Ηπατοκυτταρικός Καρκίνος Συστηματική Θεραπεία. Θωμάς Μακατσώρης Επίκ. Καθ. Παθολογίας-Ογκολογίας Ιατρική Σχολή Πανεπιστημίου Πατρών 11/5/2018

Transcription

1 Ηπατοκυτταρικός Καρκίνος Συστηματική Θεραπεία Θωμάς Μακατσώρης Επίκ. Καθ. Παθολογίας-Ογκολογίας Ιατρική Σχολή Πανεπιστημίου Πατρών 11/5/2018

2 Advisory Board Disclosures Roche, Boeringer, Sanofi, Astra Zeneca, Genesis Honoraria Roche, Sanofi, Amgen, Merck, BMS, Gilead

3

4

5

6

7

8

9 Phase III SHARP Study: Sorafenib vs Placebo in Advanced HCC Stratified by macroscopic vascular invasion and/or extrahepatic spread; ECOG PS; geographical region Pts with advanced HCC, Child-Pugh A, at least 1 untreated lesion, ECOG PS 2, no previous systemic treatment, life expectancy 12 wks (N = 602) Sorafenib 400 mg PO BID, continuous dosing (n = 299) Placebo 2 tablets PO BID, continuous dosing (n = 303) Primary endpoints: OS, time to symptomatic progression Secondary endpoint: TTP (independent review), disease control rate, safety Llovet JM, et al. N Engl J Med. 2008;359: Kane RC, et al. Oncologist. 2009;14:

10 Probability of Survival SHARP: OS, TTP OS P < Mos Since Randomization Llovet JM, et al. N Engl J Med. 2008;359: Sorafenib Placebo Probability of No Symptomatic Progression Probability of Radiologic Progression Time to Symptomatic Progression P = Time to Radiologic Progression P < Mos Since Randomization Slide credit: clinicaloptions.com

11 SHARP: Efficacy Outcome Llovet JM, et al. N Engl J Med. 2008;359: Sorafenib (n = 299) Placebo (n = 303) HR (95% CI) P Value Median OS, mos ( ) < % CI yr OS, % Median TTP (symptomatic), mos 95% CI ( ).77 Median TTP (radiologic), mos ( ) < % CI Level of response, % CR 0 0 NA PR SD Disease-control rate, %

12

13 Sorafenib in Advanced HCC (GIDEON): OS by Child-Pugh Status at Study Entry Survival Distribution Function Median OS, Mos (95% CI) Child-Pugh A (< 7) (n = 726): 10.3 ( days) Child-Pugh B (7-9) (n = 219): 4.8 ( days) Child-Pugh C (> 9) (n = 12): 2.0 (46-94 days) Days Since Start of Treatment Daniele B, et al. ASCO Abstract Slide credit: clinicaloptions.com

14 Phase III STORM: OS With Adjuvant Sorafenib for HCC After Resection or Ablation Sorafenib (n = 556) Placebo (n = 558) OS (%) Pts at Risk, n Placebo Sorafenib Bruix J, et al. Lancet Oncol. 2015;16: HR: (95% CI: ; 1-sided P =.48) Mos Slide credit: clinicaloptions.com

15

16 TACE With Doxorubicin Beads ± Sorafenib in Intermediate-Stage HCC (Phase III SPACE) Progression Probability MVI/EHS Probability TTP (Central Review) HR: P =.072 Sorafenib Median: 169 days Placebo Median: 166 days Days 1.00 Time to MVI/EHS Sorafenib Median: NR Placebo Median: NR HR: P = Days Lencioni R, et al. J Hepatol. 2016;64: Survival Probability UnTACEable Progression Probability Sorafenib Median: NR OS 0.25 Placebo HR: Median: NR P = Days 1.00 Time to UnTACEable Progression HR: P =.999 Sorafenib Median: 95 days Placebo Median: 224 days Sorafenib (n = 154) Placebo (n = 153) Days Slide credit: clinicaloptions.com

17

18 Lenvatinib: Mechanism of Action Multitargeted, oral small molecular TKI Potent against VEGFR2 and VEGFR3 Also targets VEGFR1, FGFR1-3, PDGFRα, RET, and KIT O N O CI H N O H N VEGFR Lenvatinib RAS RAF MEK T202/Y204 P ERK1/2 P T421/S424 S235/S236 FGFR X PI3K AKT mtor P S6K P S6 T389 H 2 N O Angiogenesis Finn RS, et al. ASCO Abstract TPS4153.

19 Phase III Study 304: Frontline Lenvatinib vs Sorafenib in Unresectable HCC Randomized, open-label noninferiority phase III trial Pts with unresectable, previously untreated HCC, Child-Pugh A, ECOG PS 0-1 (N = 954) Lenvatinib 8 mg or 12 mg* QD (n = 478) Sorafenib 400 mg PO BID (n = 476) *Based on body weight. Treat until progression or toxicity Primary endpoint: OS Secondary endpoints: PFS, TTP, ORR, PK, QoL ClinicalTrials.gov. NCT Cheng AL, et al. ASCO Abstract 4001.

20

21

22

23 Regorafenib: Oral Multikinase Inhibitor Targeting Multiple Tumor Pathways Cl F F F N H O N H F O N O Regorafenib N H Biochemical Activity Mean Regorafenib IC 50, nmol/l ± SD Tests, n VEGFR1 13 ± Murine VEGFR2 4.2 ± Murine VEGFR3 46 ± 10 4 TIE2 311 ± 46 4 PDGFR-β 22 ± 3 2 Inhibition of proliferation KIT PDGFR RET Inhibition of tumor microenvironment signaling PDGFR-β FGFR Inhibition of neoangiogenesis VEGFR1-3 TIE2 1. Wilhelm SM, et al. Int J Cancer. 2011;129: Mross K, et al. Clin Cancer Res. 2012;18: Strumberg D, et al. Expert Opin Investig Drugs. 2012;21: FGFR1 202 ± 18 6 KIT 7 ± 2 4 RET 1.5 ± RAF ± B-RAF 28 ± 10 6 B-RAF V600E 19 ± 6 6 Slide credit: clinicaloptions.com

24 Sorafenib vs Regorafenib: Key Molecular Difference Sorafenib H 3 C H N O N O H N O H N CF 3 CI Regorafenib H 3 C H N O N O F H N O H N CF 3 CI Slide credit: clinicaloptions.com

25

26

27 Regorafenib: Dosage and Administration Approved by the FDA in April 2017 for pts with HCC previously treated with sorafenib [1] Recommended dose: 160 mg PO QD x 3 wks Q4W [1] 2-wk washout period recommended after discontinuing sorafenib [2,3] Allows for elimination of sorafenib and metabolites Demonstrated safety with this approach in RESORCE trial 1. Regorafenib [package insert]. 2. Bruix J, et al. Lancet. 2017;389: Jordi Bruix, MD, personal communication Slide credit: clinicaloptions.com

28

29

30

31

32

33 Phase I/II CheckMate 040: Nivolumab in Advanced HCC Phase I/II Without viral hepatitis 0.1 mg/kg (n = 1) Dose Escalation (n = 48) design n = 6 n = 9 n = 10 n = 10 n = mg/kg (n = 3) 1.0 mg/kg (n = 3) 3.0 mg/kg (n = 3) 10 mg/kg (n = 13) Dose Expansion (n = 214) 3 mg/kg Sorafenib untreated or intolerant (n = 56) Sorafenib progressor (n = 57) HCV infected 0.3 mg/kg (n = 3) 1.0 mg/kg (n = 4) 3.0 mg/kg (n = 3) HCV infected (n = 50) HBV infected 0.1 mg/kg (n = 5) 0.3 mg/kg (n = 3) 1.0 mg/kg (n = 3) 3.0 mg/kg (n = 4) HBV infected (n = 51) El-Khoueiry AB, et al. Lancet. 2017;[Epub ahead of print].

34

35

36

37

38

39 Conclusions<br />(2018 perspective of systemic tx for HCC)

40 Συμπερασματα

41

42

43

44 The Challenge: First-line Randomized Phase III Trials in HCC Phase III Trial Target(s) Median TTP, Mos Median OS, Mos Sunitinib vs sorafenib [1] VEGFRs, PDGFRs, c-kit, Flt3, RET 4.1 vs 3.8 HR: 1.13 (95% CI: ; P =.83) 7.9 vs sided P =.0014 Brivanib vs sorafenib (BRISK-FL) [2] VEGFR2, FGFR 4.2 vs 4.1 HR: 1.01 (95% CI: ) 9.5 vs 9.9 HR: 1.07 (95% CI: ; P =.3116) Linifanib vs sorafenib [3] VEGFR and PDGFR 5.4 vs. 4.0 HR: 0.76 (95% CI: ; P =.001) 9.1 vs. 9.8 HR: 1.04 (95% CI: ; P = NS) Sorafenib + erlotinib vs sorafenib + placebo [4] VEGFR1,2,3, Ras, Raf, EGFR 3.2 vs 4.0 HR: 1.13 (95% CI: ; P =.18) 9.5 vs. 8.5 HR: 0.93 (95% CI: ; P =.41) Doxorubicin + sorafenib vs References sorafenib in (CALGB slidenotes ) [5] VEGFR1,2, PDGFR, Ras, Raf 4.0 vs 3.9 HR: 0.90 (95% CI: ) 8.9 vs 10.5 HR: 1.06 (95% Slide CI: credit: ) clinicaloptions.com

45

46

47 Phase III SARAH: SIRT vs Sorafenib in Locally Advanced, Inoperable HCC After 2 Rounds of TACE Probability of Survival ITT Population (N = 459) SIRT Sorafenib Median 8.0 mos 9.9 mos HR: 1.15 (95% CI: ; log-rank P =.18) Pts at Risk, n Mos Since Randomization SIRT Sorafenib Probability of Survival Pts at Risk, n SIRT Sorafenib Per Protocol Population (n = 380) SIRT Sorafenib Median 9.9 mos 9.9 mos HR: 0.99 (95% CI: ; log-rank P =.92) Mos Since Randomization Vilgrain V, et al. EASL Abstract GS-02 Slide credit: clinicaloptions.com

48 Liver Embolotherapy Techniques Technique Mechanism Pros Cons TAE Induction of ischemic necrosis at arteriolar level using permanent embolic (eg, small particles) Low cost, no chemotherapy adverse events Postembolization syndrome; may cause PEs Conventional TACE (ctace) Intrahepatic chemotherapy combined with embolization from ethiodized oil Strongest evidence for benefit based on RCT data Technical variation between operators (ctace) Systemic release of chemotherapy (ctace) Postembolization syndrome DEB-TACE Intrahepatic chemotherapy + embolization with slowrelease drug-eluting beads More standardized than ctace, lower systemic release of chemotherapy More expensive than ctace Postembolization syndrome Kishore S, et al. Curr Oncol Rep. 2017;19:40. May improve TTP Fewer sessions required No postembolization syndrome Cost: 2-3x more expensive Requires Slide credit: multidisciplinary clinicaloptions.com

49 Conclusion: How to treat pts with advanced disease? First line Second line Third line Sorafenib Lenvatinib? Immunotherapy? Ongoing phase III trial of nivolumab vs sorafenib Regorafenib Cabozantinib? Ongoing phase III study vs placebo Immunotherapy? Ongoing phase III study of pembrolizumab vs BSC Slide credit: clinicaloptions.com

50 Treatment Options for Pts With HCC Stage of Disease Treatment Option Survival Rate Early Surgery/transplantation, PEI/RFA ~ 50% to 75% at 5 yrs ~ 40% to 50% at 5 yrs *Monotherapy or combination chemotherapy, immunotherapy, internal radiation, tamoxifen, antiandrogen agents failed to Intermediate demonstrate survival benefit. TACE ~ 40% to 60% at 2 yrs Advanced (first line) Sorafenib/clinical trials < 30% at 1 yr* Llovet JM. J Gastroenterol. 2005;40:

51 Tumor Burden, Liver Function, and Performance Status Influence Prognosis First-line treatment options for each stage of HCC Therapy is decided according to tumor burden, liver function, and PS Pts: Child-Pugh A-B, preserved ECOG PS, absence of severe comorbidities Diagnosis BCLC 0 BCLC A BCLC B BCLC C BCLC D Surgery ablation TACE Sorafenib Best Death supportive care Bruix J, et al. Gastroenterology. 2016;150: Slide credit: clinicaloptions.com

52 SHARP: Drug-Related Adverse Events Adverse Event Reported in 10% of Pts, % Any Grade Llovet JM, et al. N Engl J Med. 2008;359: Sorafenib (n = 297) Placebo (n = 302) P Value Grade 3 Grade 4 Any Grade Overall incidence Grade 3 Grade 4 Any Grade Grade 3/4 Fatigue < Alopecia <.001 NA Hand foot skin reaction Rash/desquamati on < 1 0 <.001 < Anorexia 14 < < Diarrhea <.001 <.001 Nausea 11 <

53 Treatment of Advanced HCC: Probability of Survival Sorafenib Outcomes in Western Pts [1] P < Mos Since Randomization Best Response (RECIST), % Sorafenib (n = 299) Placebo (n = 303) CR 0 0 PR SD PD Progression-free rate at 4 mos Probability of Survival Sorafenib Outcomes in Asian Pts [2] Mos Response, n (%) Sorafenib (n = 150) Sorafenib Placebo Placebo (n = 76) CR 0 0 PR 5 (3.3) 1 (1.3) SD 81 (54.0) 21 (27.6) PD 46 (30.7) 41 (54.0) Not assessable 18 (12.0) 13 (17.1) 1. Llovet JM, et al. N Engl J Med. 2008;359: Cheng AL, et al. Lancet Oncol. 2009;10:25-34.

54

55

56