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

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

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

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

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