Tag: Liver Cancer (Hepatocellular)

SUMMARY: The FDA on January 14, 2019 approved CABOMETYX® (Cabozantinib) for patients with HepatoCellular Carcinoma (HCC) who have been previously treated with NEXAVAR® (Sorafenib). The American Cancer Society estimates that for 2019, about 42,030 new cases of primary liver cancer will be diagnosed in the US and 31,780 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and type II diabetes have also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide. NEXAVAR® was approved by the FDA in 2007 for the treatment of unresectable HepatoCellular Carcinoma (HCC). Patients with advanced HCC, who progress on NEXAVAR®, have a poor prognosis, with limited treatment options.

CABOMETYX® is an oral, small-molecule Tyrosine Kinase Inhibitor (TKI) which targets the Vascular Endothelial Growth Factor Receptors (VEGFR), and additionally inhibits the action of tyrosine kinases MET and AXL. Increased expression of MET and AXL is associated with tumor progression and development of resistance to VEGFR inhibitors. Previously published studies demonstrated clinical activity of CABOMETYX® in patients with advanced HepatoCellular Carcinoma (HCC).

The present FDA approval was based on the CELESTIAL trial, which is a global, randomized, double-blind, phase III study, which evaluated the benefit of CABOMETYX® in patients with advanced HCC, whose disease progressed on prior treatment with NEXAVAR® or other systemic therapies. NEXAVAR® is considered the standard first line treatment for patients with advanced HCC. In this study, 707 patients were randomized in a 2:1 ratio to receive CABOMETYX® 60 mg daily (N= 470) or placebo (N=237). Eligible patients had an ECOG performance status of 0 or 1, a Child-Pugh score of A, and had progressed on at least one prior systemic therapy for advanced HCC, with 70% having received only prior treatment with NEXAVAR® and 27% having received two prior systemic therapy regimens for advanced HCC. The median age was 64 years, 38% had Hepatitis B Virus, 24% had Hepatitis C Virus, 78% had ExtraHepatic Spread (EHS), 30% had MacroVascular Invasion (MVI) and 85% had both EHS and MVI. Both treatment groups were well balanced and patients were stratified based on etiology of disease, geographic region, and the presence of EHS and/or MVI. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included Progression Free Survival (PFS) and Objective Response Rate (ORR).

This study met the Primary endpoint at the second planned interim analysis and the median Overall Survival was 10.2 months with CABOMETYX®, compared with 8.0 months with placebo (HR=0.76; P=0.0049) , which meant a 24% reduction in the risk of death. Among patients who received NEXAVAR® alone and received CABOMETYX® as second-line treatment, the median survival was 11.3 months versus 7.2 months with placebo. (HR =0.70). CABOMETYX® also improved PFS compared to placebo and the median PFS was 5.2 months with CABOMETYX® versus 1.9 months with placebo (HR=0.44; P<0.0001). Although the Objective Response Rate was only 4% with CABOMETYX® versus 0.4% with placebo (P=0.0086), stable disease rates however were doubled (60% vs 33%). The most common grade 3 adverse events in the CABOMETYX® group was hand-foot skin reaction, hypertension, elevated liver enzymes, fatigue and diarrhea.

It was concluded that CABOMETYX® significantly improved Overall Survival and Progression Free Survival, compared with placebo, in previously treated patients with advanced HCC, and CABOMETYX® represents a new treatment option for this patient group. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. Abou-Alfa GK, Meyer T, Cheng A-L, et al. N Engl J Med 2018;379:54-63

SUMMARY: The FDA on August 16, 2018, approved LENVIMA® (Lenvatinib) for first-line treatment of patients with unresectable HepatoCellular Carcinoma (HCC). The American Cancer Society estimates that for 2018, about 42,220 new cases of primary liver cancer will be diagnosed in the US and 30,200 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and type II diabetes have also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide.

NEXAVAR® (Sorafenib) was approved by the FDA in 2007 for the treatment of unresectable HepatoCellular Carcinoma (HCC) and is the only approved agent for the first line treatment of unresectable HCC. LENVIMA® is an oral multitargeted TKI which targets Vascular Endothelial Growth Factor Receptor (VEGFR) 1-3, Fibroblast Growth Factor Receptor (FGFR) 1-4, Rearranged during Transfection tyrosine kinase receptor (RET), c-KIT, and Platelet Derived Growth Factor Receptor (PDGFR). LENVIMA® differs from other TKIs with antiangiogenesis properties by its ability to inhibit FGFR-1, thereby blocking the mechanisms of resistance to VEGF/VEGFR inhibitors. In addition, it controls tumor cell growth by inhibiting RET, c-KIT, and PDGFR beta and influences tumor microenvironment by inhibiting FGFR and PDGFR beta. Based on the activity of LENVIMA® in unresectable HCC in a phase II trial, the efficacy of LENVIMA® was evaluated comparing this agent with NEXAVAR® in treatment naïve patients with unresectable HCC.

This present approval by the FDA was based on an international, multicenter, randomized, open-label, noninferiority trial (REFLECT study) in which 954 patients with previously untreated, metastatic or unresectable HCC were randomized in a 1:1 ratio to receive LENVIMA® 12 mg orally once daily for patients with a baseline body weight of 60 kg or more and 8 mg orally once daily for patients with a baseline body weight of less than 60 kg (N=478) or NEXAVAR® 400 mg orally twice daily (N=476). Treatment was continued until radiological disease progression or unacceptable toxicity. Patients had one or more measurable target lesions, Barcelona Clinic Liver Cancer (BCLC) Stage B or C, Child-Pugh Class A, ECOG PS of 1 or less, and no prior systemic therapy. Baseline characteristics were similar in both treatment groups. The median age was 62 years, the most common Child-Pugh class was A (99%) and 79% of patients had BCLC stage C disease. Twenty percent (20%) of patients had 3 or more sites of disease involvement, and 50% of patients had underlying Hepatitis B infection. The median baseline AFP level was 133 ng/mL in the LENVIMA® group and 71 ng/mL in the NEXAVAR® group. The Primary endpoint of this study was noninferiority for Overall Survival (OS). Secondary efficacy endpoints included Progression Free Survival (PFS), Time to Progression (TTP) and Objective Response Rate (ORR).

In this study, LENVIMA® was noninferior, but not statistically superior to NEXAVAR® for Overall Survival (HR=0.92). The median OS in the LENVIMA® arm was 13.6 months and 12.3 months in the NEXAVAR® arm. There was however a statistically significant improvement in Progression Free Survival with LENVIMA® when compared to NEXAVAR®, with a median PFS of 7.3 months in the LENVIMA® group 3.6 months in the NEXAVAR® arm (HR=0.64; P<0.0001). The Objective Response Rate was higher for the LENVIMA® group as compared to NEXAVAR® group – 40.6% versus 12.4% per modified RECIST assessment (P<0.0001). The median TTP in this review was 8.9 months with LENVIMA® versus 3.7 months for NEXAVAR® (HR=0.60; P<0.0001). More patients in the LENVIMA® group experienced hypertension, decreased weight, proteinuria and decreased platelet count, whereas Palmar Plantar Erythrodysesthesia and diarrhea were more common in the NEXAVAR® group.

It was concluded that LENVIMA® is noninferior to NEXAVAR® in OS, and achieves statistically significant and clinically meaningful improvements in PFS, TTP, and ORR as first line therapy, for patients with HepatoCellular Carcinoma. 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, et al. The Lancet 2018;391:1163-1173

SUMMARY: The American Cancer Society estimates that for 2018, about 42,220 new cases of primary liver cancer will be diagnosed in the US and 30,200 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since1980. This increase has been attributed to the higher rate of Hepatitis C virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and type II diabetes have also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide. NEXAVAR® (Sorafenib) was approved by the FDA in 2007 for the treatment of unresectable HepatoCellular Carcinoma (HCC). Patients with advanced HCC, who progress on NEXAVAR®, have a poor prognosis, with limited treatment options.

CABOMETYX® (Cabozantinib) is an oral, small-molecule Tyrosine Kinase Inhibitor (TKI) which targets the Vascular Endothelial Growth Factor Receptors (VEGFR), and additionally inhibits the action of tyrosine kinases MET and AXL. Increased expression of MET and AXL is associated with tumor progression and development of resistance to VEGFR inhibitors. Previously published studies demonstrated clinical activity of CABOMETYX® in patients with advanced HepatoCellular Carcinoma (HCC).

The CELESTIAL trial is a global, randomized, double-blind, phase III study, which evaluated the benefit of CABOMETYX® in patients with advanced HCC, whose disease progressed on prior treatment with NEXAVAR® or other systemic therapies. NEXAVAR® is considered the standard first line treatment for patients with advanced HCC. In this study, 707 patients were randomized in a 2:1 ratio to receive CABOMETYX® 60 mg daily (N= 470) or placebo (N=237). Eligible patients had an ECOG performance status of 0 or 1, a Child-Pugh score of A, and had progressed on at least one prior systemic therapy for advanced HCC, with 70% having received only prior treatment with NEXAVAR® and 27% having received two prior systemic therapy regimens for advanced HCC.. The median age was 64 years, 38% had Hepatitis B Virus, 24% had Hepatitis C Virus, 78% had ExtraHepatic Spread (EHS), 30% had MacroVascular Invasion (MVI) and 85% had both EHS and MVI. Both treatment groups were well balanced and patients were stratified based on etiology of disease, geographic region, and the presence of EHS and/or MVI. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included Progression Free Survival (PFS) and Objective Response Rate (ORR).

This study met the Primary endpoint at the second planned interim analysis and the median Overall Survival was 10.2 months with CABOMETYX®, compared with 8.0 months with placebo (HR=0.76; P=0.0049) , which meant a 24% reduction in the risk of death. Among patients who received NEXAVAR® alone and received CABOMETYX® as second-line treatment, the median survival was 11.3 months versus 7.2 months with placebo. (HR =0.70). CABOMETYX® also improved PFS compared to placebo and the median PFS was 5.2 months with CABOMETYX® versus 1.9 months with placebo (HR=0.44; P<0.0001). Although the Objective Response Rate was only 4% with CABOMETYX® versus 0.4% with placebo (P=0.0086), stable disease rates however, were doubled (60% vs 33%). The most common grade 3 adverse events in the CABOMETYX® group was hand-foot skin reaction, hypertension, elevated liver enzymes, fatigue and diarrhea.

It was concluded that CABOMETYX® significantly improved Overall Survival and PFS, compared with placebo, in previously treated patients with advanced HCC, and CABOMETYX® represents a new treatment option for this patient group. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial. Abou-Alfa GK, Meyer T, Cheng A-L, et al. J Clin Oncol 36, 2018 (suppl 4S; abstr 207)

SUMMARY: The FDA on September 22, 2017, granted accelerated approval to OPDIVO® (Nivolumab) for the treatment of HepatoCellular Carcinoma (HCC), in patients who have been previously treated with NEXAVAR® (Sorafenib). The American Cancer Society estimates that about 41,000 new cases of primary liver cancer will be diagnosed in the US for 2017 and 29,000 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since1980. This increase has been attributed to the higher rate of hepatitis C virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and type II diabetes have also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HCC is the second most common cause of cancer-related deaths worldwide. NEXAVAR® (Sorafenib) was approved by the FDA in 2007 for the treatment of unresectable, HepatoCellular Carcinoma (HCC). Patients with advanced HCC who progress on NEXAVAR®, have a poor prognosis with limited treatment options.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Under normal circumstances, Immune checkpoints or gate keepers inhibit intense immune responses by switching off the T cells of the immune system and can thereby suppress antitumor immunity. These Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. Immune check point inhibitors are antibodies that target the immune checkpoint receptors and unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. OPDIVO® (Nivolumab) is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody that demonstrated significant activity in HepatoCellular Carcinoma (HCC).

The approval of OPDIVO® in HCC was based on a 154-patient subgroup of CHECKMATE-040 study, which is a multicenter, open-label trial, conducted in patients with HCC and Child-Pugh A cirrhosis, who had progressed on or were intolerant to NEXAVAR®. Enrolled patients included patients without active viral hepatitis, patients with either active HBV-Hepatitis B Virus (31%) or HCV- Hepatitis C Virus (21%). Patients with active co-infection with HBV and HCV or with Hepatitis D Virus infection were excluded. Patients received OPDIVO® 3 mg/kg by IV infusion every 2 weeks. The median age was 64 years and 80% of patients were male. The primary endpoints were safety/tolerability and Objective Response Rate (ORR) by investigator and Blinded Independent Central Review. Secondary endpoints included Duration of Response, Disease Control Rate and Overall Survival.

The confirmed Objective Response Rate as assessed by Independent Central Review was 19 % with 3 Complete Responses and 19 partial responses(13%) and 41% of the patients had stable disease. Response duration ranged from 3 months to over 38 months and 91% of responders had responses lasting 6 months or longer and 55% of the patients had responses lasting 12 months or longer. Overall responses were noted regardless of tumor cell PD-L1 expression and chronic hepatitis virus infection. Common adverse reactions included fever, rash, musculoskeletal pain, nausea, diarrhea, cough and dyspnea. There was a higher incidence of elevations in transaminases and bilirubin levels noted.

It was concluded that OPDIVO® demonstrated durable responses with long-term survival and favorable safety in patients with advanced HCC. This FDA approval provides a new treatment option for appropriate patients with HCC, who progress on prior systemic therapy. STIVARGA® (Regorafenib) is another agent presently available for this subset of patients. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study. Crocenzi TS, El-Khoueiry AB, Yau TC, et al. J Clin Oncol. 2017;35 (suppl; abstr 4013).