FDA Approves TECENTRIQ® in Combination with AVASTIN® for Hepatocellular Carcinoma

SUMMARY: The FDA on May 29, 2020, approved TECENTRIQ® (Atezolizumab) in combination with AVASTIN® (Bevacizumab) for patients with unresectable or metastatic HepatoCellular Carcinoma (HCC), who have not received prior systemic therapy. The American Cancer Society estimates that for 2020, about 42,810 new cases of primary liver cancer will be diagnosed in the US and 30,160 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 increasing 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, and majority of patients typically present at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.Synergistic-Effect-of-PD-L1-and-VEGF-Inhibition

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells. AVASTIN® (Bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds VEGF (Vascular Endothelial Growth Factor) and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells, thereby preventing endothelial cell proliferation and new blood vessel formation. AVASTIN® in addition to its established anti-angiogenic properties can further enhance TECENTRIQ®’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens. The use of TECENTRIQ® in combination with AVASTIN® therefore has a strong scientific rationale, as this combination can potentially enhance the immune system to combat a broad range of malignancies.

IMbrave150 is a global, open-label, multicenter, randomized, Phase III study in which a combination of TECENTRIQ® and AVASTIN® was compared with standard-of-care NEXAVAR®, in patients with previously untreated locally advanced or metastatic HCC. Patients were randomized 2:1 to receive TECENTRIQ® 1200 mg IV on day 1 along with AVASTIN® 15 mg/kg on day 1 of each 21-day cycle (N=336) or NEXAVAR® 400 mg orally twice daily, each day of the 21-day cycle (N=165). Treatment was continued until disease progression or unacceptable toxicity. The treatment groups were well balanced and enrolled patients had an ECOG performance status of 0 or 1, Child-Pugh Class A disease, and adequate hematologic and end-organ function. The two co-Primary endpoints were Overall Survival (OS) and Progression Free Survival (PFS). The key Secondary endpoints included Overall Response Rate (ORR), Time To Progression (TTP) and Duration of Response (DOR), as well as Patient-Reported Outcomes (PROs), Safety and Pharmacokinetics.

With a median follow up of 8.6 months, the OS was not yet reached in the TECENTRIQ® and AVASTIN® combination group compared with 13.2 months in the NEXAVAR® group (HR=0.58; P=0.0006). The median PFS was 6.8 months versus 4.3 months respectively (HR=0.59; P<0.0001). The ORR was 27% versus 12% (P<0.0001) based on the Independent Review Facility RECIST 1.1 criteria, in favor of the combination regimen. This benefit was seen across clinical subgroups and the combination regimen delayed deterioration of Quality of Life, compared with NEXAVAR®. Grade 3 and 4 Adverse Events were similar and occurred in 57% and 55% of the combination and control arms, respectively.

It was concluded that a combination of TECENTRIQ® and AVASTIN® demonstrated statistically significant and clinically meaningful improvement in both Overall Survival and Progression Free Survival, compared with NEXAVAR®, in treatment naïve patients with unresectable Hepatocelluar Carcinoma. The authors added that this is the first study in 11 years to show an improvement in Overall Survival with a new first line treatment option, compared to NEXAVAR®, and has the potential to be a practice changing treatment in Hepatocellular Carcinoma.

IMbrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Cheng A-L, Qin S, Ikeda M, et al. Annals of Oncology, Volume 30, 2019 Supplement 9. LBA3.

OPDIVO® and YERVOY®

The FDA on March 10, 2020 granted accelerated approval to the combination of OPDIVO® (Nivolumab) and YERVOY® (Ipilimumab) for patients with Hepatocellular Carcinoma (HCC), who have been previously treated with NEXAVAR® (Sorafenib). Both OPDIVO® and YERVOY® are products of Bristol-Myers Squibb Co.

FDA Approves OPDIVO®/YERVOY® Combination for Advanced Hepatocellular Carcinoma 

SUMMARY: The FDA on March 10, 2020, granted accelerated approval to the combination of OPDIVI® (Nivolumab) and YERVOY® (Ipilimumab) for patients with HepatoCellular Carcinoma (HCC) who have been previously treated with NEXAVAR® (Sorafenib). The American Cancer Society estimates that for 2020, about 42,810 new cases of primary liver cancer will be diagnosed in the US and 30,160 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 is the second most common cause of cancer-related deaths worldwide and majority of patients typically present at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.
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 by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.
OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® was approved by the FDA in 2017, for the treatment of HCC, in patients who have been previously treated with NEXAVAR®. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4).
The present FDA approval was based on the CheckMate-040 study, which is an ongoing Phase I/II, open-label, multi-cohort study, investigating OPDIVO® or OPDIVO®-based combinations in patients with advanced HCC with and without Chronic Viral Hepatitis, who are naïve, intolerant to, or who have progressed during NEXAVAR® therapy. The OPDIVO® plus YERVOY® cohort of CheckMate-040 evaluated the Safety and Efficacy of the combination, in patients with previously treated advanced HCC. This cohort included a total of 49 patients with HCC who progressed on or were intolerant to NEXAVAR®. Patients received OPDIVO® 1 mg/kg IV in combination with YERVOY® 3 mg/kg IV, every 3 weeks for four doses, followed by single agent OPDIVO® 240 mg IV every 2 weeks, until disease progression or unacceptable toxicity. The main efficacy endpoints were Overall Response Rate (ORR) and Duration of Response (DoR), as determined by Blinded Independent Central Review.
At a median follow up of 28 months, the ORR with the OPDIVO® plus YERVOY® combination was 33%, with 8% Complete Responses (CR) and a 24% Partial Responses. The Duration of Responses ranged from 4.6 to over 30.5 months, with 31% of responses lasting at least 24 months. The most common adverse events with this combination therapy were fever, fatigue, diarrhea, rash, arthralgia, dyspnea, and hypothyroidism.
It was concluded that dual Immuno-Oncology therapy with a combination of OPDIVO® plus YERVOY® represents an important milestone, for patients with advanced Hepatocellular Carcinoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma

First Line Combination of TECENTRIQ® and AVASTIN® Improves Survival in Hepatocellular Carcinoma

SUMMARY: 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 and majority of patients typically presents at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors, and thus enabling the activation of T cells. AVASTIN® (Bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds VEGF (Vascular Endothelial Growth Factor) and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells, thereby preventing endothelial cell proliferation and new blood vessel formation. The use of TECENTRIQ® in combination with AVASTIN® has a strong scientific rationale, as this combination can potentially enhance the immune system to combat a broad range of malignancies. AVASTIN® in addition to its established anti-angiogenic properties can further enhance TECENTRIQ®’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens.

IMbrave150 is a global, open-label, multicenter, randomized, Phase III study in which a combination of TECENTRIQ® and AVASTIN® was compared with standard-of-care NEXAVAR®, in patients with previously untreated locally advanced or metastatic HCC. Patients were randomized 2:1 to receive TECENTRIQ® 1200 mg IV on day 1 along with AVASTIN® 15 mg/kg on day 1 of each 21-day cycle (N=336) or NEXAVAR® 400 mg orally twice daily, each day of the 21-day cycle (N=165). Treatment was continued until disease progression or unacceptable toxicity. The treatment groups were well balanced and enrolled patients had an ECOG performance status of 0 or 1, Child-Pugh Class A disease, and adequate hematologic and end-organ function. The two co-Primary endpoints were Overall Survival (OS) and Progression Free Survival (PFS). The key Secondary endpoints included Overall Response Rate (ORR), Time To Progression (TTP) and Duration of Response (DOR), as well as Patient-Reported Outcomes (PROs), Safety and Pharmacokinetics.

With a median follow up of 8.6 months, the OS was not yet reached in the TECENTRIQ® and AVASTIN® combination group compared with 13.2 months in the NEXAVAR® group (HR=0.58; P=0.0006). The median PFS was 6.8 months versus 4.3 months respectively (HR=0.59; P<0.0001). The ORR was 27% versus 12% (P<0.0001) based on the Independent Review Facility RECIST 1.1 criteria, in favor of the combination regimen. This benefit was seen across clinical subgroups and the combination regimen delayed deterioration of Quality of Life compared with NEXAVAR®. Grade 3 and 4 Adverse Events were similar and occurred in 57% and 55% of the combination and control arms, respectively.

It was concluded that a combination of TECENTRIQ® and AVASTIN® demonstrated statistically significant and clinically meaningful improvement in both Overall Survival and Progression Free Survival compared with NEXAVAR®, in treatment naïve patients with unresectable Hepatocelluar Carcinoma. The authors added that this is the first study in 11 years to show an improvement in Overall Survival with a new first line treatment option, compared to NEXAVAR®, and has the potential to be a practice changing treatment in Hepatocellular Carcinoma. IMbrave150: Efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Cheng A-L, Qin S, Ikeda M, et al. Annals of Oncology, Volume 30, 2019 Supplement 9. LBA3

CYRAMZA® (Ramucirumab)

The FDA on May 10, 2019 approved CYRAMZA® as a single agent for HepatoCellular Carcinoma (HCC) in patients who have an Alpha FetoProtein (AFP) of 400 ng/mL or more, and have been previously treated with NEXAVAR® (Sorafenib). CYRAMZA® is a product of Eli Lilly and Company.

Aspirin Lowers Risk for Ovarian and Hepatocellular Carcinoma

SUMMARY: Aspirin (AcetylSalicylic Acid) has been studied as a chemopreventive agent for several decades and the temporal relationship between systemic inflammation and cancer has been a topic of ongoing investigation. The US Preventive Services Task Force (USPSTF) found adequate evidence that Aspirin use reduces the incidence of ColoRectal Cancer (CRC) in adults after 5-10 years of use, and recommends initiating low-dose Aspirin use for the primary prevention of CardioVascular Disease (CVD) and ColoRectal Cancer (CRC) in adults aged 50-69 years, who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose Aspirin daily for at least 10 years.MOA-of-ASPIRIN

The molecular mechanisms underlying Aspirin’s chemoprevention effects as well as the dose, duration, and timing of Aspirin chemoprevention have remained unclear. More recent data suggests that platelets may play a role in tumorigenesis as well, through the release of angiogenic and growth factors due to overexpression of COX-2. Daily low dose Aspirin inhibits COX-1 and COX-2. It is postulated that Aspirin also works by COX-independent mechanisms such as, the inhibition of NF-kB and Wnt/ β-catenin signaling, which may play a role in its chemopreventive properties.

Two recently published studies examining different doses of Aspirin in different cancers, highlight the beneficial role of Aspirin in reducing cancer risk.

The first report is a large prospective study which attempted to reproduce findings from case-control studies that reported lower Ovarian cancer risk among low-dose Aspirin users. This prospective study evaluated whether regular Aspirin or nonaspirin NonSteroidal Anti-Inflammatory Drug (NSAID) use and patterns of use was associated with lower risk of Ovarian cancer. This cohort study analyzed NSAID use and Ovarian cancer diagnosis data on 205,498 women from 2 prospective cohorts; 93 664 women in the Nurses’ Health Study (NHS), who were 93% non-Hispanic white, with a mean age at baseline of 46 years, followed up from 1980 to 2014, and 111834 women in the Nurses’ Health Study II (NHSII), who were 92% non-Hispanic white, with a mean age at baseline of 34.2 years, followed up from 1989 to 2015. For each analgesic type (Aspirin, low-dose Aspirin, nonaspirin NSAIDs, and Acetaminophen), timing, duration, frequency, and number of tablets used were evaluated, and information was updated every 2-4 years.

It was noted that among both cohorts, there were 1054 women who developed epithelial Ovarian cancer. Recent use of low-dose Aspirin (100 mg or less) was associated with a lower risk of Ovarian cancer (HR=0.77), whereas there was no such association noted with standard-dose of 325 mg Aspirin (HR=1.17). The associations between Aspirin use and risk of Ovarian cancer did not differ among premenopausal versus postmenopausal women. This study also suggested that use of non-aspirin NSAIDs, such as Ibuprofen and Naproxen, when taken in quantities of at least 10 tablets per week for multiple years was positively associated with an increased risk of Ovarian cancer. There was however no clear associations for the use of Acetaminophen.

The authors concluded that consistent with case-control studies, this prospective analysis showed a reduced risk of Ovarian cancer among regular users of low-dose Aspirin and an increased risk of Ovarian cancer with the use of nonaspirin NSAIDs. These findings suggest that low-dose Aspirin recommended for cardiovascular prophylaxis and ColoRectal Cancer risk reduction can also reduce the risk of Ovarian cancer.

The second report is another large prospective study which analyzed the data on the risk of HepatoCellular Carcinoma (HCC) within 2 populations of a total of 133 371 health care professionals who self reported use of Aspirin. In this pooled analysis, 87 507 were women, with a mean age was 62 years, and 45 864 were men, with a mean age of 64 years. Women reported data biennially since 1980 and men since 1986, on frequency, dosage, and duration of Aspirin use, and data were accessed from November 2017 through March 2018. Individuals with a cancer diagnosis at baseline (except nonmelanoma skin cancer) were excluded.

The researchers noted that regular Aspirin use of 2 or more standard dose 325 mg tablets per week was associated with a 49% reduction in risk of HCC (adjusted HR=0.51) compared to non regular use. This benefit was dose-dependent with the greatest benefit among those taking more than 5 tablets per week (P for trend =0 .006). Further, significantly lower risk for HCC was observed with increasing duration of Aspirin intake (P for trend =0.03), with this decreasing risk noted with the use of 1.5 or more standard-dose Aspirin tablets per week for 5 or more years (adjusted HR=0.41). The use of nonaspirin NSAIDs however was not significantly associated with HCC risk.

The authors from this study concluded that regular and long-term use of standard dose (325 mg) Aspirin, taken at least 2 or more times per week is associated with a dose-dependent reduction in HCC risk, which is apparent after 5 or more years of use.

Taken together, these 2 studies provide the evidence supporting the ability of regular use of Aspirin to prevent Ovarian cancer and HepatoCellular Cancer (HCC). Aspirin is rapidly emerging as a valuable chemoprevention agent for various malignancies.

Association of Analgesic Use With Risk of Ovarian Cancer in the Nurses’ Health Studies. Barnard ME, Poole EM, Curhan GC, et al. JAMA Oncol. 2018;4:1675-1682.

Association Between Aspirin Use and Risk of Hepatocellular Carcinoma. Simon TG, Ma Y, Ludvigsson JF, et al. JAMA Oncol. 2018;4:1683-1690

FDA Approves CABOMETYX® for Hepatocellular Carcinoma

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).MOA-of-CABOZANTINIB

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