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Molecular Lessons Learnt from Clinical Trials in the Last Decade

Molecular Lessons Learnt from Clinical Trials in the Last Decade. Andrew X. Zhu, MD, PhD Harvard Medical School Massachusetts General Hospital Cancer Center Jiahui International Cancer Center. Disclosure.

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Molecular Lessons Learnt from Clinical Trials in the Last Decade

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  1. Molecular Lessons Learnt from Clinical Trials in the Last Decade Andrew X. Zhu, MD, PhD Harvard Medical School Massachusetts General Hospital Cancer Center Jiahui International Cancer Center

  2. Disclosure • Advisory/consulting: Eisai, Bristol-Myers Squibb, Merck, Novartis, Astra-Zeneca, Bayer, Lilly, Exelixis, Roche-Genentech • Research funding: Merck, Novartis, Bristol-Myers Squibb, Bayer, Lilly

  3. Discussion Points • Progress has been made in advanced HCC through well conducted clinical trials • Lessons learned from clinical trials • Challenges in trial design with targeted agents and immunotherapy • Biomarker enrichment trials • Response assessment • Endpoints selection • Mechanism of drug resistance • Emerging targets and strategies in advanced HCC

  4. Shifting Therapeutic Landscape of NSCLC Pembro + chemo May 2017 Nivo Mar 2015 Pembro Oct 2015 Atezo Oct 2016 Durva Feb 2018 Crizotinib Mar 2016 Crizotinib Aug 2011 Ceritinib April 2014 Alectinib Dec 2015 Brigatinib April 2017 Lorlatinib July 2018 2017 2018 2015 2011 2012 2013 2016 2014 Erlotinib May 2013 Gefitinib July 2015 Osimertinib Nov 2015 Afatinib July 2013 Ramucirumab Dec 2014 Necitumumab Nov 2015

  5. Improving Long-Term Survival in Lung Cancer 100 + Censored 80 ALK+ NSCLC (PROFILE 1014) 60 Median follow-up ~46 months in both arms Overall Survival (%) 40 HR 0.760 (95%CI: 0.548, 1.053); aP=0.0978 20 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 4 year OS rate Crizo: 56.6% Chemo: 49.1% Months No. at risk Crizotinib Chemotherapy 172 171 157 150 144 131 128 118 111 100 98 89 89 82 79 73 65 63 51 46 36 31 20 21 8 11 1 1 0 0 Mok et al., ESMO 2017

  6. The Evolving Treatment Landscape for Advanced HCC Nivolumab Approved for 2L HCC September 2017 (accelerated) Phase 3 Keynote-240 fails to meet co-primary endpoints in 2L HCC (February 2019)7 Pembrolizumab Approved for 2L HCC November 2018 (accelerated) Phase 3 Checkmate 459 fails to meet primary endpoint in 1L uHCC (June 2019) 2005 2010 2015 2020 Ramucirumab Approved for 2L HCC (AFP >400 ng/mL) May 2019 Regorafenib2 Approved for 2L HCC April 2017 Sorafenib Approved for 1L HCC November 2007 Lenvatinib Approved for 1L HCC August 2018 Keynote 240: Median OS 13.9 months in second line HCC Checkmate 459: Median OS in first line: ? Cabozantinib Approved for 2L HCC January 2019

  7. Sorafenib in advanced HCCSHARP vs Asia-Pacific Study: Overall Survival Asia-Pacific Trial SHARP Trial P=0.014 10.7 vs 7.9 mo HR: 0.69 (0.55-0.87) 6.5 vs 4.2 mo HR: 0.68 (0.50-0.93) 1. Llovet JM, et al. N Engl J Med 2008 359:378-90 2. Cheng AL, et al. Lancet Oncology 2009

  8. Failed Phase III Trials in Advanced HCC a. LlovetJM, et al. N Engl J Med. 2008;359:378-390; b. Cheng A-L, et al. Lancet Oncology. 2009;10:25-34; c. Cheng A-L, et al. J ClinOncol. 2013; 31:4067-4075; d. Johnson PJ, et al. J ClinOncol. 2013;31:3517-3524; e. Cainap C, et al. J ClinOncol. 2015;33:172-179; f. Zhu AX, et al. J ClinOncol. 2015;33:559-566; g. Abou-Alfa GK, et al. ASCO 2016. Abstract 192; h. Qin S, et al. Oncologist. 2014;19:1169-1178; i. LlovetJM, et al. J ClinOncol. 2013;31:3509-3516; j. Zhu AX, et al. JAMA. 2014;312:57-67; k. Zhu AX, et al. Ann Oncol. 2016;27(suppl 6):vi207-vi242; l. Abou-Alfa GK, et al. ASCO 2016. Abstract 4017.

  9. Clinical Efficacy of Approved Agents in Advanced HCC • a. Llovet JM, et al. N Engl J Med. 2008;359:378-390; b. Kudo M, et al. Lancet 2018. c. Bruix J, et al. Lancet. 2017;389:56-66; d. Abou-Alfa G, et al. N Engl J Med. 2008; e. Zhu AX, et al. Lancet Oncology 2019

  10. Checkpoint Inhibitors in Second-Line • El-Khoueiry AB et al. Lancet. 2017. pii: S0140-6736(17)31046-2 • Zhu AX et al, Lancet Oncology 2018

  11. CheckMate-459: Nivolumab vs Sorafenib • Key Eligibility Criteria • Advanced HCC not eligible for or progressive after surgical and/or locoregional therapies • Child-Pugh A • (n = 726) Nivolumab R Sorafenib Press release (6/24/19): “did not achieve statistical significance OS primary endpoint per the pre-specified analysis (HR 0.85, 95%CI 0.72-1.02, p=0752)” ClinicalTrials.gov. NCT02576509. • CHECKMATE-459: Phase 3 trial of nivolumab vs sorafenib in first-line advanced HCC • Start Date: November 2015 • Primary endpoint: OS • Other endpoints: ORR, PFS, TTP, RR biomarkers

  12. KEYNOTE-240 Study Design Pembrolizumab 200 mg Q3W +BSC N=278 • Key eligibility criteria • ≥18 y • Pathologically/radiographically confirmed HCC • Progression on/intolerance to sorafenib • Child Pugh class A • BCLC stage B/C • ECOG PS 0-1 • Measurable disease per RECIST v1.1 • Main portal vein invasion was excluded Randomized 2:1* Saline-placebo Q3W +BSC N=135 • Stratification Factors • Geographic region (Asia w/o Japan vs non-Asia w/Japan) • Macrovascular invasion (Y vs N) • AFP level (≥200 vs <200 ng/mL)

  13. Overall Survival Objective Response Rate • Efficacy boundaries • p=0.0174 for OS • Median duration of response mon (range): • pembrolizumab, 13.8 (1.5+ −23.6+) • placebo, not reached (2.8−20.4+) Data Cutoff: Jan 2, 2019. Finn R et al, ASCO 2019

  14. What Lessons We Have Learned from the Clinical Trials Assessing antitumor activity in early clinical trials is critical but challenging Patient selection is important Validated therapeutic targets: VEGFR and immune checkpoints Oncogene addition theory has not been successfully proven in HCC Molecular predictors of responses and clinical benefits are lacking Tumor heterogeneity Clinical benefits to TKIs may vary depending on the underlying etiology Pattern of progression might be important in predicting clinical outcome Side effects might be associated with clinical benefits How to choose and sequence different drugs?

  15. Assessing Antitumor Activity in Early Clinical Trials Is Critical but Challenging ClinicalTrials.gov: • 1793 HCC trials registered (1353 trials with drugs) • 424 phase I trials listed • 707 phase II trials listed • 180 randomized phase II trials listed • 261 phase III trials listed • Only 5 positive phase III trials

  16. Selection of Patients in Advanced HCC Trials ECOG PS: 0 or 1 Macrovascular invasion: extent of vascular invasion VP4 Extent of tumor involvement in the liver: 50% Underlying liver function: Child Pugh A (B7)

  17. Therapeutic Targeting of the Hallmarks of Cancer Hanahan and Weinberg, Cell, 2011

  18. Genome Sequencing in HCC Guichard et al, Nat Gen 2012 Villanueva et al, Nat Rev ClinOncol2014

  19. The Landscape of Altered Genes and Pathways in HCC Schulze et al, Nature Genetics, 2015

  20. Tumor Microenvironment limit Courtesy of Dr. Lance L. Munn

  21. Multikinase Inhibitors and Antiangiogenic Agents a. LlovetJM, et al. N Engl J Med. 2008;359:378-390; b. Kudo M, et al. Lancet 2018. c. Bruix J, et al. Lancet. 2017;389:56-66; d. Abou-Alfa G, et al. N Engl J Med. 2008; e. Zhu AX, et al. Lancet Oncology 2019

  22. Biomarkers for Sorafenib • Circulating Biomarkers • High s-c-Kit and low HGF at baseline showed a trend towards improved OS [3] • Genomic Biomarkers • FGF3/FGF4 and VEGF A amplification predicted response in small number of HCC patients [4, 5] 1. Abou-Alfa GK, et al. J ClinOncol. 2006;24:4293-4300. 2. LlovetJM, et al. N Engl J Med. 2008;359:378-390. 3. LlovetJM, et al. Clin Cancer Res. 2012;18:2290-2300. 4. Arao T, et al. Hepatology, 2013; 57(4):1407-15; HorwitzE atal, Cancer Discoery, 2014. • Tissue Biomarkers • Nuclear pERK overexpression associated with prolonged TTP in phase 2 [1] • Tissue pERK staining was not associated with outcomes in phase 3[2]

  23. FGF3/FGF4 Amplification Predicting Sorafenib Sensitivity Arao et al, Hepatology 2013

  24. Proteins Identified as Potentially Predictive of Regorafenib Treatment Effect on OS *An HR >1 indicates enhanced treatment benefit with regorafenib versus placebo with decreased protein levels (or reduced treatment benefit with increased protein levels); ǂReference shows to what unit increase the HR is related to. CI, confidence interval; HR, hazard ratio; OS, overall survival; TTP, time to progression. Teufel M et al, Gastroenterology 2019

  25. Lenvatinibvs Sorafenib: Pharmacodynamic Biomarkers *P < 0.05 vs baseline; †P < 0.01 vs baseline ; ‡P < 0.0001 vs baseline; §P < 0.05 between lenvatinib and sorafenib arms. ANG-2, angiopoietin-2; C#D#, Cycle # Day #; FGF, fibroblast growth factor; LEN, lenvatinib; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; SOR, sorafenib; TTP, time to progression; uHCC, unresectable hepatocellular carcinoma; VEGF, vascular endothelial growth factor. • In biomarker analysis of REFLECT phase III study (LEN, n=279; SOR, n=128), both LEN and SOR were found to increase VEGF levels, but only LEN increased FGF19 and FGF23 levels, and decreased ANG-2 levels Finn RS et al ESMO 2018

  26. Predictive Marker of Response to Sorafenib Median OS 14 m EHS No HCV No EHS Yes HCV Yes NLR ⩽ median NLR > median TB No TB Yes Bruix J et al, J Hepatology 2017

  27. Median Post Progression-Free Survival According to the Pattern of Progression in Prospective Studies –, not applicable; NA , not available. aAnalysis performed in patients who were candidates for second- line treatment (n = 43). bData presented at 26th Conference of the Asian Pacific Association for the Study of the Liver. J Bruix et al, Nat Rev GastroenterolHepatol., 2019

  28. Clinical markers of outcome in sorafenib treatment Early dermatologic adverse events (DAE60) Overallsurvival Time toprogression Probability of progression Probability of survival DAE60 No DAE60 p=0.016 p=0.009 DAE60 No DAE60 Survival (months) TTP (months) Yes: 8.1 months (CI95%:1.6-14.5) vs. No: 3.9 months (CI95%:2.08-5.7) Yes :18.2 months (95% CI; 11.9 to 24.4) vs. No:10.1 months (CI 95%:10.1-13.0) • Courtesy of Dr. Maria Reig Reig et al; Journal of Hepatology 2014

  29. HFSR Correlation with OS in uHCCa 100 HFSR (n = 198) Events, n (%), 110 (56) Median OS (95% Cl), 14.1 months (11.7–16.5) 90 80 70 No HFSR (n = 181) Events, n (%), 123 (68) Median OS, 6.6 months (5.0–8.5) 60 HFSR Probability of survival (%) 50 40 HR = 0.52 (95% CI: 0.40–0.68), P<0.0001 (1-sided) Number at risk 30 HFSR 198 179 144 1 11 82 54 37 25 14 8 5 0 No HFSR No HFSR 181 138 81 59 41 24 19 9 7 2 0 0 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 Months from randomization aAnalysis cutoff date: February 29, 2016. Bruix J et al. Abstract O-009. Presented at: WCGIC 2017; Barcelona, Spain. Subanalysis of RESORCE Trial

  30. How to choose and sequence different drugs in HCC? • Sorafenib: HCV etiology • Lenvatinib: HBV, improved RR and PFS • Regorafenib: prior sorafenib tolerability • Cabozantinib: up to two prior regimens, sorafenib intolerance • Ramucirumab: baseline AFP > 400 ng/mL • Nivolumab and pembrolizumab: durable response

  31. Challenges in Trial Design in HCC Surrogate endpoints: PFS/TTP, response rate (RECIST vs mRECIST) Response assessment Stratification in HCC trial design How to apply biomarker and molecular signature in trial design

  32. Surrogate Endpoints in Advanced HCC Receiving Systemic Therapy OS is the gold standard in phase III HCC trials PFS/TTP? Response rate: RECIST vs mRECIST vs (irRECIST)? AFP changes? Other biomarkers?

  33. Why Considering PFS in Phase III Trials? PFS will capture antitumor activity of experimental arm OS may be affected by post-progression treatments given the availability of several approved agents Time of completion PFS is an accepted primary endpoint in phase III trials in several tumor types The surrogacy of PFS in HCC remains to be established

  34. PFS and OS in Positive Phase III Trials

  35. Correlation between PFS/TTP and Overall Survival Keynote 240: PFS for pembrolizumab vs placebo: 3.0 vs 2.8 months, HR 0.775 (0.609-0.987) Llovet JM, Montal R, Villanueva A. J Hepatol. 2019

  36. RECIST vs mRECIST

  37. Studies Assessing the Correlation of mRECISTBased Responses and OS • Supportive: • Brivanib second line phase III trial • Sorafenib • Nintedanib • Lenvatinib • Lack of correlation: • Regorafenib in RESORCE phase III trial Llovet et al, JCO 2013; Edeline et al, Cancer 2012; Meyer et al, Liver Int2007; Bruix et al, Lancet 2017; Kudo et al, GI ASCO 2019

  38. REFLECT - Global, Randomized, Open-label, Phase III Noninferiority Study • 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 • 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 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 et al. Lancet. 2018;391:1163-1173.

  39. OS by OR for the Overall REFLECT Population Landmark KM curve as function of tumor response at 2 months Landmark KM curve as function of tumor response at 4 months Landmark KM curve as function of tumor response at 6 months Median OS (months) (95% CI) 1.0 Response: 22.4 (19.7-26.0) 0.9 Nonresponse: 11.4 (10.3-12.3) HR (95% CI): 0.61 (0.49-0.76) 0.8 Mantel-Byar Test: P Value: < 0.001 0.7 y t i 0.6 l i b a 0.5 b o r 0.4 P 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Time From Randomization (Month) Number of patients at risk: Response 159 155 151 138 121 108 93 76 56 41 22 11 6 1 0 Nonresponse 795 721 571 441 362 291 241 180 129 83 51 26 10 5 0 Multivariate analysis showed OR (MPVI, baseline AFP level, treatment etc) correlated with OS CI, confidence interval; OR, objective response; OS, overall survival.

  40. Does mRECIST-Based Response Predict OS in Patients with Advanced HCC? • Authors conclusion: objective response by mRECIST is an independent predictor of OS in HCC patients in the REFLECT study • Large dataset from a positive phase III trial • Sound statistical methodology • Potential surrogacy of mRECIST based responses for OS • Caution: • Post hoc and retrospective study • No comparison with RECIST based response analyses • Not addressing the potential correlation of SD with OS • Unclear about the correlation between PFS and OS and OR with PFS • Unclear on the different magnitude of correlation of sorafenib vs lenvatinib • Additional studies are warranted for prospective validation

  41. mRECIST May Be Dependent on the Mechanism of Action of Drugs Kudo et al, Lancet 2018; Meyer et al, Liver Int2017; El-Khoueiry et al, Lancet 2017; Zhu et al, Lancet Oncol2018

  42. Stratification in Phase III Trials • ECOG PS: subjective • Macrovascular invasion: extent of vascular invasion • Extrahepatic disease • Geographic regions: Asia (except Japan) vs the rest of world • AFP: 400 ng/mL as cut-off • Etiology: when sorafenib used as control • Pattern of progression?

  43. Stratification Used in Phase III Trials

  44. Classification of HCC Nault, Galle, Marquardt J Hepatology 2018

  45. BLU-554 in Advanced HCC: FGF19 IHC-Positivity Enriches for Radiographic Tumor Reduction and Response *4 confirmed responses Kim et al, ESMO 2017

  46. REACH Study: Overall Survival in Patients with Baseline Alpha‑fetoprotein  or < 400 ng/mL AFP 400 ng/mL AFP <400 ng/mL Zhu AX, et al. Lancet Oncology 2015

  47. Putative (Adaptive) Design for Future Clinical Trials in HCC Umbrella trials Basket trials

  48. Survival According to Response to Nivolumab • Non-Conventional Benefit • PD with new lesions followed by decrease in target lesion ≥10% • PD of target lesions followed by decrease in target lesion ≥30% • PD of target lesions or new lesions followed by stabilization (<10% additional increase in target lesion + new lesions) Presented at ASCO GI 2018 • Courtesy of Prof. Bruno Sangro

  49. Predictive Biomarkers to Checkpoint Inhibitors • MSI status • PD-L1 expression (cutoff, assays used, expression on tumor cells, immune cells or both) • TMB • Immune signatures

  50. Immune Signature of HCC Sia D et al, Gastroenterology2017 Pinyol et al, CCR, 2019

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