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A Master Class on Treating Unresectable HCC Is There a Right Sequence?
Sunday, June 3, 2018 MODERATOR Tanios Bekaii-Saab, MD Professor Mayo Clinic College of Medicine and Science Co-Leader GI Cancer Program Mayo Clinic Cancer Center Phoenix, Arizona GI = gastrointestinal HCC = hepatocellular carcinoma
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Program Agenda Welcome and Introduction
Tanios Bekaii-Saab, MD Setting the Stage: The Evolving Treatment Algorithm Case 1: First-Line Treatment in Unresectable HCC Richard S. Finn, MD Case 2: Treatment Upon Disease Progression in Unresectable HCC Panel Discussion & Concluding Remarks All Faculty
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Setting the Stage The Evolving Treatment Algorithm
MODERATOR Tanios Bekaii-Saab, MD Professor Mayo Clinic College of Medicine and Science Co-Leader GI Cancer Program Mayo Clinic Cancer Center Phoenix, Arizona
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Worldwide Incidence of HCC
Countries > 12.7 China, Korea, and other parts of Asia Parts of Africa 7.7 to 12.7 United States Parts of Europe and parts of Africa 5.6 to 7.7 Mexico and Australia Brazil and other parts of South America 4 to 5.6 Canada and Russia Argentina and other parts of South America < 4 Colombia and other parts of South America Norway, Sweden, and other parts of Europe India and parts of Africa HCC = hepatocellular carcinoma WHO = World Health Organization World Health Organization. Estimated Liver Cancer Incidence Worldwide in Accessed July 31, 2018. Add to abridged transcript: There is a variety of reasons that drive these differences, including viral hepatitis trend, NASH, and others. In the United States a primary driver for HCC as we find is an increasing incidence of fatty liver and eventually NASH. *Estimated age-standardized rates (world) per 100,000 WHO. GLOBOCAN 2012: Liver Cancer Incidence Worldwide.
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What We Know About Treating HCC in 2018
Staging patients is important (physiologic and anatomic) The only curative approach is surgery (resection or transplant) Most patients are not candidates for surgery Chemoembolization (TACE) and RFA can improve survival in selected patients Eventually, most patients will require systemic treatment if they live long enough Cytotoxic chemotherapy has not had any impact on this disease Molecularly targeted and immunotherapeutic agents have helped expand the treatment landscape in HCC TACE = transarterial chemoembolization Add to abridged transcript: What do we know about treating HCC in 2018? That staging is, of course, important. Two things affect HCC and its treatment is the extent of the disease but also the extent of the liver damage, as most of these patients will have liver cancer induced in the setting of cirrhosis.
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BCLC Staging and Treatment Strategy
Figure No Longer Available BCLC = Barcelona Clinic Liver Cancer RCT = randomized controlled trial Add to abridged transcript: We rely a lot on this and other staging criteria. This is the Barcelona Clinic Liver Cancer Staging and Treatment Strategy. As you can see, it essentially classifies patients from the very early stage to the early stage, intermediate, advanced, and terminal. For the intermediate stage, it is typically TACE, although some of these patients are being included in first-line studies with systemic therapies. Some patients may still benefit from the systemic therapies. Advanced stage, of course, we have now first and second-line and perhaps even beyond second-line options. Bruix J, et al. Gastroenterology. 2016;150: Reprinted from Gastroenterology, Vol 150, Bruix J, et al., Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma, , Copyright 2016, with permission from Elsevier
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How to Best Sequence Patients With Advanced Disease
First Line Second Line Third Line Fourth Line Sorafenib Regorafenib Cabozantinib (P) Nivolumab Lenvatinib (P) Nivolumab Ongoing phase 3 study of pembrolizumab vs BSC CP7 : Nivolumab? Cabozantinib (P) AFP = α fetoprotein BSC = best supportive care Ongoing phase 3 trial of nivolumab vs sorafenib AFP > 400 : Ramucirumab (P) P = data/study pending.
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Case 1 First-Line Treatment in Unresectable HCC
Richard S. Finn, MD Associate Professor of Medicine Department of Medicine Division of Hematology/Oncology Geffen School of Medicine at University of California, Los Angeles Add to abridged transcript: I am going to walk you through some of the issues that are evolving in the management of front-line advanced liver cancer. We are talking about unresectable liver cancer which can be a heterogenous group of patients. Patients can be unresectable for characteristics of their tumor or they can be unresectable for characteristics of their liver disease. That is why the Barcelona criteria tries to stratify patients.
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Case 1 Unresectable HCC 65-y-old man with HCV undergoes a liver ultrasound for screening when he sees a new PCP Ultrasound reveals a mass in the liver Follow-up with a CT scan reveals a 5.2-cm lesion in segment 6 and second lesion in segment 5 measuring 1.3 cm Lesions are hypervascular with delayed washout in a cirrhotic liver Labs: 9 > 12.8 < 94 T bili 0.9 Alb 3.7 Cr 0.8 INR 1.1 AST 60 ALT 54 AFP 23,000 ng/mL Past medical history: hypertension, neuropathy Alb = albumin ALT = alanine aminotransferase AST = aspartate aminotransferase Cr = creatinine CT = computed tomography HCV = hepatitis C virus INR = international normalized ratio PCP = primary care provider T bili = total bilirubin Add to abridged transcript: Keep in mind ultrasound is the current recommended screening tool, not relying only on a serum biomarker like AFP, but ultrasound is the backbone. He has got a second lesion in segment 5, 1.3 centimeters. These are hypervascular with delayed washout, so this is diagnostic of liver cancer in a cirrhotic patient; no biopsy is needed. His platelet count is 94,000 so he does have some portal hypertension. This is a patient who will not be resectable. Having a platelet count under 100,000 is often used by most surgeons as a representation of the amount of portal hypertension. Even though anatomically this patient might be a candidate for surgery, with the platelets under 100,000, that is a sign of portal hypertension. This patient's liver function is good. If we look at a Child-Pugh score, which is 1 of the ways we assess liver function, there is no mention of ascites [PH] or encephalopathy. Clinically, his bilirubin is normal, his albumin is normal, and his INR is normal. This is a patient with what we would call intermediate liver cancer, a multi-focal, well-compensated, Barcelona B.
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Case 1 Unresectable HCC (cont)
Add to abridged transcript: The right lobe is there, you can see it is nodular consistent with cirrhosis, and you see a hypervascular lesion there in the right lower lobe. Image courtesy Richard S. Finn, MD.
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Patient Undergoes TACE With Initial Good Local Response
AFP nadirs at 5000 Repeat imaging 3 mo later shows development of multiple lesions in chest Patient remains asymptomatic, well-compensated Proceeds to systemic treatment Add to abridged transcript: The other scenario we could see here is he gets imaged and he has new lesions on the left lobe. That patient might be still considered for chemoembolization; those are lesions that had not been treated. Let us say he had a chemoembolization and the lesion treated at 1 month is still not controlled. He undergoes another chemoembolization and it is still not controlled. That patient is someone who is failing TACE. He has had repeated TACE, the tumor is not controlled, and he is also a candidate for systemic treatment even though they do not have disease outside the liver. If the follow-up imaging showed that his tumor was now invading into the portal vein or into the vasculature. Again, that stage migrates this patient to advanced disease. It is important to keep this in mind because we are going to be talking later about all the activity in the new and exciting drugs that are happening in liver cancer. One of the main challenges in getting patients to treatment is getting patients at the appropriate time. If patients undergo repeated local or regional therapy, each time they have that done, there is some liver dysfunction that occurs. Often in the community, the medical oncologist will get a patient referred after they have had numerous TACE, they are decompensated, they have ascites, they have elevated bilirubin, and it is very hard to impact the survival of that patient because at that point they have decompensated liver disease and that is their risk of death, not cancer. Patients can have advanced disease, be appropriate candidates for systemic treatment without having over [PH] metastatic disease. That is an important message.
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BCLC Staging and Treatment Strategy
Add to abridged transcript: Just referring back to the Barcelona Staging System, we talked about that this patient now has category C disease because they have extrahepatic spread. Similarly, if they had invasion to a branch of the portal vein or they had symptomatic disease, these patients are not candidates for chemoembolization or local or regional therapy. When we did not have any systemic treatments available, we did tend to do TACE repeatedly even beyond progression. Now that we have systemic treatments that have proven to extend survival, it is important that we transition patients early. Bruix J, et al. Gastroenterology. 2016;150:
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Phase 3 SHARP Trial Study Design
Eligibility criteria HCC verified by histology Child-Pugh class A ECOG PS 0-2 No prior systemic anticancer treatment Prior hormonal therapy allowed Prior surgical or locoregional treatments allowed Measurable disease Stratification Macroscopic vascular invasion and/or extrahepatic spread ECOG PS Geographical region Sorafenib 400 mg po bid continuous dosing (n = 299) N = 602 R 1:1 Placebo 2 tablets po bid continuous dosing (n = 303) AE = adverse event bid = twice daily ECOG PS = Eastern Cooperative Oncology Group performance status FHSI8-TSP = Functional Assessment of Cancer Therapy–Hepatobiliary Symptom Index 8 OS = overall survival po = per os (by mouth) R = randomized SHARP=Sorafenib Hepatocellular carcinoma Assessment Randomized Protocol Add to abridged transcript: The only drug that is approved in the United States and globally, uniformly, worldwide is sorafenib and that is based on the SHARP study. This is an old study now, but importantly we learn that you can improve survival with advanced liver cancer. They took patients who were Child-Pugh A, so patients who had well-compensated liver disease. It is in that population that you can show that you can improve survival. Someone is going to die of cirrhosis even if you make their tumor disappear; you might not improve their survival because they will die of underlying liver disease. Treatment continued until radiographic and symptomatic progression or any AEs requiring withdrawal Treatment cycle defined as 6 wk Primary endpoints: OS, time to symptomatic progression (FHSI8-TSP) Secondary endpoints: time to radiologic progression, disease control rate, safety Llovet JM, et al. N Engl J Med. 2008;359:
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Phase 3 SHARP Trial Efficacy
Endpoint Sorafenib n = 299 Placebo n = 303 HR (95% CI) P Value mOS (ITT population), mo 10.7 7.9 0.69 (0.55, 0.87) < .001 mTTP, mo 5.5 2.8 0.58 (0.45, 0.74) Overall response,* % CR PR 2 1 SD 71 67 PD, % 18 24 Progression-free rate at 4 mo, % 62 42 CI = confidence interval CR = complete response HR = hazard ratio ITT = intent-to-treat mOS = median overall survival mTTP = median time to progression PR = partial response SD = stable disease Add to abridged transcript: This study was shown to improve survival by about 3 months; 7.9 to 10.7 or a 31% decrease in the risk of death. This has been consistent in many studies. Interestingly, we know that the response rate with sorafenib is single-digit, very uncommon to see a real radiographic resist response. What we do see is a doubling in time to progression in progression-free survival. By slowing progression, we were able to improve overall survival. Here you see that response data, very low numbers. *Not assessable: sorafenib (8.7%), placebo (8.3%). Llovet JM, et al. N Engl J Med. 2008;359:
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Phase 3 SHARP Trial Toxicity
Sorafenib n = 297 Placebo n = 302 Toxicity All Grade 3/4 Anorexia 14 < 1 3 1 Weight loss 9 2 Alopecia HFSR 21 8 Pain (abdominal) Nausea 11 Vomiting 5 Diarrhea 39 Liver dysfunction Bleeding 7 4 < 2 HFSR = hand-foot skin reaction Add to abridged transcript: The toxicity profile with this drug is well known. Really GI and skin toxicity are issues. The hand-foot skin reaction generally can be managed with prophylactic creams or urea-based creams and education. As far as diarrhea, things like loperamide and dose reductions are appropriate. Llovet JM, et al. N Engl J Med. 2008;359:
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Pivotal Trials Demonstrated OS Benefit With Sorafenib in uHCC
Endpoint SHARP[a] ASIA-PACIFIC[b] Sorafenib n = 299 Placebo n = 303 n = 150 n = 76 mOS, mo 10.7 7.9 6.5 4.2 HR (95% CI) 0.69 (0.55, 0.87) 0.68 (0.50, 0.93) P value < .001 .014 uHCC = unresectable hepatocellular carcinoma Add to abridged transcript: Asia-Pacific study showed that the hazard ration was exactly the same, 0.68, but notice the control arms did differently; 8 months in West in the SHARP study, 4 months in Asia-Pacific, reflecting some regional differences in how patients are managed. In Asia-Pacific, a lot more TACE is done and by the time they get referred for systemic treatment the natural history of those patients is very short. Sorafenib consistently increased OS in different patient populations across geographic regions and etiologies a. Llovet JM, et al. N Engl J Med. 2008;359: ; b. Cheng AL, et al. Lancet Oncol. 2009;10:25-34.
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Pooled Analysis Conducted to Help Identify Predictive Factors for Sorafenib Treatment
To identify prognostic factors for HCC and predictive factors of response to sorafenib treatment, a pooled analysis of 827 randomly assigned patients in the SHARP (n = 601) and Asia-Pacific (n = 226) phase 3 trials was performed SHARP study Asia-Pacific study Pooling Multivariate analysis* Interaction test* HR* mOS† Univariate analysis* To identify prognostic factors for OS To assess consistency of the efficacy of sorafenib or identify predictive factors for treatment response Add to abridged transcript: There have been efforts to try to identify the patients who do better with sorafenib. There has been no biomarker that has been identified. This study tries to identify clinical characteristics that are associated with better outcome. *Using the Cox proportional hazard regression model. †Based on Kaplan-Meier methodology. Bruix J, et al. J Hepatol. 2017;67:
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Treatment Interaction
Identification of Potential Baseline Characteristics Associated With Treatment Benefit Baseline covariates N* mOS (mo) PBO vs SOR HR (SOR/PBO) [95% CI] Treatment Interaction P Value† BCLC Stage B 113 13.4 15.1 0.78 [0.46, 1.32] .431 Stage C 714 6.0 8.5 0.69 [0.57, 0.83] Tumor burden Absent 229 10.6 15.7 0.53 [0.37, 0.78] .081 (present vs absent) Present 598 5.6 7.3 0.77 [0.64, 0.93] MVI No 515 10.0 12.7 0.70 [0.56, 0.88] .947 (yes vs no) Yes 310 4.5 0.69 [0.53, 0.89] EHS 365 7.2 13.8 0.55 [0.42, 0.72] .015 462 7.0 0.84 [0.67, 1.05] MVI without EHS 689 9.5 0.74 [0.62, 0.90] .283 136 6.8 0.53 [0.35, 0.80] No. of target lesions 1 208 8.8 0.73 [0.51, 1.05] .078 (0, 1, 2, 3, > 3) 2 165 9.3 11.8 0.59 [0.40, 0.89] 3 147 5.5 11.5 0.49 [0.32, 0.75] > 3 295 6.4 0.85 [0.65, 1.12] EHS = extrahepatic spread MVI = metastatic vascular invasion PBO = placebo SOR = sorafenib Add to abridged transcript: You can see that patients who have Barcelona B disease do better than Barcelona C. Also, you see tumor burden here, whether or not you had macrovascular invasion or extrahepatic spread. When that was absent, you can see the survival with sorafenib was up to 16 months. That is a group who probably progressed on TACE but still did not have extrahepatic disease or macrovascular invasion. They had a TACE reimaged and the disease is progressing very quickly. *In the sorafenib group, 1 patient with BCLC stage D was excluded. †Assessed using the Wald test of individual effects. Bruix J, et al. J Hepatol. 2017;67:
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Phase 3 Trials of First-Line Therapy in Advanced HCC
Study Drug (Trial Acronym) Mechanism Control N Primary Endpoint Sorafenib + doxorubicin (CALGB-80802)[a] Sorafenib: multikinase inhibitor (VEGFR, PDGFR, Raf, others) Doxorubicin: cytotoxic Sorafenib 356 OS Sorafenib + erlotinib (SEARCH)[b] Erlotinib: RTKI of EGFR-1 732 Linifanib[c] Multikinase inhibitor (VEGFR, PDGFR, others) 1035 Brivanib (BRISK-FL)[d] Selective inhibitor of FGFR + VEGFR 1714 Lenvatinib (REFLECT)[e] Multikinase inhibitor (VEGFR, FGFR, others) 954 Negative Negative Negative EGFR-1 = epidermal growth factor receptor 1 FGFR = fibroblast growth factor receptor PDGFR = platelet-derived growth factor receptor RTKI = receptor tyrosine kinase inhibitor VEGFR = vascular endothelial growth factor receptor a. Sorafenib Tosylate With or Without Doxorubicin Hydrochloride in Treating Patients With Locally Advanced or Metastatic Liver Cancer b. Nexavar-Tarceva Combination Therapy for First Line Treatment of Patients Diagnosed With Hepatocellular Carcinoma (SEARCH). c. Efficacy and Tolerability of ABT-869 Versus Sorafenib in Advanced Hepatocellular Carcinoma (HCC). d. First Line Hepato Cellular Carcinoma (HCC) (BRISK FL). e. A Multicenter, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-Line Treatment of Subjects With Unresectable Hepatocellular Carcinoma. Add to abridged transcript: This study, the REFLECT study, was presented last year and since has been published in Lancet. This drug has been approved in Japan, based on these results. We expect approval in the United States in the near future. Negative Noninferior a. ClinicalTrials.gov. NCT ; b. ClinicalTrials.gov. NCT ; c. ClinicalTrials.gov. NCT ; d. ClinicalTrials.gov. NCT ; e. ClinicalTrials.gov. NCT
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REFLECT Study Lenvatinib
Lenvatinib is an oral multikinase inhibitor that targets VEGFR(1-3), FGFR(1-4), PDGFRα, RET, and KIT[a-d] There have been 4 failed phase 3 trials in front-line HCC in the past 10 y[e-h] In a global, randomized, open-label, phase 3 noninferiority study, lenvatinib was noninferior to sorafenib for OS, and significantly improved PFS, TTP, and ORR in patients with untreated advanced HCC[i] In Vitro Kinase Inhibitory Profiles[c] IC50 (nmol/L) Lenvatinib Sorafenib VEGFR1 4.7 21 VEGFR2 3.0 VEGFR3 2.3 16 FGFR1 61 340 FGFR2 27 150 FGFR3 52 FGFR4 43 3400 RET 6.4 15 KIT 85 140 PDGFRα 29 1.6 PDGFRβ 160 BRAF 8700 310 RAF1 1600 46 IC50 = half maximal inhibitory concentration ORR = overall response rate PFS = progression-free survival TTP = time to progression Add to abridged transcript: Lenvatinib, like sorafenib, is a small molecule tyrosine kinase inhibitor. It is very potent against this activity, against the VEGF receptor access. Also differentiating it a little bit, it does have pretty potent activity against the fibroblast growth factor receptor, which has been implicated in liver cancer as well as resistance to angiogenesis. Also, it has activity against RET and KIT, which I think the role of those targets in liver cancer are a little less clear. a. Matsui J, et al. Int J Cancer. 2008;122: ; b. Matsui J, et al. Clin Cancer Res. 2008;14: ; c. Tohyama O, et al. J Thyroid Res. 2014;2014:638747; d. Yamamoto Y, et al. Vasc Cell. 2014;6:18; e. Cheng AL, et al. J Clin Oncol. 2013;31: ; f. Johnson PJ, et al. J Clin Oncol. 2013;31: ; g. Cainap C, et al. J Clin Oncol. 2015;33: ; h. Zhu AX, et al. J Clin Oncol. 2015;33: ; i. Kudo M, et al. Lancet. 2018;391:
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Lenvatinib vs Sorafenib in First Treatment of uHCC
Global, randomized, open-label, phase 3 noninferiority study: Patients stratified by region (Asian-Pacific or Western), MVI and/or EHS (yes or no), ECOG PS (0 or 1), and by body weight (< 60 kg or ≥ 60 kg) Primary endpoint: OS Secondary endpoints: PFS, TTP, ORR, QoL, 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) qd Patients with uHCC (N = 954) No prior systemic therapy for uHCC ≥ 1 measurable target lesion per mRECIST BCLC stage B or C Child-Pugh A ECOG PS ≤ 1 Adequate organ function R 1:1 Sorafenib (n = 476) 400 mg bid BW = body weight mRECIST = modified Response Evaluation Criteria in Solid Tumors PK = pharmacokinetic qd = once daily QoL = quality of life Add to abridged transcript: This was a global study powered for non-inferiority. Here you see the study design. Over 900 patients, again like the SHARP study, took patients who were Child-Pugh A, they could be Barcelona B intermediate or C, as long as they were appropriate candidates for systemic treatment. This study, unlike the other studies in liver cancer, excluded patients who had more than 50% of their liver involved with tumor or bowel duct invasion or invasion into the main portal vein. That is the portal vein outside the liver, not a branch of the portal vein but outside the liver. This criteria excluding these patients was really built on the idea that the prognosis for these patients is very poor and that it might be very hard to improve an outcome for someone with these disease characteristics. Here you see the stratification factors. Very typical: region, whether or not they had vascular invasion or extrahepatic disease, ECOG, but also weight. Weight is the unique thing to lenvatinib, dosed by greater or less than 60 kilos, 12 milligrams vs 8 [PH] milligrams. This comes from a phase 2 data which showed that the metabolism of the drug in patients with cirrhosis is different than in patients who do not have liver disease. This study was powered to see an improvement in overall survival. Initially, non-inferiority meeting its equivalent. If the non-inferiority endpoint was met then they would look at overall survival superiority. Kudo M, et al. Lancet. 2018;391:
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Lenvatinib vs Sorafenib Patient Characteristics
Category Lenvatinib (n = 478) Sorafenib (n = 476) Sex, n (%) Male 405 (85) 401 (84) Region, n (%) Asia-Pacific 321 (67) 319 (67) Child-Pugh class, n (%) A B 475 (99) 3 (1) 471 (99) 5 (1) BCLC stage, n (%) B (intermediate stage) C (advanced stage) 104 (22) 374 (78) 92 (19) 384 (81) Add to abridged transcript: Here you see the baseline characteristics of the patients. You can see it is well balanced. Kudo M, et al. Lancet. 2018;391:
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Lenvatinib vs Sorafenib Patient Characteristics (cont)
Potential imbalance in study because of following factors Baseline AFP level Poor prognostic factor Hepatitis C-related liver disease Patients with hepatitis C who are treated with sorafenib do better than patients with hepatitis B OS up to 14 mo Characteristic Category Lenvatinib (n = 478) Sorafenib (n = 476) Etiology of chronic liver disease, n (%) Hepatitis B Hepatitis C 251 (53) 91 (19) 228 (48) 126 (26) Baseline AFP level group (ng/mL), n (%) < 200 ≥ 200 255 (53) 222 (46) 286 (60) 187 (39) Median baseline AFP level (ng/mL) 133.1 71.2 ü Add to abridged transcript: One thing to point out on this slide is there was a slight imbalance by AFP with more patients on the lenvatinib arm having a higher AFP; AFP greater than 200. We know that AFP is a baseline poor prognostic factor, so maybe there was an imbalance against lenvatinib based on that. The other thing that was slightly imbalanced is hepatitis C. We have seen in several studies that patients who have hepatitis C-related liver disease and get sorafenib, they seem to do better than the patients with hepatitis B. Their survival in studies has been up to 14 months. Again, 2 things that potentially were not accounted for in the balancing of the study. Kudo M, et al. Lancet. 2018;391:
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Primary Endpoint mOS Study met primary endpoint of noninferiority
Improvement in OS but not statistically significant Upper limit of CI for HR (1.06) was still under noninferiority boundary of 1.08 Endpoint Lenvatinib n = 478 Sorafenib n = 476 mOS, mo 13.6 12.3 HR (95% CI) 0.92 (0.79, 1.06) Add to abridged transcript: It is the first positive study in front-line liver cancer with an improvement in survival. Kudo M, et al. Lancet. 2018;391:
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Forest Plot of OS in Subgroup Analyses
Figure No Longer Available Add to abridged transcript: Here you see the breakdown and the forest plot of how patients with these various characteristics did. You can see that while all of these essentially cross 1, they tend to be consistently on the side of lenvatinib. The one thing I would point out that does not cross 1 is high AFP. I mentioned that there was an imbalance against lenvatinib. Very interestingly, the patients with the higher AFP actually had a very significant benefit from lenvatinib, so a hazard ratio of 0.78 and it does not cross 1. I would also like to point out, again, on this slide, you do not just have the hazard ratios, you have the median survival for these groups. It gives a reflection about the prognostic significance of many of these. For example, look at patients who had Barcelona stage B disease, that intermediate group, survival was about 18 months. That is a big number. These are patients who historically and still are felt to be TACE candidates, even though they have probably progressed on TACE. Kudo M, et al. Lancet. 2018;391: Reprinted from Lancet, Vol 391, Kudo M, et al.,Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial, , Copyright 2018, with permission from Elsevier
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Secondary Endpoint PFS and TTP
Other endpoints showed superiority with lenvatinib mPFS (assessed per mRECIST) and mTTP were significantly improved Endpoint Lenvatinib n = 478 Sorafenib n = 476 HR (95% CI) P Value mPFS, mo 7.4 3.7 0.66 (0.57, 0.77) < .0001 mTTP, mo 8.9 0.63 (0.53, 0.73) mPFS = median progression-free survival Add to abridged transcript: Modified RECIST criteria is not just measuring the size of the tumor but changes in the enhancing component. Kudo M, et al. Lancet. 2018;391:
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Maximum Change in Tumor Size by mRECIST
Parameter Lenvatinib (n = 478) Sorafenib (n = 476) ORR*, n (%) 115 (24.1) 44 (9.2) 95% CI 20.2, 27.9 6.6, 11.8 CR 6 (1) 2 (< 1) PR 109 (23) 42 (9) SD 246 (51) 244 (51) Durable stable disease† 167 (35) 139 (29) PD 71 (15) 147 (31) Not evaluable/unknown 46 (10) 41 (9) DCR = disease control rate NE = not evaluable PD = progressive disease Add to abridged transcript: Keep in mind, this was an open-label study. An open-label study can add some bias to our assessments. What was done was a retrospective blinded review. *ORR is defined as CR + PR, according to mRECIST; †Durable SD is defined as SD lasting ≥ 23 wk. Percentage change in tumor size is truncated at 100% (rectangles). Kudo M, et al. Lancet. 2018;391: ; Cheng AL, et al. ASCO® Abstract 4001. Reprinted with permission of author, Ann-Lii Cheng
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Tumor Assessments Lenvatinib
Parameter mRECIST by Investigator mRECIST by Independent Review RECIST v1.1 by Independent Review Lenvatinib (n = 478) ORR, n (%) 115 (24.1) 194 (40.6) 90 (18.8) 95% CI 20.2, 27.9 36.2, 45.0 15.3, 22.3 Odds ratio (95% CI)* 3.13 (2.15, 4.56) 5.01 (3.59, 7.01) 3.34 (2.17, 5.14) BOR, n (%) CR 6 (1) 10 (2) 2 (< 1) PR 109 (23) 184 (38) 88 (18) SD 246 (51) 159 (33) 258 (54) Durable stable disease† 167 (35) 84 (18) 163 (34) PD 71 (15) 79 (17) Not evaluable/unknown 46 (10) BOR = best overall response Add to abridged transcript: Here you are looking at the lenvatinib data with the modified RECIST investigator-assessed and the modified RECIST independent review. You see in the independent review the modified RECIST was even higher, it was up to 40%. If we look at just the conventional RECIST by the independent review, it was 19%, 18.8%; that is pretty big number, we have not seen that with small molecule inhibitors in the liver cancer space. *Lenvatinib vs sorafenib. †Stable disease lasting ≥ 23 wk. Kudo M, et al. Lancet. 2018;391:
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Tumor Assessments Sorafenib
Parameter mRECIST by Investigator mRECIST by Independent Review RECIST v1.1 by Independent Review Sorafenib (n = 476) ORR, n (%) 44 (9.2) 59 (12.4) 31 (6.5) 95% CI 6.6, 11.8 9.4, 15.4 4.3, 8.7 BOR, n (%) CR 2 (< 1) 4 (1) 1 (< 1) PR 42 (9) 55 (12) 30 (6) SD 244 (51) 219 (46) 250 (53) Durable stable disease† 139 (29) 90 (19) 118 (25) PD 147 (31) 152 (32) Not evaluable/unknown 41 (9) 46 (10) 43 (9) Add to abridged transcript: Here is the sorafenib data. I showed you that investigator-assessed, modified RECIST was 9%, the independent review was 12%, and still the RECIST review, conventional RECIST, 6%, consistent with the SHARP data where the response rate was 2 or 3%. We are seeing real responses with lenvatinib that we are not previously seeing with sorafenib. Keep in mind that sorafenib in this study gave a survival of 12 months in a global study. That number has not been seen either. *Lenvatinib vs sorafenib. †Stable disease lasting ≥ 23 wk. Kudo M, et al. Lancet. 2018;391:
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Most Frequent TEAEs (≥ 25%)
TEAEs with lenvatinib vs sorafenib Similar frequency: diarrhea Greater frequency: hypertension and proteinuria Lesser frequency: hand-foot syndrome Different in their toxicities but similar in their ability to affect OS Lenvatinib (n = 476) Sorafenib (n = 475) Adverse Event, n (%) Any Grade Grade 3/4 Hypertension 201 (42) 111 (23) 144 (30) 68 (14) Diarrhea 184 (39) 20 (4) 220 (46) Decreased appetite 162 (34) 22 (5) 127 (27) 6 (1) Decreased weight 147 (31) 36 (8) 106 (22) 14 (3) Fatigue 141 (30) 18 (4) 119 (25) 17 (4) Hand-foot syndrome 128 (27) 249 (52) 54 (11) Proteinuria 117 (25) 27 (6) 8 (2) Alopecia 0 (N/A) TEAE = treatment-emergent adverse event Add to abridged transcript: Hypertension is more of an issue with lenvatinib than with sorafenib. Both of them are VEGF receptor inhibitors, that is a class effect, but hypertension as well as proteinuria is more frequent with lenvatinib. Whereas hand-foot syndrome really is not so common, certainly grade 3 or 4 hand-foot syndrome is less than we see with sorafenib in the overall incidence. Kudo M, et al. Lancet. 2018;391:
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Serum Analyses Pharmacodynamic Biomarkers
ANG2 = angiopoietin-2 PIVKA-II = protein-induced vitamin K absence/antagonist II Add to abridged transcript: We showed some interesting biomarker data. Here looking at patients enrolled in the study at changes in these specific biomarkers over time. In red, you have lenvatinib; in blue, you have sorafenib. You can see that both drugs cause an increase in the VEGF levels, serum VEGF levels over time, showing engagement of the VEGF receptor. When the VEGF receptor is blocked, it has been described that there is this compensatory increase in VEGF, but we do not see a decrease in angiopoietin-2 with sorafenib and we do see that with lenvatinib. That is felt to be secondary to additional effects on the vasculature with lenvatinib. Similarly, you can see there are modification of several of the FGFs, FGF23 and FGF19, are increased with lenvatinib and there is really no change with sorafenib. This is some biologic evidence that the drugs do affect people differently. These are some pharmacodynamic data. (??) Finn RS, et al. Ann Oncol. 2017;28(suppl_5): v605-v649. Abstract LBA30. Images courtesy of Richard S. Finn, MD.
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Radioembolization for HCC
Form of brachytherapy Similar to chemoembolization Uses radiation rather than chemotherapy to cut off blood supply 90Y-loaded microspheres are used to deliver a high-dose of radiation Beads are injected into the hepatic artery by maneuvering through the femoral artery 90Y = yttrium 90 Sangro B, et al. J Hepatol. 2012;56:
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Large Series of Radioembolization in HCC
Figure No Longer Available NC = not calculable PVT = portal venous thrombosis Add to abridged transcript: There has been very interesting data, mostly single-arm, single institution studies, looking at that radioembolization appears to be safe and effective in Barcelona B, but these are not randomized studies. There has also been some data looking at patients who are Barcelona C, those are patients who have invasion into the portal vein. In these single-arm studies, they have shown that they get various survival data; 10 months with branch vs 17. As we see in the modern randomized studies with sorafenib, we are seeing 18 months in these populations. Salem R, et al. Hepatology. 2013;58: Copyright © 2013, John Wiley and Sons *Unpublished data for branch and main PVT cohorts provided by authors. Salem R, et al. Hepatology. 2013;58:
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SARAH Study Design Phase 3 randomized, open-label, head-to-head study of SIRT vs sorafenib in advanced HCC Study indicated the potential to demonstrate noninferiority It is unclear if noninferiority analysis was prespecified/study is powered to support such a claim Primary endpoint: mOS Secondary endpoints: AEs, PFS, tumor RR, general and hepatic-specific QoL, healthcare costs Patients stratified by ECOG PS (0 vs 1 or 2), vascular invasion (obstruction of portal vein or any branch vs none), prior TACE and institution N 467 Study start Dec 2011 Study completion Apr 2016 Data readout Apr 2017 SIR-Spheres® radioembolization Sorafenib 400 mg bid HCC with ≥ 1 measurable unidimensional lesion by mRECIST R Treatment interruptions and dose reductions to 400 mg qd permitted for drug-related AEs Inclusion Criteria BCLC stage C with/without portal vein thrombosis or A/B* ECOG-PS 0-1 Child-Pugh A-B7 Adequate hematologic and renal function Bilirubin ≤ 50 µmol/L, AST, or ALT ≤ 5× ULN, INR ≤ 1.5 Exclusion Criteria Extrahepatic metastasis Previously treated advanced HCC Child-Pugh > 7 or active GI bleeding or encephalopathy or ascites refractory to diuretic therapy Severe peripheral vascular disease precluding catheterization RR = response rate SIRT = selective internal radiation therapy ULN = upper limit of normal Add to abridged transcript: There were several randomized studies that were aimed to evaluate this. The SARAH study randomized patients to SIR-Sphere 90Y vs sorafenib who had Barcelona stage C disease with or without portal vein thrombosis. These would have been patients who had prior TACE and then progressed after TACE. There has been a trend, I would say, though not evidenced-based, that between TACE into the start of systemic treatment, 90Y has been used, even though there has been no high-level evidence to support that. As you see in this study, there is high-level evidence not to do it. *New lesions postradical therapy and unsuitable for further radical therapy or no objective response after ≥ 2 TACE sessions. ClinicalTrials.gov. NCT ; Vilgrain V, et al. Lancet Oncol. 2017;18:
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SARAH Primary Endpoint OS
26.6% of patients did not get SIRT and 7.2% sorafenib per protocol No significant difference in OS between groups Not noninferiority study but a negative study Upper limit of CI for HR in ITT population was 1.41 Endpoint ITT Population Per-Protocol Population SIRT n = 237 Sorafenib n = 222 n = 174 n = 206 mOS, mo 8.0 9.9 HR (95% CI) 1.15 (0.94, 1.41) 0.99 (0.79, 1.24) P value .18 .92 Add to abridged transcript: Here you see the primary endpoint. The curves overlap. There was no difference between overall survival between the groups; 9.9 months with sorafenib vs 8 months with SIR-Sphere. Look at the confidence intervals on these. The upper limit of the confidence interval is up to This was not a non-inferiority study; this was a negative study. It was geared for superiority, it did not meet its endpoint. Just like all those drugs we saw in phase 3 studies that did not meet their endpoint, they are not approved, and they are not generally used. Vilgrain V, et al. Lancet Oncol. 2017;18:
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SIRveNIB Study Eligibility Criteria and Study Design
Phase 3 multicenter, open-label, randomized controlled trial of SIRT vs sorafenib in locally advanced HCC Unequivocal diagnosis of HCC (AASLD criteria or histology) that is locally advanced but without extra-hepatic metastases With or without portal vein thrombosis BCLC B and BCLC C without distant metastases ≥ 1 lesion with dimension ≥ 10 mm Age ≥ 18 y ECOG performance status 0 to 1 Child-Pugh A-B (up to 7 points) Adequate hematologic, renal, and hepatic function Life expectancy ≥ 3 mo Not having > 2 prior administrations of hepatic artery-directed therapy No prior hepatic artery-directed therapy within past 4 wk Locally advanced HCC (not amenable to curative treatment) Informed consent Screening Randomization 1:1 Assessment for suitability for SIRT Sorafenib 400 mg bid SIRT with 90Y resin microspheres 3-mo follow-up until disease progression by central CT review Study conclusion 3-mo follow-up until death Not suitable Stratified by site, portal vein thrombosis AASLD = American Association for the Study of Liver Diseases Add to abridged transcript: The patients in this study could have had prior TACE or just de novo advanced disease, but they had not been treated for advanced setting [PH]. ClinicalTrials.gov. NCT ; Chow PKH, et al. ASCO® Abstract 4002.
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SIRveNIB Study OS in ITT Population
Negative study Upper limit of CI for HR was 1.42 Consistent with data from SARAH trial Endpoint SIRT n = 182 Sorafenib n = 178 mOS, mo 8.84 10.02 HR (95% CI) 1.12 (0.88, 1.42) P value .360 Again, a very consistent result and that is negative. Chow PKH, et al. ASCO® Abstract 4002.
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SORAMIC Trial Palliative Cohort An Investigator-Initiated Trial
Sorafenib RFA Curative arm R Placebo Recruitment for study Check-in Exclusion criteria Informed consent CE-MSCT Assignment to study arm Sorafenib Primovist- MRI CE-MSCT = contrast-enhanced multislice spiral computed tomography MRI = magnetic resonance imaging RFA = radiofrequency ablation Abstract: The impact of combining selective internal radiation therapy (SIRT) with sorafenib on overall survival in patients with advanced hepatocellular carcinoma: The SORAMIC trial palliative cohort (5449) Add to abridged transcript: This study took patients and randomized them with advanced disease to the combination of radioembolization and sorafenib vs sorafenib. SIRT Sorafenib R Ricke J. EASL Abstract 5449.
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Sorafenib vs SIRT/Sorafenib OS (ITT)
Negative study Upper limit of CI for HR was 1.24 Consistent results with 2 previous studies Endpoint Sorafenib n = 208 SIRT/Sorafenib n = 216 mOS, mo 11.47 12.13 HR (95% CI) (0.8133, ) P value .951 Add to abridged transcript: We now have 3 negative studies. People can look and try to explain why they are negative, but they are negative. You might want to repeat them with lessons learned, but at this point there is no high level evidence to support using radioembolization instead of systemic therapy. Based on these 3 studies, no evidence to support using radioembolization instead of systemic therapy Ricke J. EASL Abstract 5449.
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HCC Guidelines 2018 EASL Guidelines HCC 2018 – High Levels of Evidence[a] Sorafenib, lenvatinib (first line) Regorafenib, cabozantinib (second line) Chemoembolization RFA PEI (< 2 cm) LT/LDLT-Milan AASLD Guidelines HCC 2018 – Level 1 Evidence[b] Stage 0: resection Stage B: TACE Stage C: sorafenib (1L), lenvatinib (1L), regorafenib (2L), cabozantinib (2L) EASL = European Association for the Study of the Liver LDLT = living donor liver transplantation LT = liver transplantation PEI = percutaneous ethanol injection Accessed May 23, 2018. Add to abridged transcript: Chemoembolization is a very appropriate treatment in the right patient. Patient selection is critical to everything we do. Therefore it is important to know the appropriate patient for chemoembolization and that is the patient with intermediate disease, no vascular invasion, who gets a TACE, and has a good response. a. EASL HCC Guidelines b. Heimbach JK, et al. Hepatology. 2018;67:
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Conclusions Sorafenib has been the standard of care for advanced HCC for a decade Lenvatinib has been shown to be noninferior to sorafenib for OS Higher response rate Improved PFS and TTP Side effect profiles differ More hypertension and proteinuria with lenvatinib More HFSR with sorafenib Phase 3 studies of 90Y in advanced HCC have been negative Results of CheckMate 459 are eagerly awaited (nivolumab vs sorafenib)[a] Add to abridged transcript: You cannot make the argument that patients who are candidates for systemic treatment should get radioembolization and not systemic treatment. (??) Nivolumab is approved in the US conditionally, based on the results of this phase 3 study comparing nivolumab to sorafenib in the front-line setting. a. ClinicalTrials.gov. NCT
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Case 2: Treatment Upon Disease Progression in Unresectable HCC
MODERATOR Tanios Bekaii-Saab, MD Professor Mayo Clinic College of Medicine and Science Co-Leader GI Cancer Program Mayo Clinic Cancer Center Phoenix, Arizona
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Case Study 2 65-y-old man with HCV (treated) underwent liver resection in July 2014 Pathology showed T2 HCC (1.6-cm well-differentiated HCC with vascular invasion) In August 2015, he developed enlarged retroperitoneal lymph nodes on CT scan AFP = 9245 ng/mL He was started on sorafenib and tolerated it well, with dose adjustment at 12 mo His AFP was normalized and retroperitoneal lymph nodes decreased in size He now has rising AFP ≤ 500 ng/mL Chest CT scan showed new bilateral pulmonary nodules He remained Child Pugh class A, ECOG PS 0, with good organ function
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Therapeutic Targeting of the Hallmarks of Cancer and Ongoing HCC Trials
Single-Agent Studies Antiangiogenic agents Sunitinib, brivanib, bevacizumab, ramucirumab, TSU-68, linifanib, cediranib, pazopanib, lenvatinib, lenalidomide, axitinib EGFR inhibitors Erlotinib, gefitinib, lapatinib, cetuximab mTOR inhibitors Everolimus, temsirolimus, sirolimus, CC-223 MEK inhibitors Selumetinib (AZD6244), refametinib Histone deacetylase inhibitor Ganetespib (STA-9090) Oncolytic virus JX-594 Immune-based therapy Tremelimumab, PD-1 and PD-L1 inhibitors Combination Studies With sorafenib Everolimus, AZD6244, bevacizumab, temsirolimus, vorinostat, GC33, OSI-906, OMP-4F28 Without sorafenib Bevacizumab plus erlotinib MEK = MAPK/ERK/kinase mTOR = mammalian target of rapamycin PD-1 = programmed cell death 1 PD-L1 = programmed death-ligand 1 Add to abridged transcript: Recently, and you will hear the data tomorrow, ramucirumab in higher α-fetoprotein patients has shown some positive data and will go through some of that data in the next few slides. Hanahan D, Weinberg RA. Cell. 2011;144: Zhu AX, et al. ASCO® Education Book
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Current Landscape for Second-Line HCC
Regorafenib: approved according to improved OS[a] Nivolumab: approved according to durable ORR[b] Cabozantinib: positive OS benefits[c,d] Brivanib: failed[e] Everolimus: failed[f] Ramucirumab: failed in REACH*[g] and positive in REACH-2[h] ADI-PEG 20: failed[i] Tivantinib: failed†[j] Pembrolizumab: pending[k] ADI-PEG 20 = arginine deiminase formulated with polyethylene glycol Zhu AX, Baron AD, Malfertheiner P, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: analysis of REACH trial results by Child-Pugh score. JAMA Oncol Sep 22. doi: /jamaoncol [Epub ahead of print] Add to abridged transcript: Nivolumab, conditionally approved based on durable overall response. Pembrolizumab is at least a data pending, but it shows very similar profile to nivolumab with a good response rate and overall good outcomes from a single-arm study, we will talk about briefly and will be presented at ASCO too. *In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. †Compared with placebo, tivantinib significantly benefited patients with second-line HCC, especially if Met+, with manageable safety profile at 240 mg bid. a. Bruix J, et al. Lancet. 2017;389:56-66; b. El-Khoueiry AB, et al. Lancet. 2017;389: ; c. Kelley RK, et al. Ann Oncol. 2017;28: ; d. Abou-Alfa GK, et al. ASCO® GI Abstract 207; e. Llovet JM, et al. J Clin Oncol. 2013;31: ; f. Zhu AX, et al. JAMA. 2014;312:57-67; g. Zhu AX, et al. JAMA Oncol. 2016: ; h. Zhu AX, et al. ASCO® Abstract 4003; i. Abou-Alfa GK, et al. J Clin Oncol. 2016;34(suppl). Abstract 4017; j. Rimassa L, et al. Lancet. 2018;19: ; k. Finn RS, et al. J Clin Oncol. 2017;35(suppl 4S). Abstract TPS503.
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Multikinase Inhibitors and Novel Antiangiogenic Agents in HCC
Regorafenib[a] Oral TKI targeting VEGFR1-3, TIE2, PDGFRβ, KIT, RET, RAF Cabozantinib[b] Oral TKI targeting MET, AXL, and VEGFR Ramucirumab[c] Human IgG1 monoclonal antibody against VEGFR2 IgG = immunoglobulin G TKI = tyrosine kinase inhibitor Add to abridged transcript: VEGF receptor targeting seems to be the constant among all 3. This is a disease that is pretty dependent on vasculature and targeting VEGF makes a lot of sense in this disease. a. Bruix J, et al. Lancet. 2017;389:56-66; b. Kelley RK, et al. Ann Oncol. 2017;28: ; c. Zhu AX, et al. Lancet Oncol. 2015;16:
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Acquired Resistance to Sorafenib
Resistance is driven by activation of IGF and FGF signaling Figure No Longer Available FGF = fibroblast growth factor IGF = insulin-like growth factor IGFR = insulin-like growth factor receptor Add to abridged transcript: We understand that some of the mechanisms of resistance to sorafenib are primarily driven by FGFR and by IGF, and many of those targets are targets of regorafenib. Reproduced Tovar V, et al. Gut. 2017;66: With permission from BMJ Publishing Group Ltd. Tovar V, et al. Gut. 2017;66:
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Regorafenib vs Placebo in the Second Line (RESORCE)
Patients with HCC with documented radiologic progression during sorafenib treatment Stratification factors: Geographic region (Asia vs rest of the world) Macrovascular invasion (yes or no) Extrahepatic disease (yes or no) ECOG PS (0 vs 1) AFP (< or ≥ 400 ng/mL) (N = 573) Regorafenib 160 mg po (4 tablets of 40 mg) 3 wk on, 1 wk off (4-wk cycle) (n = 379) Placebo (n = 194) R 2:1 Add to abridged transcript: This was a study that required patients to progress on sorafenib. There were requirements that sorafenib would be maintained on a dose of 400 milligrams prior to progression, as 1 criteria for enrollment, All patients received best supportive care Patients were treated until disease progression, death, withdrawal, or unacceptable toxicity Primary endpoint: OS in ITT population Secondary endpoints: PFS, TTP, RR, DCR, ORR Bruix J, et al. Lancet. 2017;389:56-66.
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RESORCE Trial Efficacy
Endpoint* Regorafenib (n = 379) Placebo (n = 194) Statistic mOS, mo 10.6 7.8 HR = 0.63 (95% CI, 0.50, 0.79) P < .0001 mPFS, mo 3.1 1.5 HR = 0.46 mTTP, mo 3.2 HR = 0.44 ORR, % 4.1 P = .005 DCR, % 65.2 36.1 Add to abridged transcript: The study came back positive for its primary endpoint, overall survival. *Based on mRECIST. Bruix J, et al. Lancet. 2017;389:56-66.
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RESORCE Trial Safety TEAE, % Regorafenib (n = 374) Placebo (n = 194)
Any grade ≥ 3 AE 67 39 Hypertension 15.2 4.7 HFSR 12.6 0.5 Fatigue 9.1 Diarrhea 3.2 Dose modifications because of AEs 68.2 31.1 Drug discontinuations because of AEs 25 19 Deaths occurring ≤ 30 d after last dose 13.4 19.7 Add to abridged transcript: Rate of hand-foot syndrome reaction was less than what you would expect for this agent. Likely because of how you select patients at point of entry to the study, those that were able to tolerate sorafenib primarily. Part of it is also that patients have been educated quite extensively during their exposure to sorafenib. Between them and their treating physicians are quite in tune with the hand-foot syndrome reaction and that may explain why it is lesser in HCC, at least on this study, than on the correct study, say in colorectal cancer. Bruix J, et al. Lancet. 2017;389:56-66.
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Exploratory Analysis Survival With Sequence of Sorafenib and Regorafenib
Sorafenib Regorafenib All patients N = 374 mOS, mo (95% CI) = 26.0 (22.6, 28.1) Asia n = 143 mOS, mo (95% CI) = 21.5 (19.6, 27.8) Rest of the world n = 231 mOS, mo (95% CI) = 26.8 (23.3, 29.1) Sorafenib Placebo All patients N = 193 mOS, mo (95% CI) = 19.2 (16.3, 22.8) Asia n = 73 mOS, mo (95% CI) = 15.6 (12.2, 24.9) Rest of the world n = 120 mOS, mo (95% CI) = 20.1 (17.5, 25.9) Finn RS, Merle P, Granito A, et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial. J Hepatol Apr 26. pii: S (18)32018-X. doi: /j.jhep [Epub ahead of print] Add to abridged transcript: When looking at the study published by Dr Finn, it is in the Journal of Hepatology, looking at an exploratory analysis, survival or sequence of sorafenib and regorafenib. When we look at all patients, patients who started with sorafenib followed by regorafenib, the median overall survival is 26 months in a disease where without treatment patients would succumb within 6 to 7 months. For those patients who went from sorafenib into the placebo arm, their survival is 19.2 months. When we look at Asia vs the rest-of-the-world, it is pretty consistent that the advantage is for the regorafenib component, sorafenib to regorafenib, 21.5, almost 27 month in the rest-of-the-world vs Asia, which I think is pretty impressive. Finn RS, et al. J Hepatol. 2018;69:
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CELESTIAL Phase 3 Trial Study Design
Patients with HCC with prior sorafenib exposure Stratification factors: Etiology; HBV (± HCV), HCV (− HBV), other Extrahepatic spread and/or macrovascular invasion (yes, no) Geographic region; Asian, other regions (N ~ 760) Cabozantinib 60 mg qd (n ~ 500) Placebo qd (n ~ 250) R 2:1 Cabozantinib vs placebo HBV = hepatitis B virus HRQoL = health-related quality of life Add to abridged transcript: Another agent that made it to eventually be added to the armamentarium of treatment we think, at least it is now at the FDA but there is not a reason to think that this will not be approved, is that agent cabozantinib. As I said, is primarily a MET and VEGF inhibitor. It is an oral agent. International study (~ 200 sites, 26 countries), blinded treatment Primary endpoint: OS Secondary endpoints: PFS and ORR Other: safety, biomarkers, bone effects, HRQoL No crossover between treatment arms Treatment beyond radiographic progression if patient deemed to be benefiting ClinicalTrials.gov. NCT ; Abou-Alfa GK, et al. ASCO® GI Abstract 207. Confidential
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CELESTIAL Trial OS and PFS
Primary endpoint of mOS Positive results with cabozantinib Assessment of subgroup analysis Second- and third-line patients did equally well PFS curves separated early and remained separated for ≥ 1 y Endpoint Cabozantinib n = 470 Placebo n = 237 HR (95% CI) P Value mOS, mo 10.2 8.0 0.76 (0.63, 0.92) .0049* mPFS,† mo 5.2 1.9 0.44 (0.36, 0.52) < .0001 Add to abridged transcript: Another study that shows positive results in the second-line setting, although many patients were third-line who presented in this study. All patients second and third-line did equally well when looking at the subgroup analysis. Curves separate quite early and they remain separated for at least a year plus, which certainly speaks to the activity of cabozantinib in this setting. (durable) *Critical P ≤ .021 for second interim analysis; †PFS assessed per RECIST 1.1. Abou-Alfa GK, et al. ASCO® GI Abstract 207.
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CELESTIAL Trial Grade 3/4 Toxicities
Grade 3/4 TRAEs reported in ≥ 10% of patients (cabozantinib [n = 467] vs placebo [n = 237]) Any TRAE: 68% vs 36% Palmar-plantar erythrodysesthesia: 17% vs 0% Hypertension: 16% vs 2% AST increased: 12% vs 7% Fatigue: 10% vs 4% Diarrhea: 10% vs 2% Grade 5 TRAEs Cabozantinib (6 patients): hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper GI hemorrhage, pulmonary embolism, hepatorenal syndrome Placebo (1 patient): hepatic failure TRAE = treatment-related adverse event Add to abridged transcript: This agent has toxicities and they can be quite significant in some patients. Abou-Alfa GK, et al. ASCO® GI Abstract 207.
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REACH Trial Study Design
BCLC stage B/C Child-Pugh A ECOG PS 0 or 1 Previously received sorafenib (stopped because of progression or intolerance) Adequate hematological and biochemical parameters Stratification factors Geographic region Etiology of liver disease Ramucirumab IV 8 mg/kg q2w and BSC Placebo q2w and BSC Treatment until disease progression, unacceptable toxicity, death R 1:1 q2w = once every 2 weeks Add to abridged transcript: Ramucirumab is a monoclonal antibody targeting VEGFR-2. Primary endpoint: OS Secondary endpoints: PFS, TTP, ORR, safety, patient-reported outcomes Zhu AX, et al. Lancet Oncol. 2015;16: 55
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REACH Trial OS Primary endpoint was not reached
Increased mOS with ramucirumab vs placebo in ITT population, but P value was not significant AFP ≥ 400 ng/mL (poorer prognostic group) Statistically significant increase in mOS with ramucirumab AFP < 400 ng/mL Nonsignificant difference in mOS between treatment groups Endpoint ITT Population AFP ≥ 400 ng/mL AFP < 400 ng/mL Ramucirumab n = 283 Placebo n = 282 n = 119 n = 131 n = 160 n = 150 mOS, mo 9.2 7.6 7.8 4.2 10.1 11.8 HR (95% CI) 0.87 (0.72, 1.05) 0.67 (0.51, 0.90) 1.09 (0.84, 1.43) P value .14 .006 .51 Zhu AX, et al. Lancet Oncol. 2015;16:
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REACH-2 Ramucirumab vs Placebo in HCC With Elevated Baseline AFP
Patients with advanced HCC Child-Pugh A BCLC B/C ECOG PS 0-1 Progression on or intolerance to sorafenib No other systemic therapy Baseline AFP ≥ 400 ng/mL ITT N = 292 Ramucirumab IV 8 mg/kg q2w and BSC n = 197 Placebo q2w and BSC n = 95 Treatment until disease progression, unacceptable toxicity, withdrawal of consent R 2:1 IV = intravenous Add to abridged transcript: REACH-2 study essentially looked at patients with HCC who had α-fetoprotein more or equal to 400. Primary endpoint: OS Zhu AX, et al. ASCO® Abstract 4003. 57
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REACH-2 Efficacy and Safety
Baseline characteristics were generally balanced between arms Endpoint Ramucirumab n = 197 Placebo n = 95 HR (95% CI) P Value mOS, mo 8.5 7.3 0.710 (0.531, 0.949) .0199 mPFS, mo 2.8 1.6 0.452 (0.339, 0.603) < .0001 ORR, % 4.6 1.1 .1697 DCR (ORR + SD), % 59.9 38.9 .0006 Grade ≥ 3 AEs (≥ 5% patients in ramucirumab arm), % Hypertension 12.2 5.3 Hyponatremia 5.6 Add to abridged transcript: Ramucirumab improved survival on this study, with 8.5 vs 7.3 months. One can argue that this is a very modest improvement of 1.2 months, the hazard ratio is borderline at 1.710, but the P-value was statistically significant. Response rate was negligible in both arms, although the disease control rate was higher in the ramucirumab arm. Toxicities were predictable for ramucirumab; hypertension primarily and perhaps hyponatremia. Zhu AX, et al. ASCO® Abstract 4003.
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Tumors Use Complex, Overlapping Mechanisms to Evade and Suppress the Immune System
Ineffective presentation of tumor antigens eg, downregulation of MHC I Recruitment of immunosuppressive cells eg, Tregs, MDSCs Tumor release of immunosuppressive factors eg, TGF-β, IDO, IL-10 T-cell checkpoint dysregulation eg, CD27, 4-1BB, CTLA-4, LAG-3, OX-40, PD-1 CD = cluster of differentiation CTLA-4 = cytotoxic T-lymphocyte antigen-4 IDO = indoleamine 2,3-dioxygenase IL = interleukin LAG-3 = lymphocyte activation gene-3 MDSC = myeloid-derived suppressor cell MHC = major histocompatibility complex TGF-β = transforming growth factor beta Tregs = regulatory T cells Vesely MD, et al. Ann Rev Immunol. 2011;29: ; Mellman I, et al. Nature. 2011;480:
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Immune-Based Approaches in HCC
Cancer vaccines and oncolytic viruses[a] Injected directly into the tumor Produce both a direct kill and a vaccine effect Studies with checkpoint inhibitors Phase 1 trial of tremelimumab (CTLA-4 inhibitor) in HCV-related HCC[b] Phase 1 trial of nivolumab (PD-1 inhibitor) in HCC[c] Add to abridged transcript: Both trials looked promising enough to move forward with an immune-based approach in HCC. a. Greten TF, et al. Clin Cancer Res. 2013;19: ; b. Sangro B, et al. J Hepatol. 2013;59:81-88; c. Sangro B, et al. J Clin Oncol. 2013;31(15_suppl). Abstract TPS3111.
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CheckMate 040 Study Design
Primary endpoint Safety and tolerability (escalation) Objective response rate* (expansion) Secondary endpoint ORR* (escalation) DCR TTR DoR OS Other Biomarker assessments Patient-reported outcomes† Phase 1 Dose Escalation 0.1 to 10 mg/kg IV q2w (n = 48) Sorafenib-experienced (2L) (n = 37) Sorafenib-naïve/intolerant (1L) (n = 11) Uninfected (n = 23) HCV-infected (n = 10) HB EQ-5D-infected (n = 15) All Patients (N= 262) Phase 2 Dose Escalation 3 mg/kg IV q2w (n = 214) Uninfected (n = 113) HCV-infected (n = 50) HBV-infected (n = 51) Sorafenib-experienced (2L) (n = 145) Sorafenib-naïve/intolerant (1L) (n = 69) DoR = duration of response q6w = every 6 weeks Add to abridged transcript: CheckMate-040 was presented and published essentially included a phase 1 dose escalation, followed by a phase the thought was that perhaps patients with viral infection will have more inflammation or were more likely to respond to treatment, so the cohorts included uninfected HCV infected and then HBV infected. (Rationale: patients with viral infection will have more inflammation and will be more likely to respond to treatment) There were also cohorts of first-line and second-line with sorafenib-experienced and sorafenib-naïve. Disease assessment imaging (CT or MRI) q6w Interim analysis data cutoff date: August 8, 2016 Median follow-up was 13.3 mo in the dose-escalation phase and 10.5 mo in the dose-expansion phase *RECIST v1.1; †Baseline and every 6 wk through week 25 using the EQ-5D utility index and VAS. Melero I, et al GI Symposium. Abstract 226.
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CheckMate 040 Nivolumab Efficacy
Patients who responded to treatment had a durable response Endpoint* Uninfected Untreated/ Intolerant (n = 56) Uninfected Progressor (n = 57) HCV-Infected (n = 50) HBV-Infected (n = 51) All Patients (n = 214) ORR, % 23 21 20 14 mDoR, mo 8.4 NR 9.9 DCR, % 75 61 66 55 64 mPFS, mo 5.4 4.0 NR = not reported Add to abridged transcript: Most impressive in this is the duration of response. Those patients who actually had a response, their median duration of response was 9.9 months, so around 10 months. These were not just patients who respond to treatment but when they do, they tend to have a durable response. *Determined by investigator assessment using RECIST version 1.1. El-Khoueiry A, et al. Lancet. 2017;389:
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CheckMate 040 Quality of Response and Survival
Responses were observed irrespective of PD-L1 expression on tumor cells[b] Endpoint Sorafenib-Naïve ESC + EXP Sorafenib-Experienced ESC Sorafenib-Experienced EXP mTTR, mo[a] 2.7 1.4 2.8 mDoR, mo[a] 17.15 19.35 16.59 12-mo OS, %[a] 73 58 60 18-mo OS, %[a] 57 46 44 mOS, mo[a] 28.6 15.0 15.6 ORR in PD-L1 < 1% cohort, %[b] – 15.4 17.2 ORR in PD-L1 ≥ 1% cohort, %[b] 22.2 32.0 ESC = escalation EXP = expansion mDOR = median duration of response mTTR = median time to response Add to abridged transcript: When you look at the sorafenib-naïve patients, the median overall survival was 28.6 months; for those that were sorafenib-experienced, they had a median overall survival was 15.6 months which is very interesting in this line. May I remind you that this was a phase 2 study, so this was a non-randomized study. It was large, but it was an unrandomized study and certainly led to the approval of nivolumab with a conditional approval, pending the study that Richard discussed. a. Crocenzi T, et al. J Clin Oncol. 2017(suppl). Abstract 4013; b. Sangro B, et al. EASL Abstract GS-010.
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Safety Dose-Expansion Phase
Patients, n (%) Uninfected (n = 113) HCV-Infected (n = 50) HBV-Infected (n = 51) All-Dose Expansion (n = 214) Any Grade Grade 3/4 Any TRAE 84 (74) 22 (19) 40 (80) 15 (30) 35 (69) 3 (6) 159 (74) 40 (19) TRAEs (≥ 5%) Fatigue 34 (30) 2 (2) 8 (16) 1 (2) 7 (14) 49 (23) 3 (1) Pruritus 18 (16) 14 (28) 13 (25) 45 (21) 1 (< 1) Rash 16 (14) 9 (18) 33 (15) 2 (1) Diarrhea 19 (17) 5 (10) 27 (13) Nausea 10 (9) 6 (12) 17 (8) Dry mouth 9 (8) 2 (4) 13 (6) Decreased appetite 6 (5) 11 (5) Laboratory TRAEs (≥ 5%) AST increase 4 (4) 16 (7) 9 (4) ALT increase 7 (6) 5 (2) Add to abridged transcript: These are some of the safety. Not very much different from what you expect from immune agents, similar PD-1s in other settings. No toxicities that were surprising on this study. Sangro B, et al. EASL Abstract GS-010.
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KEYNOTE-224 Pembrolizumab in HCC
Response, N = 104 n (%) 95% CI ORR (CR + PR) 18 (17) 9.8, 24.9 DCR (CR + PR + SD) 64 (62) 51.5, 70.9 BOR CR 1 (1.0) 0.0, 5.2 PR 17 (16) 9.1, 23.8 SD 46 (44) PD 34 (33) No assessment 6 (6) Add to abridged transcript: Pembrolizumab in HCC, in this study of 104 patients, did show very similar results from what you see with nivolumab. When we look at those responders with immune agents such as PD-L1 inhibitors checkpoint inhibitors, not only is that we are interested in seeing a response, but we want to see how durable is the response. In this case, it was not reached yet at the median but the duration of response beyond 9 months was found in 12 patients, 12 responders which is about 80% of the patients who actually had a response. If the patient has a response, it is very likely that their response will last closer to the year with pembrolizumab. Very similar results to what we see with nivolumab. The median time to response was 2.1 months and this is not atypical for this class of agent. mTTR was 2.1 mo and mDoR ≥ 9 mo was n = 12 (77%) Zhu AX, et al. Lancet Oncol. 2018;19:
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Ongoing Immunotherapy Clinical Trials in HCC
Treatment Planned N Therapy line Enrollment Start Date Nivolumab (anti–PD-1) vs sorafenib (NCT ) 726 First line 11/2015 Pexastimogene devacirepvec (Pexa-Vec) + sorafenib vs sorafenib (NCT ) 600 10/2015 Atezolizumab + bevacizumab vs sorafenib (IMbrave150; NCT ) 480 3/2018 Durvalumab (anti–PD-L1) + tremelimumab (anti CTLA-4) (HIMALAYA; NCT ) 1200 10/2017 Pembrolizumab (anti–PD-1) vs BSC (NCT ) 408 Second line 5/2016 Durvalumab + tremelimumab (NCT ) 440 Add to abridged transcript: There are a number of ongoing immunotherapy clinical trials in HCC in both first-line and second-line. There is another study called IMbrave150 with atezolizumab and bevacizumab vs sorafenib. We have seen some results here in a poster presentation with atezolizumab plus bevacizumab that showed a response rate that was close to 60%, so pretty impressive, although again there are a number of limitations to how to interpret that study. We will see what the third - - what this study actually shows. The study has been enrolling only for a few months. ClinicalTrials.gov.
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How to Select Each Agent in Clinical Decision
No level 1 evidence for superiority of any of the approaches Survival benefits with sorafenib-regorafenib and sorafenib-nivolumab sequence Safety profiles different with every agent Tumor burden and aggressiveness of the tumor Child Pugh Score and PS Predictive biomarkers (AFP)? Add to abridged transcript: There is no level 1 evidence for superiority of any of those approaches. We learned about lenvatinib and sorafenib being in a non-inferiority study, but there is no evidence of superiority of 1 approach vs the other. Safety profiles are of course different with every agent and should be part of a discussion with the patient. A lot of these tyrosine kinase inhibitors tend to be tough and will require multiple dose modifications. The immune therapy agents, so the PD-L1 agents, tend to have less toxicities. However, some of the toxicities which are relatively uncommon can be quite significant for the patients. Most of these studies include a Child-Pugh score A only. The nivolumab study, allowed for Child-Pugh B7, so the first B scores, so between 7, 8 and 9. Those patients with Child-Pugh score 7 behave a little bit worse than the Child-Pugh A but tend to be better off than the B8 and B9. This could be an option to be considered in those patients. The others do not have the data to support them.
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Panel Discussion and Concluding Remarks
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Conclusion How to Best Sequence Patients With Advanced Disease
First Line Second Line Third Line Fourth Line Sorafenib Regorafenib Cabozantinib (P) Nivolumab Lenvatinib (P) Nivolumab Ongoing phase 3 study of pembrolizumab vs BSC CP7 : Nivolumab? Cabozantinib (P) P = pending Add to abridged transcript: Dr. Finn: When we have a patient, who gets front-line sorafenib and then progresses, as we sit here today we have regorafenib or nivolumab. How do you decide between the 2? I think at the end of the day, it comes back to something we discussed before which is: in order to maximize second-line agents, we need to get to front-line agents. Ideally, we have the opportunity to go from sorafenib to regorafenib to maybe to nivolumab or trying nivolumab first and then getting to regorafenib. The other thing to keep in mind is sorafenib does not have a response rate. When do we stop sorafenib? Historically, before we had a second-line option you might keep a patient on sorafenib until they have symptomatic progression. It is important now that we transition patients when they have radiographic progression. That is how patients were selected for the regorafenib study, the tumors were growing, they were asymptomatic still or they did not have of the main symptoms and they can go into the regorafenib study. Male Speaker 1: [01:11:51] Let me ask you this question: lenvatinib gets approved, you see your next patient with HCC, what are you going to do? Sorafenib or lenvatinib? Dr Finn: [01:12:01] We understand now that sorafenib and lenvatinib are essentially equivalent for OS, but they did have differences in toxicity as well as secondary endpoints. Certainly, if we look at toxicity issues, a patient who has pre-existing hypertension, kidney disease or diabetic nephropathy, I might steer away from lenvatinib because it does cause hypertension or proteinuria. Let us say that toxicity is not the issue. If I have a patient with a larger tumor then I need response. We all see these patients who present with large tumors, that these patients if they progress, they will become very symptomatic very quickly. That might be a patient who I might favor lenvatinib in because it has the higher response rate. It is not clear that there is any group that really does better than the other. For a patient who has high AFP, there is that data that suggests that lenvatinib might favor those patients. Ongoing phase 3 trial of nivolumab vs sorafenib AFP > 400: Ramucirumab (P) P = data/study pending.
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Rationale Behind Combination Approaches
Targeted therapy (anti-angiogenic) induces Hypoxia Treg population ↑PD-L1 expression Localized therapy (TACE/RFA/PEI) induces High antigen load Damage to liver cells Tumor-specific T-cell response Tumor microenvironment is a major driver among the vasculature, PD-L1 expression, and some immunosuppressive elements Add to abridged transcript: Chen Y, et al. Hepatology. 2015;61: Greten TF, et al. Clin Cancer Res. 2013;19:
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Emerging Targets and Combination Therapies
Several new drugs developed for HCC in the past 2 y Sequencing of treatments can be difficult Due to limited data and quickly evolving treatment landscape Many emerging targeted therapies eg, against FGF19 amplification occurring in a subset of liver cancers Evaluation of combination immunotherapies Checkpoint inhibitors: durvalumab + tremelimumab in HIMALAYA study[a] Small molecule and checkpoint inhibitor: lenvatinib + pembrolizumab in HCC trial[b] High ORR in RCC[c] Anti-angiogenic and checkpoint inhibitor: bevacizumab + atezolizumab in IMbrave150 phase 3 study[d] High ORR in phase 1b study in HCC[e] RCC = renal cell carcinoma c. Lee C-H, Makker V, Rasco D, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma [ESMO abstract 847O]. Ann Oncol. 2017;28(suppl_5). e. Stein S, Pishvaian MJ, Lee MS, et al. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC) [ASCO abstract 4074]. J Clin Oncol. 2018;36(suppl). Add to abridged transcript: Dr Finn: [01:23:13] The positive activity in the past year and a half, 2 years, is unprecedented. It is really difficult for us to know how to sequence things without data because it has changed so fast. There has been a lot of great science done in liver cancer. For example, FGF19, fibroblast growth factor 19 amplification occurs in a subset of liver cancers on about 8%. There are drugs that are now designed to target just that alteration. Lenvatinib and pembrolizumab has shown very high response rates in kidney cancer. We are seeing from a relatively small phase 1 study, response rates up to 40%. That is in front-line, that is higher than the 20% we have seen with nivolumab in the front-line setting or in the single-arm, phase 2 study or with lenvatinib single agent. It certainly does speak to some synergy. Along that line of anti-angiogenesis and immunotherapy, you commented on the bevacizumab/atezolizumab phase 1 study that showed a response rate of 60%. Clearly, small numbers, not a long-term follow-up but that regimen is going into phase 3 development as well, that study is now open, the IMbrave150. I think there has been a big movement to development in front-line, but still what are we going to do second-line? If IO and TKIs become front-line, how do we interpret all the data we have in second-line after sorafenib? The challenge is we are not going to be able to answer that question with a high-level of evidence any time soon because no-one is going to repeat studies. a. ClinicalTrials.gov. NCT ; b. ClinicalTrials.gov. NCT ; c. Lee C-H, et al. Ann Oncol. 2017;28(suppl_5): v295-v329. Abstract 847O; d. ClinicalTrials.gov. NCT ; e. Stein S, et al. J Clin Oncol. 2018;36(suppl). Abstract 4074.
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Managing Patients With HCC Faculty Recommendations
Stay involved in patient care Patients with intermediate disease Refer to interventional radiology for procedure Make sure to see patients again after procedure Multidisciplinary tumor board Used in large centers for patients with complicated disease Includes surgeons, hepatologists, interventional radiologists, oncologists, etc Regular follow-up appointments Assess patients Ensure patient is not decompensating Add to abridged transcript: Dr Finn: [01:26:19] I think it is important though to highlight, we have all these agents and all these drugs, but it does us no good if the patients that are coming into clinic for systemic treatment are decompensated and very sick.
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Key Takeaways Regorafenib and nivolumab are the only currently approved second-line agents for advanced HCC Cabozantinib pending and ramucirumab [AFP > 400] Angiogenesis pathway is important in hepatocarcinogenesis Despite the negative data of several VEGFR TKIs, phase 3 trials with regorafenib, lenvatinib, cabozantinib and ramucirumab > 400 showed positive survival benefits Anti–CTLA-4 and anti–PD-1/PD-L1 preliminary data confirmed safety and response, and ongoing trials will help to define the role of checkpoint inhibitors in HCC Potential synergistic effect of immune checkpoint inhibitors with locoregional therapy and other systemic therapies under investigation Identification of relevant predictive markers and applying molecular classification are important in predicting response and enriching the population in future HCC trial design: proof of concept trials needed Add to abridged transcript: "In second line at least, we have 2 agents, we have heard about the first-line. Cabozantinib is pending and now ramucirumab has data with α-fetoprotein of more than 400. It tells us interestingly that angiogenesis is an important element in hepatocellular carcinogenesis, and it even seems a strategy where you target VEGF across multiple lines of therapy seems to continue to induce a benefit. The immunotherapy is being stretched [PH] probably checkpoint inhibitors, PD-1, anti-PD-1 heading the charge. We are seeing some interesting data with PD-L1 and with CTLA-4. We are trying to bring these immune therapies into earlier stages with local or regional therapies and other systemic therapies, as Rich mentioned. There continues to be significant work in trying to identify predictive biomarkers and applying molecular classifications to understand how we are going to select even better the population of patients in future HCC trials.“ Have to figure out where to transition...it is unclear to me.
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Current and Emerging Treatments for HCC
Figure No Longer Available CLT = cadaveric liver transplantation PS = performance status PST = performance status test ttc = treatment Add to abridged transcript: "This is how it looks today. This may change by ASCO GI maybe or even by next ASCO, when Rich and myself will sit back and perhaps have another discussion. It will be an even more complicated landscape than it is looking today. Exciting times to be treating a disease that had almost no options a few years ago.“ Still have to figure out where to transition...it is unclear to me. Llovet JM, et al. J Natl Cancer Inst. 2008;100: ; Subramaniam S, et al. Chin Clin Oncol. 2013;2:33. By permission of Oxford University Press.
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