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End-Points and Rationale for Phase III Trials in HCC: Adjuvant, Intermediate, and Advanced HCC

End-Points and Rationale for Phase III Trials in HCC: Adjuvant, Intermediate, and Advanced HCC. Richard S. Finn, MD Professor of Clinical Medicine Division of Hematology/ Oncology Director, Signal Transduction and Therapeutics Program Jonsson Comprehensive Cancer Center at UCLA

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End-Points and Rationale for Phase III Trials in HCC: Adjuvant, Intermediate, and Advanced HCC

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  1. End-Points and Rationale for Phase III Trials in HCC: Adjuvant, Intermediate, and Advanced HCC Richard S. Finn, MD Professor of Clinical Medicine Division of Hematology/ Oncology Director, Signal Transduction and Therapeutics Program Jonsson Comprehensive Cancer Center at UCLA Geffen School of Medicine at UCLA

  2. Disclosures • Consultant: Astra Zeneca, Bayer, Bristol Myers Squibb, Eisai, Eli-Lilly, Exilixis, Merck, Novartis, Pfizer, Roche/ Genentech

  3. Endpoints • The goal of what we do is to improve clinical benefit • The gold-standard for demonstrating clinical benefit is overall survival • Unambiguous and not subjective • ORR, PFS, TTP • Subject to cross-over, takes a long time, includes non-cancer deaths • If a new agent does not improve OS, then how do we justify its expense and side effects?

  4. Benefits of Surrogates? • “Surrogates” • Overall response rate (ORR) • Time to progression (TTP) • Progression-free survival (PFS) • Health-related quality of life (HRQOL) • More rapid read-out then conventional endpoints (OS) • Smaller samples size • But….. • Dependent on imaging (subjective, technique, timing) • Do not always correlate with OS

  5. Overall Survival in Front-Line Advanced HCC is Improving

  6. Reasons for Improved Survival • Better patient selection • Less advanced disease • Liver function • Less pre-treatment (LRT) • Better toxicity management • Effective treatments beyond progression

  7. Effective Treatments Beyond Progression

  8. PFS≤0.6 correlated with OS PFS 0.6-0.7 “uncertain” Based mostly on second-line trials Most relevant to earlier stage/ line trials

  9. The Challenge with OS OS = PFS+SPP • OS = PFS+ (PFS2+PFS3+PFSx) SPP, survival post-progression

  10. SPP survival post-progression

  11. REFLECT Study Study Schema Global, randomized, open-label, phase 3 noninferiority study • Patients with unresectable HCC (N = 954) • No prior systemic therapy for unresectable HCC • ≥ 1 Measurable target lesion per mRECIST • BCLC stage B or C • Child-Pugh A • ECOG PS ≤ 1 • Adequate organ function • Patients with ≥ 50% liver occupation, clear bile duct invasion, or portal vein invasion at the main portal vein were excluded • Primary endpoint: • OS • Secondary endpoints: • PFS • TTP • ORR • Quality of life • PK lenvatinib exposure parameters • Tumor assessments were performed according to mRECIST by the investigator Lenvatinib (n = 478) 8 mg (BW < 60 kg) or 12 mg (BW ≥ 60 kg) once daily • Stratification • Region: • (Asia-Pacific or Western) • MPVI and/or EHS: • (yes or no) • ECOG PS: • (0 or 1) • Body weight: • (< 60 kg ≥ 60 kg) Randomization 1:1 Sorafenib (n = 476) 400 mg twice daily BCLC, Barcelona Clinic Liver Cancer; BW; body weight; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EHS, extrahepatic spread; MPVI, macroscopic portal vein invasion; mRECIST, modified Response Evaluation Criteria In Solid Tumors; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; TTP, time to progression. Kudo M, Finn RS, Qin S Lancet 2018

  12. REFLECT Study Secondary Endpoint: Kaplan-Meier Estimate of PFS by mRECIST Kudo M, Finn RS, Qin S Lancet 2018

  13. REFLECT Study Primary Endpoint: Kaplan-Meier Estimate of OS Kudo M, Finn RS, Qin S et al. Lancet 2018

  14. REFLECT Second Line Treatments Alsina ASCO GI 2019

  15. Nivolumab in Advanced HCC RR (dose esc, n=48): 15% RR (dose exp, n=214): 20% mOS (dose esc, n=48): 15 mos mOS (dose exp, n=214): NR FDA Label: 14.8 % RR BICR (n=154) Median DoR: 16.6 mos El Kouheiry 2017 The Lancet DOI: (10.1016/S0140-6736(17)31046-2)

  16. Overall Survival by Best Overall Response 1.0 Median OS NR (95% CI: NE–NE) Probability ofSurvival 0.9 0.8 0.7 Complete or partial response (n=22) Stable disease (n=65) Progressive disease (n=59) 0.6 0.5 0.4 Median OS 16.7 mos(95% CI: 13.8–20.2) 0.3 0.2 Median OS 8.9 mos(95% CI: 7.3–13.4) 0.1 n=146* 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (months) *Best overall response was unable to be determined in 8 patients. BOR, best overall response; CI, confidence internal; OS, overall survival; mo, month; NE, not estimable; NR, not reached. El-Khoueiry AB et al. Oral presentation at 2018 Gastrointestinal Cancer Symposium. Abstract 475.

  17. Checkmate-459: 1L Nivolumab vs SorafenibPhase 3 Study Design Phase III, Multi-center, Randomized Clinical Trial (N=726) Nivolumab vs Sorafenib as 1L Treatment in Patients With Advanced HCC Unacceptable toxicity Or disease progression* * Patients may be treated beyond progression under protocol-defined circumstances Follow-up And Survival follow-up Nivolumab 240 mg (30 minutes IV Q2W) Advanced HCC Systemic therapy naïve Did Not Meet Its Endpoint- June 2019 R1:1 Sorafenib 400 mg po BID Stratify HCV vs non-HCV EHS/MVI Geography (Asia vs non-Asia) Press Release: HR=0.85 [95% CI: 0.72-1.02]; p=0.0752 • Primary Endpoint: OS Clinicaltrials.gov. NCT02576509. Accessed May 21, 2018.

  18. Ongoing Phase 3 Studies Front-line

  19. BGB-A317_001 (HCC patients):Best Percent Change from Baseline in Target Lesions (N=46) • Efficacy evaluable = 49 • PR=6 • SD=19 • ORR=12.2% Data cut off date: 4/27/2018 Lin ESMO 2018

  20. RATIONAL 301: OVERALL STUDY DESIGN Qin ILCA 2018 *The initial infusion (Cycle 1, Day 1) will be administered over 60 minutes; if well tolerated, subsequent infusions may be administered over 30 minutes. After tislelizumab infusion, patients will be monitored for 2 hours during Cycles 1 and 2, and for ≥30 minutes from Cycle 3 onward. **Treatment beyond the initial investigator-assessed disease progression will be permitted in both treatment arms if pseudo progression is suspected or there is reasonable belief that the patient could derive benefit from the treatment. • This global, phase 3, randomized, multicenter study (NCT03412773) was designed to evaluate the efficacy and safety of tislelizumab compared with sorafenib as a first-line treatment of advanced HCC • Approximately 640 patients will be enrolled globally

  21. Will increasing exposure to systemic treatments improve OS? Bejjani and Finn 2019 Clin Liv Disease 2019

  22. Will increasing exposure to systemic treatments improve OS? Survival post progression Bejjani and Finn 2019 Clin Liv Disease 2019

  23. Finn RS ASCO 2019

  24. Finn RS ASCO 2019

  25. Post-study Anticancer Therapy aIncluded both with/without prior exposure to other post-treatment anticancer medications. bIncluded regorafenib, lenvatinib, cabozantinib, and ramucirumab. Data cut-off: Jan 2, 2019.

  26. Exploratory Sensitivity Analyses: Impact of Post-Treatment Anticancer Medications on OS Adjusted for treatment switches in both arms. IPCW, inverse probability of censoring weighting.aHR based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by geographic region, macrovascular invasion and AFP (ng/mL), and bootstrap 95% CI for both the 2-stage model and IPCW. bOne-sided p-value based on the IPCW log-rank test; based on stratified log-rank test, adjusted for treatment switch for the 2-stage model. c p=0.0090 and d p=0.002, one-sided p-values based on bootstrap percentiles.

  27. BRISK -TA Secondary Endpoints TTDP Primary Endpoint: OS TTES/VI TTP Kudo, Han , Finn et al Hepatology 2014

  28. TACTICS Kudo ASCO GI 2019

  29. TACTICS Kudo ASCO GI 2019

  30. TACTICS Kudo ASCO GI 2019

  31. SIRveNIB: Efficacy: Time to Progression • Treated population • Intent-to-treat population Median TTP (months) Events SIRT 6.08 (95% CI 4.17 to 6.60) 133 Sorafenib 5.36 (95% CI 4.07 to 5.65) 143 Hazard ratio 0.88 (95% CI 0.69 to 1.11); P = 0.287 Median TTP (months) Events SIRT 6.41 (95% CI 6.01 to 8.64) 97 Sorafenib 5.39 (95% CI 4.07 to 5.72) 136 Hazard ratio 0.73 (95% CI 0.56 to 0.95); P = 0.019 Presented by: Prof. Pierce K. H. Chow

  32. SIRveNIB: Efficacy: Overall Survival • Treated population • Intent-to-treat population Median OS (months) Events SIRT 8.84 (95% CI 7.52 to 10.84) 135 Sorafenib 10.02 (95% CI 8.57 to 13.80) 131 Hazard ratio 1.12 (95% CI 0.88 to 1.42); P = 0.360 Median OS (months) Events SIRT 11.27 (95% CI 9.17 to 13.57) 94 Sorafenib 10.41 (95% CI 8.57 to 13.83) 124 Hazard ratio 0.86 (95% CI 0.66 to 1.13); P = 0.273 Presented by: Prof. Pierce K. H. Chow

  33. Ongoing Phase 3 Intermediate Stage

  34. STORM: RFS (independent review) 100 75 RFS probability (%) 50 HR = 0.940 (sorafenib / placebo) 95% CI 0.780-1.134 p=0.26 (1-sided) ~6% reduction in risk of recurrence or death 25 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Months Number at risk 558 556 442 349 387 298 322 244 295 221 266 192 250 172 229 153 213 135 166 102 121 70 88 50 21 6 15 4 1 1 PlaceboSorafenib CI, confidence interval Bruix Lancet Onc 2015

  35. STORM: Overall survival 100 75 50 OS probability (%) 25 HR = 0.995 (sorafenib / placebo) 95% CI 0.761-1.300 p=0.48 (1-sided)a 0 64 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Months Number at risk PlaceboSorafenib 558 556 540 503 520 482 504 460 477 445 450 419 433 395 420 383 403 367 381 340 298 251 212 176 134 110 78 62 29 21 5 5 aFirst planned OS interim analysis alpha = 0.000449 (1-sided) Bruix Lancet Onc 2015

  36. Ongoing Phase 3 Adjuvant

  37. Phase 3 Optima Study A Phase III, Global, Randomized, Double Blind, Dummy-ControlledStudy of ThermoDox Using Standardized RFA for Single HCC 3-7 cm • Primary • Endpoint • - OS • Secondary • Endpoints • Key Inclusion Criteria • Non-resectable • Single HCC 3-7 cm • Child-Pugh A • ECOG 0 • Candidate for RFA • No prior treatment Randomization 50 mg/m2 ThermoDox + sRFA (≥45 min) Dummy infusion + sRFA (≥45 min) - PFS - Safety n = 550 www.clinicaltrials.gov - NCT02112656

  38. The FDA now Accepts PFS as an appropriate endpoint for approval in HCC https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM614369.xlsx

  39. Conclusions (I): • We have made significant progress in the management of HCC • Advanced HCC is still incurable • Goal should be to improve survival with maintaining quality of life • Incremental benefits from the sequencing of drugs with clinical activity improves survival • The earlier the stage studied, the increased risk to OS with post-progression therapies because of survival post-progression (SPP)

  40. Conclusion (II) • Advanced Disease Front-line • PFS is probably a reasonable endpoint • MOA may be relevant (may not capture full benefit of IO) • Clinically meaningful increases, not just statistical • Absolute increase, not just hazard ratio • Advanced Disease Second-line • OS is still required • PFS at some point depending on benefits of sequencing • Control arm? Dealers choice

  41. Conclusions (III): • Intermediate Stage • Most challenging • systemic therapy with LRT, after LRT, vs LRT? • OS will be difficult to show with post-progression therapies • Defining progression • PFS, TTP, “unTACEable progression” • Adjuvant (after curative resection) • Unmet need • Disease-free/ recurrence-free survival

  42. Acknowledgements: • Ronald Busuttil • Saeed Sadeghi • Hepatology(Choi, Durazo, El Kabhany, Han, Saab, Tong) • IR (Gomes, Lu, McWilliams, Padia, Raman) • Surgery (Agopian, DiNorcia, Farmer, Kaldas) • LCC Office (Mia Camcam, Kholett Manansala, Kym Perkins, Stacy Williams) • Liver Cancer Research Team: Alice Polyakov, Sa-Heim Davis, Lia Ethridge, Jasper Pascual, Ivana Melgar, Liseet Gonzalez

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