FDA Approves Lenvima (lenvatinib) for First-line Treatment of Unresectable Hepatocellular Carcinoma (HCC)

In continuation of my update on lenvatinib

Woodcliff Lake, NJ and Kenilworth, announced today that the U.S. Food and Drug Administration (FDA) approved the kinase inhibitor Lenvima (lenvatinib) for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). This approval was based on results from REFLECT (Study 304), where Lenvima demonstrated a proven treatment effect on overall survival (OS) by statistical confirmation of non-inferiority, as well as statistically significant superiority and clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR) when compared with sorafenib in patients with previously untreated unresectable HCC.

“Unresectable hepatocellular carcinoma is an extremely difficult-to-treat cancer, with no new first-line systemic therapy options for more than a decade,” said Dr. Ghassan Abou-Alfa, medical oncologist, Memorial Sloan Kettering Cancer Center. “REFLECT is the first-ever positive Phase 3 trial against an active comparator in unresectable HCC. The efficacy and safety data from REFLECT are important findings for oncologists and others in the multidisciplinary teams who treat liver cancer, as well as for our patients who are affected by it.”

Adverse reactions, some of which can be serious or fatal, may occur with Lenvima, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, and wound healing complications. Based on the severity of the adverse reaction, Lenvima should be monitored, withheld or discontinued. Based on its mechanism of action and data from animal reproduction studies, Lenvima can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception. For more information, see “Important Safety Information” below.

REFLECT showed that Lenvima achieved the primary endpoint, demonstrating a treatment effect on OS by statistical confirmation of non-inferiority to sorafenib. Patients treated with Lenvima experienced a median OS of 13.6 months compared to 12.3 months with sorafenib (HR: 0.92; 95% CI: 0.79–1.06). The OS analysis was conducted when 351 events had occurred in the Lenvima arm and 350 events had occurred in the sorafenib arm, as prespecified in the statistical analysis plan. In addition, Lenvima showed statistically significant superiority and clinically meaningful improvements in the secondary efficacy endpoints of PFS and ORR, as confirmed by a blinded independent imaging review (IIR):

• Median PFS was doubled with Lenvima compared to sorafenib: 7.3 months versus 3.6 months (HR: 0.64; 95% CI: 0.55–0.75; p<0.001) per blinded independent imaging review based on mRECIST criteria, and 7.3 months with Lenvima versus 3.6 months with sorafenib (HR: 0.65; 95% CI: 0.56–0.77) per RECIST 1.1.
• Lenvima showed nearly 3.5 times the ORR of sorafenib: 41% (95% CI: 36-45%) vs. 12% (95% CI: 10-16%) per blinded independent imaging review based on mRECIST criteria, respectively (p<0.001), and 19% (95% CI: 15-22%) with Lenvima versus 7% (95% CI: 4-9%) with sorafenib per RECIST 1.1.
  • Per mRECIST: Treatment with Lenvima resulted in complete response (CR) = 2.1% (n=10) vs. 0.8% (n=4) with sorafenib; treatment with Lenvima resulted in partial response (PR) = 38.5% (n=184) vs. 11.6% (n=55) with sorafenib
  • Per RECIST 1.1: Treatment with Lenvima resulted in CR = 0.4% (n=2) vs. 0.2% (n=1) with sorafenib; treatment with Lenvima resulted in PR = 18.4% (n=88) vs. 6.3% (n=30) with sorafenib

In addition, median time to progression (TTP) was doubled with Lenvima compared to sorafenib: 7.4 months versus 3.7 months (HR: 0.60; 95% CI: 0.51–0.71; p<0.0001) per blinded independent imaging review based on mRECIST criteria, and 7.4 months with Lenvima versus 3.7 months with sorafenib (HR: 0.61; 95% CI: 0.51–0.72; p<0.0001) per RECIST 1.1. Time to progression is defined as time from randomization to radiological progression. Deaths during follow-up without evidence of radiological progression are censored. This differs from PFS and is less correlative to overall survival.

In REFLECT, the most common adverse reactions (≥20%) observed in patients treated with Lenvima were hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism and nausea. The most common serious adverse reactions (≥2%) reported in patients treated with Lenvima were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%) and decreased appetite (2%).

The most common adverse reactions (≥20%) observed in patients who received sorafenib were palmar-plantar erythrodysesthesia syndrome, diarrhea, fatigue, hypertension, abdominal pain, decreased appetite, rash, decreased weight and arthralgia/myalgia. The most common serious adverse reactions (≥2%) reported in patients who received sorafenib were ascites (2%) and abdominal pain (2%).

It is also important to note that the dose for Lenvima for patients with unresectable HCC is based on the patient’s weight (12 mg for patients weighing 60 kilograms or more, 8 mg for patients weighing less than 60 kilograms); the recommended dosage and dose adjustments are described in the full prescribing information.

“Eisai strives to be a leading global R&D-based pharmaceutical company, driven by our human health care (hhc) mission to improve the lives of patients and their loved ones,” said Shaji Procida, President and Chief Operating Officer, Eisai Inc., and Commercial Head of the Oncology Business Group, Americas at Eisai. “That purpose is what has propelled us toward this win for patients with unresectable hepatocellular carcinoma. Our goal is to bring monumental solutions to patients and health care providers, changing expectations for the oncology landscape, and we look forward to continuing this work in our ongoing collaboration with Merck.”

“We are pleased by the FDA approval of Lenvima as it marks an important advancement in the treatment of unresectable hepatocellular carcinoma,” said Dr. Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories. “With our shared mission to find solutions for difficult-to-treat cancers, we look forward to working with Eisai to help bring this needed option to patients and physicians.”

Lenvima, a kinase inhibitor, was first approved in the U.S. in February 2015 for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). In May 2016, Lenvima was approved in the U.S. in combination with everolimus, for patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. Under the collaboration, Eisai and Merck initiated co-commercialization activities for Lenvima in the U.S. in June 2018. Since the initial launch, more than 10,000 patients were treated with Lenvima, which is approved in more than 50 countries worldwide.

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FDA Approves Lenvima (lenvatinib) for First-line Treatment of Unresectable Hepatocellular Carcinoma (HCC)

Sorafenib increases progression-free survival and disease control rate in NSCLC patients

In continuation of my update on Sorafenib

Sorafenib, a tyrosine kinase inhibitor (TKI) targeting the receptors for vascular endothelial growth factor, platelet derived growth factor, and mast/stem cell growth factor, modestly increases progression-free survival (PFS), time to progression, and disease control rate in non-small cell lung cancer (NSCLC) patients who have relapsed or failed two or three previous treatment regimens.

Lung cancer kills more people than breast, prostate, colorectal cancer combined. There are a number of treatment options now available for advanced NSCLC, the most common type of lung cancer, but almost all patients either fail or relapse after a period of clinical benefit. Patients that have relapsed or failed to respond to greater than two previous conventional chemotherapeutic treatments have very limited choices for further therapy.

A team of international investigators from 33 countries in Europe, North and South America, and Asia-Pacific conducted a relatively large phase III, randomized, double-blind, placebo-controlled trial comparing sorafenib plus best supportive care to best supportive care. This MISSION (Monotherapy admInistration of Sorafenib in patientS wIth nOn-small cell luNg cancer) trial was conducted to evaluate the efficacy and safety of sorafenib in the third or fourth-line setting with overall survival (OS) as the primary outcome measure, with PFS and other measures as a secondary endpoints.

The results published in the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer, show that the median PFS was statistically increased in the sorafenib (N=350) vs placebo groups (N=353) (2.8 versus 1.4 months; hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.51-0.72, p<0.0001), however the median OS was not different (8.2 versus 8.3 months; HR 0.99; 95% confidence interval [CI] 0.84-1.17, p=0.47). Time to progression was significantly greater (2.9 versus 1.4 months; HR 0.54; 95% CI 0.45-0.65, p<0.0001) with sorafenib than with placebo as was disease control rate (47.1% versus 24.7%, p=0.00086). Retrospective subgroup analyses showed that epidermal growth factor receptor (EGFR) mutation positive patients receiving sorafenib (N=44) had significantly longer OS (13.9 versus 6.5 months; HR 0.48; 95% CI 0.30-0.76, p=0.002) and PFS (2.7 versus 1.4 months; HR 0.27; 95% CI 0.16-0.46, p<0.001) than those receiving placebo (N=45).

Sorafenib increases progression-free survival and disease control rate in NSCLC patients

Sorafenib and vitamin K combo as anticancer drug against pancreas cancer....

We know that Sorafenib, is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (heptacellular carcinoma).

Sorafenib is a small molecular inhibitor of several protein kinases. (Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous. These pathways include Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor and kinases and c Kit the receptor for Stem cell factor. A growing number of drugs target most of these pathways). Sorafenib is unique in targeting the Raf/Mek/Erk pathway. After the FDA (US), approval in 2005 & European Commission in 2006, the drug was used to treat both forms of cancers. Now something interesting has been achieved by Dr. Brian Carr (a professor of Medical Oncology at the Jefferson Medical College of Thomas Jefferson University). Vitamin K1 or vitamin K2, plus sorafenib (Nexavar) each have shown activity against the growth of human cancer cells by inhibiting the extracellular signal-regulated kinase (ERK) pathway. The basis for the research lies in the fact that, sorafenib has demonstrated success at extending survival in patients with hepatocellular carcinoma (HCC, or primary liver cancer), hand-foot syndrome is a common adverse effect that affects approximately 20 percent of patients who receive the drug. It typically manifests as painful sores on the soles of patients' feet that can prevent the patients from walking, Dr. Carr said. Profound tiredness and weight loss is also seen in at least 30 percent of patients.

The research is of great significance because of the fact that in the pancreas cancer study, Dr. Carr and his colleagues tested each K vitamin in combination with sorafenib in pancreatic cell lines. Each combination inhibited cell growth, induced cell death and decreased the expression of ERK. They found that when combining vitamin K and sorafenib, the sorafenib dose required for inhibiting cancer cell growth decreased by more than 50 percent. The conclusions are really great 1. The dose required is reduced to half; 2. reduced side effects and 3. vitamin an established drug, no need of toxicological studies.... Congrats, Dr. Dr. Brian Carr and group..

Sorafenib effect on HCC survival depends on hepatitis status

For patients with advanced unresectable hepatocellular carcinoma, the effect of sorafenib on overall survival (OS) is dependent on patients' hepatitis. Richard Jackson, from the Liverpool Cancer Trials Unit in the United Kingdom, and colleagues undertook an individual patient data meta-analysis of three prospective randomized trials in which sorafenib was the control arm. Data were included for 1,643 patients with advanced unresectable hepatocellular carcinoma who received sorafenib.

The researchers found that patients who were both hepatitis B virus (HBV) negative and hepatitis C virus (HCV) positive had improved OS for sorafenib (log [hazard ratio], −0.27). In this subgroup, the median unadjusted survival was 12.6 and 10.2 months for sorafenib and other treatments, espectively. Other patient subgroups defined by HBV and HCV did not have improvement in OS. Consistent results were seen across all trials.

"There is consistent evidence that the effect of sorafenib on OS is dependent on patients' hepatitis status," the authors write. "There is an improved OS for patients negative for HBV and positive for HCV when treated with sorafenib ."

One author disclosed financial ties to the pharmaceutical industry; Bristol-Myers Squibb, Pfizer, and AbbVie gave access to data from studies in which they acted as sponsor.

Read at : http://ascopubs.org/doi/full/10.1200/JCO.2016.69.5197

 http://medicalxpress.com/news/2017-01-sorafenib-effect-hcc-survival-hepatitis.html

Novel combination therapy shows strong response in phase 1 trial

In continuation of my update on Sorafenib, Premetrexed,  Vandetanib
"Though phase 1 studies are designed to evaluate the safety of a new therapy, we had strong preclinical evidence suggesting this novel drug combination could work against a variety of cancers, so we hoped that we would see a response in our patients in this early phase trial," said Andrew Poklepovic, M.D., lead investigator on the study. "With this trial, we established a safe dosing schedule, and we will now be testing the efficacy of the therapy in the phase 2 study."

The results of the clinical trial were recently published online by the journal Oncotarget (PMID: 27213589). The study enrolled 37 patients between October 2011 and December 2014. Of those patients, 36 received treatment and 33 were evaluated for response. One patient had a complete response, meaning all detectable traces of the tumor disappeared, while four patients had a partial response, which means that the tumor volume shrank by at least 30 percent. The therapy stabilized disease progression in an additional 15 patients, with some of these patients responding for up to a year. The therapy was found to be particularly active in breast cancer patients.

"Some dose-limiting toxicities associated with pemetrexed were observed in one cohort of patients, but those who were eligible were switched to the dosing schedule of the second cohort, which was found to safe and tolerable," says Poklepovic, medical oncologist and member of the Developmental Therapeutics research program at Massey as well as assistant professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine.

The trial is based on pre-clinical research conducted by a team of Massey scientists led by Paul Dent, Ph.D., who is the Universal Corporation Chair in Cancer Cell Signaling and a member of the Cancer Cell Signaling research program at Massey, and Richard Moran, Ph.D., who recently retired after 22 years at Massey and more than four decades in the field. Pemetrexed was co-developed by Moran, and is now a first-line therapy for non-small cell lung cancer (NSCLC) and mesothelioma. Sorafenib is used to treat liver, kidney and thyroid cancer. In 2011, a research team led by Dent and including Moran discovered that the two drugs synergize to induce profound killing of cancer cells through a toxic form of autophagy, a process that normally re-cycles components of cells to provide energy for maintaining cell growth and survival. The drug combination hyper-activated the autophagy process within cancer cells, causing them to literally eat themselves to death (PMID: 21622715).

 Sorafenib  Pemetrexed

  Vandetanib    Lapatinib

The phase 2 study is not the only continuation of the research. Because the initial results of the phase 1 study were so promising, Dent started a new project to discover the best "third drug" that could act to further enhance the anti-cancer properties of the pemetrexed and sorafenib combination. This work has also recently been published in Oncotarget, and it showed that the combination therapy could be enhanced by a class of drugs known as ERBB1/2/4 inhibitors (PMID: 27015562).

"We discovered in mouse models of breast cancer that the drugs lapatinib and vandetanib significantly enhanced the anti-tumor effect of the pemetrexed and sorafenib therapy without any apparent toxicity to normal tissue. We made a nearly identical observation when adding the drug afatinib in experiments involving non-small cell lung cancer," says Dent. "Based on this data, we will be submitting a grant application to the National Cancer Institute for funding that will hopefully provide data that could allow us to open a future phase 1 trial testing the addition of an ERBB1/2/4 inhibitor to pemetrexed and sorafenib in patients with advanced solid tumors."

Dent was able to determine that ERBB1/2/4 inhibitors could increase the effectiveness of the combination therapy by using a novel technology called a multiplex assay. The multiplex assay is a broad, unbiased screening approach that allows researchers to simultaneously examine the levels of multiple hormones in the blood and determine the activities of enzymes in cancer cells. Using this technology, the researchers discovered that the enzyme ERBB1 was activated in response to the pemetrexed and sorafenib therapy.

"Unlike alternative methods where a certain degree of guesswork is required, the multiplex assay allowed us to observe exactly how the cancer cells responded to therapy," says Dent. "We were surprised to see that the enzyme ERBB1 was activated because it is ordinarily thought to protect cancer cells from chemotherapy. We went on to successfully use ERBB1/2/4 inhibitors as our third drug because of this unexpected data."

The multiplex assay provided Dent's team with such invaluable additional information about how the sorafenib and pemetrexed combination worked in the mouse models that they will now be using the assay in several of their clinical trials moving forward, including the new phase 2 trial of pemetrexed and sorafenib.

"The multiplex assay will allow us to track specific levels of hormones in the blood as patients undergo treatment, which could potentially give us a molecular 'fingerprint' of the point at which tumors develop resistance to the therapy," says Dent. "Ongoing preclinical experiments show that it could be possible to pinpoint exactly how the cancer cells are developing resistance to therapies, which might eventually allow oncologists to develop in real time a personalized therapy designed to overcome drug resistance in an individual patient's tumor."

Ref : http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=9434

Synergistic activity of Sorafenib and Sulforaphane abolishes pancreatic cancer...

In continuation of my update on "Sorafenib", I find this info interesting to share with...

A team led by Professor Dr. Ingrid Herr, Head of the Department of Molecular Oncosurgery, a group of the Department of Surgery at Heidelberg University Hospital, have come up with an interesting finding, i.e.,  Sorafenib  (used for advanced liver and kidney cancer) also appears to be effective against cancer stem cells in pancreatic cancer. It inhibits resistant tumor stem cells and is also especially effective in combination with sulforaphane, an organic compound found in broccoli. 

In their tests on cancer cells and mice, the researchers showed that sorafenib inhibited typical properties of cancer stem cells from pancreas tumors and greatly reduced tumor growth. However, this effect lasted only for a short time and after four weeks, new colonies of cancer stem cells formed that no longer reacted to further treatment with sorafenib. The resistance is probably related to a certain metabolic pathway, the NF-kB pathway, that is activated by sorafenib, claims the researchers. 

Naturally occurring substance(s) e.g., sulforaphane (vegetables from the cruciferous family such as broccoli and cauliflower possess a high content of sulforaphane, an anti-cancer compound)  that block precisely this undesired NF-KB pathway and thus make the dangerous cells vulnerable.  The experiments show that sulforaphane prevents the activation of the NF-kB pathway by sorafenib and hence the combination treatment reinforces the effect of sorafenib without causing additional side effects. Researchers conclude that the invasive potential of cancer cells was prevented  and  metastasis was completely blocked in cell culture experiments. 

"We assume that nutrition may be a suited approach to break therapy resistance of cancer stem cells and thus make tumor treatment more effective," Professor Herr suggested....

Ref : http://cancerres.aacrjournals.org/content/70/12/5004

Tivozanib Bests Sorafenib in Metastatic Renal Cell Carcinoma

In continuation of my update on Tivozanib  and  Sorafenib

Among patients with metastatic renal cell carcinoma, progression-free survival was longer in those receiving tivozanib versus sorafenib as third- or fourth-line therapy, according to a study published online Dec. 3 in The Lancet Oncology.

Brian I. Rini, M.D., from the Cleveland Clinic Taussig Cancer Institute, and colleagues conducted an open-label randomized trial at 120 academic hospitals in 12 countries and enrolled patients older than 18 years with histologically or cytologically confirmed metastatic renal cell carcinoma and at least two previous systemic treatments, including at least one with a vascular endothelial growth factor receptor inhibitor. Patients were randomly assigned to either tivozanib 1.5 mg orally once daily in four-week cycles or sorafenib 400 mg orally twice daily on a continual basis (175 patients to each); patients were followed for a median of 19 months.

The researchers found that median progression-free survival was significantly longer with tivozanib than sorafenib (5.6 versus 3.9 months; hazard ratio, 0.73). Hypertension was the most common grade 3 or 4 treatment-related adverse event (20 and 14 percent of tivozanib- and sorafenib-treated patients, respectively). Serious treatment-related adverse events occurred in 11 percent of tivozanib and 10 percent of sorafenib patients. There were no reports of treatment-related deaths.

"These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy," the authors write.

Several authors disclosed financial ties to pharmaceutical companies, including AVEO Oncology, which manufactures tivozanib and funded the study.

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30735-1/fulltext

Scientists show how sorafenib can be dangerous to the heart..

In continuation of my update on sorafenib

Studying mice with the equivalent of a heart attack, researchers found that the drug sorafenib (Nexavar) - which inhibits proteins called tyrosine kinase receptors (RTKs), and is used in kidney and liver cancer treatment - can interfere with heart stem cell activity, affecting the heart's ability to repair itself after injury. The findings suggest that sorafenib and other similar drugs that target these kinds of protein receptors may raise the risk for heart attack for some cancer patients with underlying heart disease, as well as affect the heart's ability to repair damage. By understanding how these cancer drugs can affect the heart, scientists and clinicians may be able to devise new treatment strategies to lessen such potentially damaging effects of often vital cancer drugs.

"The goal is not to take the drug off of the market - it's a very good and useful drug that cancer patients need. We're trying to understand how this cancer drug and others like it can affect the heart, and what types of individuals might be at risk for problems," said senior author Steven Houser, PhD, Professor and Chair of Physiology at Temple University School of Medicine and Director of Temple's Cardiovascular Research Center. "Our results are beginning to provide a clearer picture of some of the potential physiological mechanisms at play."

Ref : http://heartsurgery.templehealth.org/content/news.htm?inCtx4news_id=42&inCtx4view=24

Scientists show how sorafenib can be dangerous to the heart

Exelixis Announces U.S. FDA Approval of Cabometyx (cabozantinib) Tablets for Previously Treated Hepatocellular Carcinoma

In continuation of my update on Cabometyx (cabozantinib)

Exelixis, Inc. announced that the U.S. Food and Drug Administration (FDA) approved Cabometyx (cabozantinib) tablets for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. HCC is the most common form of liver cancer and the fastest-rising cause of cancer-related death in the U.S. 

“This new indication for Cabometyx is an important treatment advance for patients with this aggressive form of liver cancer, a community in need of new therapeutic options,” said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. “This approval is an important milestone as we continue to explore how Cabometyx may benefit people with difficult-to-treat-cancers beyond renal cell carcinoma. We would like to thank the patients and clinicians who participated in CELESTIAL and to acknowledge the team at the FDA for their continued collaboration during the review of our application.”

The FDA’s approval of Cabometyx was based on results from the CELESTIAL phase 3 pivotal trial of Cabometyx for patients with advanced HCC who received prior sorafenib. Cabometyx demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo. On November 15, 2018, Exelixis’ partner Ipsen received approval from the European Commission for Cabometyx tablets as a monotherapy for HCC in adults who have previously been treated with sorafenib.

“Patients with this form of advanced liver cancer have few treatment options, particularly once their disease progresses following treatment with sorafenib,” said Ghassan K. Abou-Alfa, M.D., Memorial Sloan Kettering Cancer Center, New York and lead investigator on CELESTIAL. “Physicians are eager for new options for these patients, and the results of the CELESTIAL trial demonstrate that Cabometyx has the efficacy and safety profile to become an important new therapy in our efforts to slow disease progression and improve treatment outcomes.”

In the pivotal CELESTIAL trial, median OS was 10.2 months with cabozantinib versus 8.0 months with placebo (HR 0.76, 95 percent CI 0.63-0.92; p=0.0049). Median progression-free survival (PFS) was more than doubled, at 5.2 months with cabozantinib and 1.9 months with placebo (HR 0.44, 95 percent CI 0.36-0.52; p<0.0001). Objective response rates per RECIST 1.1 were 4 percent with cabozantinib and 0.4 percent with placebo (p=0.0086). Disease control (partial response or stable disease) was achieved by 64 percent of patients in the cabozantinib group compared with 33 percent of patients in the placebo group.

Adverse events in CELESTIAL were consistent with the known safety profile of cabozantinib. The most common (≥10 percent) grade 3 or 4 adverse events in the cabozantinib group compared to the placebo group were palmar-plantar erythrodysesthesia (17 percent vs. 0 percent), hypertension (16 percent vs. 2 percent), increased aspartate aminotransferase (12 percent vs. 7 percent), fatigue (10 percent vs. 4 percent) and diarrhea (10 percent vs. 2 percent). Treatment-related grade 5 adverse events occurred in six patients in the cabozantinib group (hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism and hepatorenal syndrome) and in one patient in the placebo group (hepatic failure). Sixteen percent of patients in the cabozantinib arm and three percent of patients in the placebo arm discontinued treatment due to treatment-related adverse events.

“While we’ve seen some progress in the treatment of primary liver cancer in recent years, the patient community still needs new and better options,” said Andrea Wilson, President and Founder of Blue Faery: The Adrienne Wilson Liver Cancer Association. “The approval of Cabometyx has been eagerly anticipated, making this an important day for patients diagnosed with this devastating disease.”

In December 2018, Exelixis and its partner Ipsen announced the initiation of COSMIC-312, a phase 3 pivotal trial of cabozantinib in combination with atezolizumab versus sorafenib in previously untreated advanced HCC. The trial will also explore single-agent activity of cabozantinib in the first-line setting. For more information about the trial, visit ClinicalTrials.gov.

https://en.wikipedia.org/wiki/Cabozantinib



Exelixis Announces U.S. FDA Approval of Cabometyx (cabozantinib) Tablets for Previously Treated Hepatocellular Carcinoma

FDA Approves Fotivda (tivozanib) for the Treatment of Adult Patients with Relapsed or Refractory Advanced Renal Cell Carcinoma

In continuation of my update on Tivozanib

AVEO Oncology (Nasdaq: AVEO)   announced  the U.S. Food and Drug Administration (FDA)   approval of  Fotivda (tivozanib) for the treatment of adults with relapsed or refractory advanced renal cell carcinoma (RCC) who have received two or more prior systemic therapies. Fotivda is an oral, next-generation vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI).

“Today’s approval of Fotivda provides a new tool for treating patients with kidney cancer who have relapsed or become refractory to two or more prior systemic therapies,” said Brian Rini, MD, Chief of Clinical Trials at Vanderbilt Ingram Cancer Center and principal investigator of the TIVO-3 trial. “With advances in RCC treatment, patients are living longer, increasing the need for proven, well tolerated treatment options in the relapsed or refractory setting. The TIVO-3 study is the first positive Phase 3 study in RCC patients who received two or more prior systemic therapies, and also the first Phase 3 RCC study to include a predefined population of patients who have received prior immunotherapy, the current standard of care in earlier-line treatment. With this approval, I believe Fotivda represents an attractive intervention, and expect it to play a meaningful role in the evolving RCC treatment landscape.”

“We believe in Fotivda’s potential to provide a differentiated treatment option for the growing number of individuals in the U.S. with relapsed or refractory RCC, and today marks the culmination of many years of hard work and determination of many individuals to bring this therapy to patients,” said Michael Bailey, president and chief executive officer of AVEO. “With today’s approval, AVEO begins its journey as a commercial-stage company, a noteworthy accomplishment in our industry. On behalf of the entire AVEO team, I would like to thank all the patients, their families, and caregivers whose tireless efforts made this day possible.”

“Relapsed or refractory RCC is a devastating disease for which patient outcomes can be limited due to the tradeoff between tolerability and efficacy,” said Dena Battle, president of KCCure. “The FDA approval of Fotivda represents an exciting, meaningful advancement by providing a new treatment option for this patient population.”

AVEO plans to make Fotivda available to patients in the U.S. by March 31, 2021.

The approval of Fotivda is based on AVEO’s pivotal Phase 3 study, TIVO-3, comparing Fotivda to sorafenib in relapsed or refractory advanced RCC following two or more prior systemic therapies. The application is also supported by three additional trials in RCC and includes safety data from over 1,000 clinical trial subjects.

Patients (n=350) enrolled in the TIVO-3 study were randomized 1:1 to receive either Fotivda or sorafenib. The main efficacy outcome measure was progression-free survival (PFS), assessed by a blinded independent radiology review committee. Other efficacy endpoints were overall survival (OS) and objective response rate (ORR).

Median PFS was 5.6 months (95% CI: 4.8, 7.3) in the Fotivda arm (n=175) compared with 3.9 months (95% CI: 3.7, 5.6) for those treated with sorafenib (HR 0.73; 95% CI: 0.56, 0.95; p=0.016). Median OS was 16.4 (95% CI: 13.4, 21.9) and 19.2 months (95% CI: 14.9, 24.2), for the Fotivda and sorafenib arms, respectively (HR 0.97; 95% CI: 0.75, 1.24). The ORR was 18% (95% CI: 12%, 24%) for the Fotivda arm and 8% (95% CI: 4%, 13%) for the sorafenib arm.

The most common (≥20%) adverse reactions were fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis. The most common grade 3 or 4 laboratory abnormalities (≥5%) were decreased sodium, increased lipase, and decreased phosphate.

The recommended tivozanib dose is 1.34 mg once daily with or without food for 21 days every 28 days on treatment followed by 7 days off treatment (28 day cycle) until disease progression or unacceptable toxicity.

https://en.wikipedia.org/wiki/Tivozanib

Sorafenib, sunitinib provide no benefit to patients with locally advanced kidney cancer

Findings from a federally funded study suggest that patients with locally advanced kidney cancer should not be treated with either adjuvant (post-surgery) sorafenib or sunitinib. The average period to disease recurrence was similar between those who received sorafenib or sunitinib after surgery (5.6 years) and those treated with placebo (5.7 years). The study will be presented at the upcoming 2015 Genitourinary Cancers Symposium in Orlando.

"These drugs didn't reduce disease recurrence, but on average they did not appear to worsen patient outcomes either," said lead study author Naomi B. Haas, MD, an Associate Professor of Medicine at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, Pa. "We are still analyzing the various groups of patients enrolled on this trial, and we hope that analysis of patient specimens collected on this study may provide clues into subsets of patients who might still benefit from these therapies."

Sorafenib, sunitinib provide no benefit to patients with locally advanced kidney cancer

Liver Cancer Drug Fails to Live Up to Early Promise...

In continuation of my update on everolimus

Although it looked promising in early studies, the drug everolimus didn't improve survival for people with advanced liver cancer in its latest trial, a new study found.

The findings from the phase 3 clinical trial are disappointing because earlier research suggested that everolimus (Afinitor) prevented tumor progression and improved survival for in advanced liver cancer. Normally, these patients can expect a median overall survival of less than one year.

The only drug currently shown to significantly improve survival of advanced liver cancer patients is sorafenib (Nexavar). But that drug's benefits are temporary and the cancer eventually progresses, according to background information in the new study.

The current study included 546 adults with advanced liver cancer whose disease progressed during or after treatment with sorafenib, or who could not take sorafenib. The patients were divided into two groups, with 362 given everolimus and 184 given a placebo.

Liver Cancer Drug Fails to Live Up to Early Promise 

Regorafenib drug improves survival rates in patients with hepatocellular carcinoma

 In continuation of my update on Regorafenib

Oral multikinase inhibitor regorafenib achieves significantly improved survival rates compared to placebo in patients with hepatocellular carcinoma, according to data from the phase III RESORCE trial, presented at the ESMO 18th World Congress of Gastrointestinal Cancer in Barcelona, Spain.

"Systemic treatment for hepatocellular carcinoma has long consisted of just one agent - sorafenib -which was shown to provide a significant improvement in life expectancy almost 10 years ago, but no other agent has surpassed its benefits," said the study's principal investigator Dr Jordi Bruix, Head of the BCLC group at the Hospital Clínic and Scientific Director of the Network for Biomedical Research for Hepatic and Digestive Diseases (CIBEREHD).

While the last decade has seen many potential new agents for hepatocellular carcinoma fail in clinical trials, phase I and II data from early regorafenib trials were promising, and led to the initiation of this international, multi-center phase III trial.

Researchers enrolled 573 patients with intermediate or advanced stage hepatocellular carcinoma, who had all been previously treated with sorafenib, and randomized them 2:1 to 160mg oral regorafenib or placebo once daily for 1-3 of each four week cycle, in addition to best supportive care.

After a median of 3.6 months of treatment, patients on regorafenib showed a 38% reduction in the risk of death and a 54% reduction in the risk of progression or death compared to placebo.

Mean progression-free survival was 3.1 months with regorafenib and 1.5 months with placebo, while median overall survival was 10.6 months for regorafenib and 7.8 months with placebo.

Overall, 65.2% of patients on regorafenib showed complete or partial response or stable disease, compared to 36.1% of the placebo group.

Regorafenib had a similar safety and side effect profile to sorafenib, with hypertension, hand-foot skin reaction, fatigue and diarrhea all being significantly more common in patients taking the drug.

Dr Bruix said that the benefits of the drug were evident regardless of the cause or stage of the tumor, but analysis of biomarkers would reveal whether there might be certain sub-groups of patients likely to derive even greater benefit from this treatment.

"This is a very difficult to treat cancer but now we have an effective second-line agent, which is good news for the patients and also for the field as interest in further developments will be stimulated," Dr Bruix said.

Ref : http://www.esmo.org/Press-Office/Press-Releases/Regorafenib-Shows-Significant-Survival-Gains-in-Refractory-Liver-Cancer

FDA Approves Inlyta for advanced kidney cancer (renal cell carcinoma)

The U.S. FDA,  approved Inlyta (axitinib) to treat patients with advanced kidney cancer (renal cell carcinoma) who have not responded to another drug for this type of cancer. 

The safety and effectiveness of Inlyta were evaluated in a single randomized, open-label, multi-center clinical study of 723 patients whose disease had progressed on or after treatment with one prior systemic therapy. The study was designed to measure progression-free survival, the time a patient lived without the cancer progressing. Results showed a median progression-free survival of 6.7 months compared to 4.7 months with a standard treatment (sorafenib).

The most common side effects observed in greater than 20 percent of patients in the clinical study were diarrhea, high blood pressure (hypertension), fatigue, decreased appetite, nausea, loss of voice (dysphonia), hand-foot syndrome (palmar-plantar erythrodysesthesia), weight loss, vomiting, weakness (asthenia) and constipation.

More...

RADIANT-3 study results show everolimus significantly extends progression-free survival in patients with advanced pancreatic neuroendocrine tumors...

We know that Everolimus (RAD-001, marketed by Novartis under the  tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine and Afinitor in oncology) is the 42-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.

The FDA has approved everolimus for the treatment of advanced kidney cancer on March 30, 2009 and for organ rejection prophylaxis on April 22, 2010. Now Novartis Pharmaceuticals Corporation announced that the  Phase III study of Afinitor® (everolimus, see structure) tablets plus best supportive care met its primary endpoint, showing the drug significantly extended progression-free survival, or time without tumor growth, in patients with advanced pancreatic neuroendocrine tumors (NET). The study, RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors), is part of the largest clinical trial program of its kind. 

Everolimus is approved under the trade name Afinitor® (everolimus) tablets for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.  

As  per the claim by   Herve Hoppenot, President, Novartis Oncology, Everolimus was developed to inhibit the mTOR protein, which is a critical target in treating various cancers, including NET. Results from RADIANT-3 demonstrate that everolimus has the potential to become an important treatment option for patients with advanced pancreatic NET, where there is a major unmet need.

"These study results will serve as the basis of worldwide regulatory filings for everolimus and bring us one step closer to our goal of offering these patients a new therapy."...says Herve Hoppenot...

Ref : http://www.novartis.com/newsroom/media-releases/en/2010/1421290.shtml

Tivozanib Improves RCC (renal cell carinomas) Survival

Tivozanib (see structure, AV-951) is an oral VEGF receptor tyrosine kinase inhibitor. It is undergoing clinical trial investigation for the treatment of renal cell carinomas. An oral quinoline urea derivative, tivozanib suppresses angiogenesis by being selectively inhibitory against vascular endothelial growth factor.

The positive results of this Phase 2 trial informed the design and implementation of TIVO-1, a pivotal Phase 3 clinical study in advanced RCC demonstrating tivozanib superiority over sorafenib in the primary endpoint of PFS in the first-line setting, top-line data from which were reported in January 2012.

“Current RCC therapies are associated with toxicities that can interfere with patients’ treatment regimens and impact treatment efficacy and activities of daily living,” said Dmitry A. Nosov, M.D., Ph.D., senior clinical researcher at the Blokhin Oncology Research Center, Moscow, Russian Federation, lead author of the Phase 2 study and TIVO-1 investigator.

“Despite recent progress in treating patients with RCC, patients and physicians would benefit from a new RCC treatment option that delivers both improved efficacy and a more tolerable safety profile. The combined tivozanib efficacy and safety data demonstrated in this Phase 2 study supports tivozanib as a potential advancement in the RCC treatment landscape.”

Based on the positive Phase 2 data and success of the TIVO-1 trial, AVEO and its collaborator Astellas Pharma Inc. are moving forward with plans for submitting the tivozanib NDA in RCC in the third quarter of 2012, with the MAA submission to follow.

“We believe that the efficacy and safety profile consistently demonstrated by tivozanib and recently validated in our Phase 3 TIVO-1 trial represent an important step forward in the treatment of patients who have advanced RCC,” said William Slichenmyer, M.D., Sc.M., chief medical officer, AVEO. “We are pleased with the opportunity to collaborate with tivozanib study investigators on publishing these positive Phase 2 data in the Journal of Clinical Oncology, and look forward to advancing our work with our global partners at Astellas to bring tivozanib to patients who can benefit from this therapy.”....

http://jco.ascopubs.org/content/30/14/1678.abstract?sid=1fe73024-e1cc-481f-acc3-1dc09b596f7f

FDA approves cancer drug Afinitor for treatment of rare genetic disorder

 We know that Afinitor ( see structure) is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation and inhibition of mTOR kinase activity. Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

Afinitor is specifically indicated for the treatment of advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Afinitor is supplied as a 5 mg or 10 mg tablet designed for oral administration. The recommended initial dose of the drug is 10 mg, to be taken once daily at the same time every day, either with or without food. Afinitor tablets should be swallowed whole with a glass of water; they should not be chewed or crushed....Now FDA approves the drug....

 FDA approves cancer drug Afinitor for treatment of rare genetic disorder