New Insights: Systemic Therapy for Advanced Hepatocellular Carcinoma (HCC)

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1 New Insights: Systemic Therapy for Advanced Hepatocellular Carcinoma (HCC) Thomas W.T. Leung Associate Director and Honorary Consultant Comprehensive Oncology Centre Hong Kong Sanatorium and Hospital Hong Kong International Oncology Forum 9 September 2018

2 Localized and small HCC Local ablation with RFA, microwave, ethanol Localized but not suitable for local ablation Intra-arterial therapy Transarterial chemoembolization (TOCE or TACE, DEB-TACE) Radioembolization with yttrium-90 microspheres External radiotherapy (SBRT, proton therapy) All others including metastatic disease Systemic Therapy Chemotherapy, targeted therapy, immunotherapy

3 The era of cytotoxic chemotherapy ( ) HCC is in general chemotherapy resistant Objective response rates (> PR) are below 10% No convincing evidence that it prolongs survival

4 Treatment for Advanced HCC: Systemic Single-Agent Chemotherapy Authors, year Study type Agent(s) n PR (%) CR (%) Survival Sciarrino et al, 1985 Tan et al, 1986 Hochster et al, 1985 Okada et al, 1993 Pohl et al, 2001 Retrospective Doxorubicin % at 1 year Phase II Epirubicin weeks Phase II Epirubicin ND Phase II Cisplatin ND Retrospective Epirubicin months PR = partial response; CR = complete response

5 HAG and CT scan before Doxorubicin

6 CT Scan After 6 Cycles of Doxorubicin Surgery was done after treatment and patient has complete remission afterwards

7 Treatment for Advanced HCC: Systemic Combination Chemotherapy Authors, year Study type Agent(s) n Morstyn et al, 1983 Phase II Doxorubicin + streptozotocin PR (%) CR (%) Median survival months Falkson et al, 1999 Phase II Doxorubicin + clofazimine weeks Leung et al, 1999 Phase II PIAF* months Ikeda et al, 2005 Phase II 5-FU, mitoxantrone + cisplatin months Kim et al, 2006 Phase II Epirubicin, cisplatin, UFT, and leucovorin weeks *PIAF = cisplatin, doxorubicin, 5-fluorouracil (5-FU) and interferon-α (IFN-α)

8 Response to PIAF Chemotherapy CT scan before treatment

9 Response to PIAF Chemotherapy CT scan after 6 cycles of PIAF (Surgery performed after chemo)

10 Patient M/55 Hepatitis B carrier, AFP 727ng/ml Child A CT scan 4 September 2017: 11.6x9.9.2cm with portal vein thrombus PET CT scan on 7 September 2017

11 6 cycles combination chemotherapy PIAF from 9/2017 to 2/2018 AFP normalized Operated in Feb 2018 Complete remission afterwards

12 Treatment for Advanced HCC: Systemic Chemotherapy (randomized studies) Authors, year Study type Agent(s) n PR (%) CR (%) Survival p for difference Lai et al, 1988 RCT Doxorubicin vs 60 N/A N/A 10.6 weeks No therapy 46 N/A N/A 7.5 weeks Yeo et al, 2005 Phase III RCT Doxorubicin vs months 0.83 PIAF months Choi et al, 1998 RCT Doxorubicin vs weeks ND 5-FU, methotrexate, cyclophosphamide + vincristine 19 N/A N/A 6.5 weeks PIAF = cisplatin, doxorubicin, 5-fluorouracil (5-FU) and interferon-α (IFN-α)

13 Targeting the Molecular Pathways Involved in HCC - The Targeting Therapy Era 1. Molecular pathogenesis 2. Signalling pathways involved in proliferation, cell survival and angiogenesis 3. Molecular-targeted therapies in clinical development

14 Targeted agents for HCC Anti-angiogenic targets Antiproliferative targets Agents VEGF VEGFR PDGFR EGFR Raf mtor Bevacizumab BMS Cediranib Erlotinib Gefitinib Lapatinib RAD001 Sorafenib Sunitinib Thalidomide TSU-68

15 Sorafenib Multi-kinase inhibitor Targets angiogenesis Targets proliferation through the Raf/MEK/ERK pathway The first molecular-targeted therapy to show an OS benefit in patients with HCC in a phase III trial 1 1. Llovet JM, et al. ASCO 2007, Chicago, IL, USA

16 Survival probability Phase III SHARP Trial: OS (Intention-to-treat) Sorafenib Median: 46.3 weeks (10.7 months) (95% CI: ) Placebo Median: 34.4 weeks (7.9 months) (95% CI: ) 0.25 Patients at risk Sorafenib: Placebo: Hazard ratio (S/P): 0.69 (95% CI: ) p= * Weeks *O Brien Fleming threshold for statistical significance was p= Llovet JM, et al. Presented at ASCO 2007, Chicago, IL, USA

17 Phase III SHARP Trial: Response Sorafenib Placebo n (%) n (%) Total number of patients Overall response Complete response (CR) 0 0 Partial response (PR) 7 (2.3) 2 (0.7) Stable disease (SD) 211 (71) 204 (67) Progressive disease (PD) 54 (18) 73 (24) Progression-free rate at 4 months (%) Duration of treatment (median, weeks) FSHI8-TSP: no significant differences between treatment groups (p=0.77) RECIST = Response Evaluation Criteria In Solid Tumors Llovet J, et al. ASCO 2007, Chicago, USA

18 Survival probability Asia-Pacific Study: Overall Survival Sorafenib Median: 6.5 mo (95% CI: ) Placebo Median: 4.2 mo (95% CI: ) HR (S/P): % CI: P= Months Patients at Risk Sorafenib Placebo Cheng A, et al. J Clin Oncol. 2008;26. Abstract Updated from oral presentation at ASCO; Chicago, IL; June 2008.

19 Asia-Pacific Study: RECIST Response Sorafenib (n=150) Placebo (n=76) ORR (CR+PR), % 3 1 CR 0 0 PR 3 1 SD, % PD, % DCR,* % *DCR = CR + PR maintained for 4 weeks + SD documented at least 12 weeks from baseline. Cheng A, et al. J Clin Oncol. 2008;26. Abstract Updated from oral presentation at ASCO; Chicago, IL; June 2008.

20 Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. Abou-Alfa GK, Johnson P, Knox J, Davidenko I, Lacava J, Leung T, Mori A, Leberre M-A, Voliotis D, and Saltz LB (JAMA 304(19): , 2010)

21 Results DXR/sorafenib DXR/placebo (n=47) (n=49) TTP (months) OS (months) PFS (months) Response 2 (4) 1 (2) (CR+PR) n(%) Response (SD) 36 (77) 27 (55) Definitive analysis (data from March 2007 cutoff, independent assessment, TTP: 38 events, OS: 51 events, PFS: 70 events )

22 Proportion of Patients Exploratory Comparison Per Protocol: Overall Survival Median OS: Doxorubicin + sorafenib: 13.8 (95% CI: 9.1-can not be estimated) Doxorubicin + placebo: 6.5 (95% CI: ) Hazard Ratio: 0.51 p= Total # of events: months Months From Randomization STRATA: Doxorubicin plus sorafenib Doxorubicin + placebo Censored treatment: Doxorubicin + sorafenib Censored treatment: Doxorubicin + placebo

23 Multiple kinase inhibitor: RET, KIT, PDGFR VEGFR1-3 FGFR, PDGFRβ FGFR1-4 Dual inhibition of VEGF and FGF pathways, thus inhibiting angiogenesis and tumour growth

24 Randomization 1:1 Study Schema: Phase III REFLECT Study Compare the Efficacy and Safety of Lenvatinib vs Sorafenib in First-line Treatment of Patients With Unresectable HCC Global, randomized, open-label, phase 3 non-inferiority study Patients with unresectable HCC (N=954) No prior systemic therapy for unresectable HCC 1 measurable target lesion per mrecist BCLC-B (not applicable for TACE) or BCLC-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 Stratification Region: (Asia-Pacific or Western) MVI and/or EHS: (yes or no) ECOG-PS: (0 or 1) Body weight: (<60 kg or 60 kg) Lenvatinib (N=478) 8 mg (BW <60 kg) or 12 mg (BW 60 kg) once daily Sorafenib (n = 476) 400 mg twice daily Primary objective: OS Secondary objectives: PFS TTP ORR Quality of life PK lenvatinib exposure parameters * Tumor assessments were performed according to mrecist by the investigator BCLC = Barcelona Clinic Liver Cancer; BW = body weight; ECOG-PS = Eastern Cooperative Oncology Group Performance Status; EHS = extrahepatic spread; HCC = hepatocellular carcinoma; MVI = 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; TACE = trans-catheter arterial chemoembolization; TTP = time to progression. 1. Cheng AL et al. Oral abstract presented at the ASCO Annual Meeting, Chicago, IL, USA. Jun 4, 2017; 2. Finn R et al. Poster presented at the ASCO 50th Annual Meeting, Chicago, IL, USA. May 30 Jun 3, 2014.

25 Maximum tumor shrinkage (%) Maximum tumor shrinkage (%) Secondary Endpoint: ORR ORR, n, % (95% CI) Odds ratio (95% CI), p value Lenvatinib (N=478) % (20.2, 27.9) 3.13 (2.15, 4.56), p< Sorafenib (N=476) % (6.6, 11.8) CR, n, % 6 1.3% 2 0.4% PR, n, % % % SD, n, % % % SD 23 weeks, n, % % % PD, n, % % % Unknown/NE, n, % % % DCR, n, % (95% CI) % (71.7, 79.4) % (56.1, 64.9) Percentage change in tumor size is truncated at 100% (rectangles) ORR is defined as CR + PR, according to mrecist Lenvatinib (N=433) Sorafenib (N=436) CR (n=6) CR (n=2) CI = confidence interval; CR = complete response; DCR = disease control rate; NE = not evaluable; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease; wks = weeks. 1. Cheng AL et al. Oral abstract presented at the 2017 ASCO Annual Meeting, Chicago, IL, USA. Jun 4, 2017.

26 Outcomes LEN SOR HR Median OS, mos (95% CI) Median PFS, mos (95% CI)* Median TTP, mos (95% CI)* 13.6 ( ) 12.3 ( ) 0.92 ( ) 7.4 ( ) 3.7 ( ) 0.66 ( ) 8.9 ( ) 3.7 ( ) 0.63 ( ) ORR, n (%)* 115 (24) 44 (9) *P <

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28 Lenvatinib* versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial Kudo M, Finn RS, Qin S, Han K, Ikeda K, Piscaglia F, et al. The Lancet 391: , March 24, 2018 *Lenvatinib was approved by FDA and EU in August 2018 as first line treatment for unresectable hepatocellular carcinoma

29 Patient M/44 Hepatitis B carrier CT scan showed bilobar HCC AFP > 40,000ng/ml Inoperable 30

30 Start on oral Lenvatinib 12mg qd po July 2018 Reassess PET CT scan in October 2018 AFP 6245ng/ml 31

31 Inhibit tyrosine kinases including VEGF, MET and AXL VEGF, MET and AXL promote tumour progression and angiogenesis MET and AXL are associated with resistance to VEGF-targeted therapy

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36 Presented By Ghassan Abou-Alfa at 2018 Gastrointestinal Cancers Symposium

37 NEJM 2018; 379:54-63 July issue CONCLUSIONS Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group.

38 The Era of Immuno-oncology - Nivolumab (anti PD-1) Nivolumab is a fully human (IgG4) monoclonal antibody inhibitor of the programmed death-1 (PD-1) receptor that restores T-cell mediated antitumor activity CheckMate 040 (NCT ) is a phase 1/2 multi-cohort of study of nivolumab in sorafenibnaive and -experienced patients with advanced HCC 3

39 CheckMate 040 Study Design CheckMate 040 Study Sorafenib Naive n = 11 Dose Escalation mg/kg n = 48 Sorafenib Experienced n = 37 All Patients (N = 262) Sorafenib Naive n = 69 Dose Expansion 3 mg/kg n = 214 HCV Infected HBV Infected Uninfected Sorafenib Experienced n = 145 Disease assessment imaging (CT or MRI) every 6 weeks Study Endpoints Primary Safety and tolerability (escalation) ORR a (expansion) Secondary ORR a (escalation) Disease control rate Time to response Duration of response Overall survival Other Biomarker assessments Viral kinetics on treatment ORR, objective response rate. a RECIST v1.1. 5

40 Objective Response Rates in CheckMate 040 Blinded Independent Central Review All Patients (N = 262) Dose Escalation mg/kg ORR: 16.7% Dose Expansion 3 mg/kg ORR: 16.8% n = 48 n = 214 Sorafenib Naive n = 11 Sorafenib Experienced n = 37 Sorafenib Naive n = 69 Sorafenib Experienced n = 145 HCV Infected (n = 30) HBV Infected (n = 43) Uninfected (n = 72) ORR: 9.1% ORR: 18.9% ORR: 21.7% BICR (blinded independent central review) using RECIST v1.1. Median follow-up was 13.3 months in the doseescalation phase and 12.9 months in the doseexpansion phase 7

41 Patients, n (%) Baseline Characteristics Sorafenib-Experienced Patients Dose-Expansion Phase HCV Infected (n = 30) HBV Infected (n = 43) Uninfected (n = 72) Age, median (range), years 64.5 (53 81) 56.0 (22 81) 65.5 (19 80) Male 25 (83) 31 (72) 56 (78) Race White 17 (57) 4 (9) 46 (64) Asian 13 (43) 37 (86) 25 (35) Black 0 2 (5) 1 (1) BCLC stage B or C 28 (93) 43 (100) 72 (100) Extrahepatic metastases 16 (53) 36 (84) 51 (71) Vascular invasion 9 (30) 12 (28) 20 (28) Child-Pugh score 5 15 (50) 34 (79) 48 (67) 6 13 (43) 9 (21) 24 (33) > 6 2 (7) 0 0 AFP 400 mg/l a 9 (30) 21 (49) 25 (35) Prior treatments Surgical resection 15 (50) 35 (81) 45 (63) Radiotherapy 4 (13) 11 (26) 21 (29) Local treatment for HCC 15 (50) 33 (77) 37 (51) Sorafenib (progression) b 27 (90) 42 (98) 63 (88) Sorafenib (intolerance) b 3 (10) 1 (2) 8 (11) a Baseline α-fetoprotein (AFP) levels not reported in 5 patients; b One patient (uninfected) was neither intolerant of sorafenib nor a progressor. 8

42 Best Overall Response Sorafenib-Experienced Patients Dose-Expansion Phase Patients, n (%) HCV Infected (n = 30) HBV Infected (n = 43) Uninfected (n = 72) All Patients (N = 145) Objective response, BICR using RECIST v1.1 6 (20.0) 6 (14.0) 9 (12.5) 21 (14.5) Complete response 1 (3.3) 1 (2.3) 0 Partial response 5 (16.7) 5 (11.6) 9 (12.5) Stable disease 9 (30.0) 14 (32.6) 37 (51.4) Progressive disease 11 (36.7) 22 (51.2) 23 (31.9) Not evaluable 4 (13.3) 1 (2.3) 3 (4.2) Objective response, BICR using mrecist 9 (30.0) 8 (18.6) 10 (13.9) 27 (18.6) Objective response, INV using RECIST v1.1 8 (26.7) 6 (14.0) 14 (19.4) 28 (19.3) Complete response 0 1 (2.3) 2 (2.8) Partial response 8 (26.7) 5 (11.6) 12 (16.7) Stable disease 11 (36.7) 18 (41.9) 35 (48.6) Progressive disease 8 (26.7) 19 (44.2) 20 (27.8) Not evaluable 3 (10.0) 0 3 (4.2) BICR, blinded independent central review; INV, investigator assessment. Disease control rate in all patients by BICR (RECIST v1.1) was 55.9% High concordance (88.3%) of responder and non-responder status by BICR and INV 10

43 Probability of survival HCV Infected (n = 30) HBV Infected (n = 43) Uninfected (n = 72) All Patients (N = 145) Median OS (95% CI) a NR NR 16.7 (11.3 NE) 16.7 (13.2 NE) 12-mo OS rate (95% CI), % a 67.1 ( ) 55.6 ( ) 59.7 ( ) 59.9 ( ) NR, not reached; NE, not estimable. a Kaplan-Meier method. Overall Survival Sorafenib-Experienced Patients Dose-Expansion Phase Months 14

44 Tumor-cell PD-L1 Expression and ORR Sorafenib-Experienced Patients Dose-Expansion Phase Objective Responses a HCV Infected (n = 28) HBV Infected (n = 41) Uninfected (n = 57) Tumor-cell PD-L1 expression 1%, n/n (%) b [95% CI] 3/8 (37.5) [ ] 2/8 (25.0) [ ] 2/9 (22.2) [ ] Tumor-cell PD-L1 expression < 1%, n/n (%) b [95% CI] 3/20 (15.0) [ ] 4/33 (12.1) [ ] 6/48 (12.5) [ ] a BICR using RECIST v1.1; b Tumor-cell PD-L1 expression not evaluable in 19 patients (HCV, n = 2; HBV, n = 2; uninfected, n = 15). Objective responses occurred irrespective of PD-L1 expression on tumor cells Tumor-cell PD-L1 expression was measured using the pharmdx 28-8 IHC assay (Dako) 15

45 HCV Infected (n = 30) HBV Infected (n = 43) Uninfected (n = 72) Any Grade Any Grade Any Grade n (%) Grade 3/4 Grade 3/4 Grade 3/4 Patients with any treatment-related AE 25 (83) 9 (30) 30 (70) 4 (9) 53 (74) 11 (15) Treatment-related AEs ( 5%) a Fatigue 6 (20) 1 (3) 5 (12) 0 24 (33) 2 (3) Pruritus 8 (27) 1 (3) 9 (21) 0 10 (14) 0 Rash 6 (20) 0 6 (14) 0 11 (15) 1 (1) Diarrhea 5 (17) 0 4 (9) 1 (2) 11 (15) 1 (1) Nausea 3 (10) 0 1 (2) 0 8 (11) 0 Dry mouth 1 (3) 0 2 (5) 0 5 (7) 0 Decreased appetite 2 (7) 1 (3) 3 (7) 0 3 (4) 0 Laboratory treatment-related AEs ( 5%) a Safety Sorafenib-Experienced Patients Dose-Expansion Phase ALT increased 2 (7) 1 (3) 2 (5) 0 6 (8) 2 (3) AST increased 2 (7) 2 (7) 1 (2) 0 5 (7) 2 (3) Blood bilirubin increased b 1 (3) (3) 0 Platelet count decreased 2 (7) 2 (7) 6 (14) 2 (5) 0 0 a Reported in 5% of all patients (N = 145), any grade; b Blood bilirubin increases were < 5% for all patients. Overall safety profile of nivolumab was similar to that of other tumor types with no new safety signals Most ALT and AST elevations were reversible with established algorithms 17

46 Conclusions Sorafenib-Experienced Patients Dose-Expansion Phase In sorafenib-experienced patients with or without chronic viral hepatitis, nivolumab* demonstrated: Long-term survival and durable objective responses with extended follow-up that were consistent across etiologies Safety profiles of nivolumab in patients with or without chronic viral hepatitis were similar to what has been observed in other tumor types Hepatic safety events, including ALT/AST elevations, were manageable and reversible No new safety signals were observed *Nivolumab was approved by FDA in 2018 to treatment HCC previously exposed to sorafenib 18

47 CheckMate 040 Lancet Jun 24;389(10088):

48 Patient F/83 Hepatitis B and C negative, non drinker AFP 245,827ng/ml, CT scan showed cirrhotic liver and right lobe HCC PET CT scan showed 12.3cm right lobe HCC, more 18-FDG avid than C11 acetate

49 Inoperable due to small cirrhotic liver as assessed by HPB surgeon Offered sorafenib but patient refused 6 months of intravenous Nivolumab Normalised AFP 3.4ng/ml after treatment PET CT scan showed metabolic quiescent and complete regression of the right lobe tumour In complete remission one year after diagnosis 50

50 Patient: M/74 Hep B carrier, chronic smoker and drinker HCC previously treated by TACE and RFA and sorafenib Multiple bone metastases from PET CT scan, AFP 18ng/ml

51 IVI Nivolumab for 6 months PET CT scan showed most bone metastases had achieved metabolic quiescent 52

52 HCC is no longer a drug therapy resistant disease (chemotherapy, tyrosine kinase inhibitors, anti PD-1 therapy etc) Combination therapy is next to explore and pending results Anti PD-1/PD-L1 with different tyrosine kinase inhibitors Anti PD-1/PD-L1 with CTLA-4 Systemic therapy should be included as part of multimodality treatment CLINICAL TRIALS for advanced HCC in the following settings Post operation adjuvant therapy Induction treatment as downstaging or bridging therapy, for resection or liver transplantation Adjunctive therapy to TACE, SIRT, RFA or SBRT