randomized study (Toca 5) in patients with rhgg Currently enrolling patients with raa or rgbm, at 1st or 2nd recurrence, no prior Avastin in rhgg, tumor 5cm 17

18 Thanks to all the patients, their families and caregivers who have supported this work. Financial support provided by 18

19 Tocagen presentations at SNO Oral presentations: 11/17/2017, 2:10-2:25 pm (Adult Clinical Trials I) Intravenous delivery of Toca 511 in patients with high grade glioma results in quantifiable expression of cytosine deaminase in tumor tissue (Tobias Walbert, MD PhD) 11/17/2017, 3:40-3:45 pm (Adult Clinical Trials II) Durable responses observed in IDH1 wildtype and mutant recurrent rhgg with Toca 511 & Toca FC treatment (Timothy Cloughesy, MD) E-talk presentation: 11/18/2017, 5:40pm Immunological activation in responding patients with recurrent HGG after treatment with Toca 511 & Toca FC: Results from a phase 1 trial (Derek Ostertag, PhD) Poster presentation: 11/18/2017, 7:30-9:30 pm Toca 511 and 5-FC induces T cell-mediated antitumor immunity in a mouse glioma model which is enhanced by the addition of a therapeutic antibody against CTLA-4 and correlative with a reduction in memory T regulatory cells (Douglas Jolly, PhD) 19