Sorafenib (Nexavar)

[CaroleHammett]

Although not mentioned in the first article below, sorafenib (Nexavar) was originally developed for kidney cancer and, in addition to liver cancer, is also used off label in lung cancer, although the mfgr. recently dropped squamous cell types from its lung cancer clinical trials due to adverse reactions (see second article below).

Note: I included both articles here because it appears the second (earlier) one hasn't ever been posted to this website.

Carole

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1. http://www.sciencedaily.com/releases/20 ... 161027.htm

Targeted Therapy Combination Overcomes Treatment Resistance In Liver Cancer, Study Suggests

ScienceDaily (Apr. 15, 2008) — Researchers at the University of Pennsylvania School of Medicine and Abramson Cancer Center reported April 13 at the annual meeting of the American Association for Cancer Research that combining two targeted therapies overcomes treatment resistance in liver cancer cell lines. The team is currently designing a trial to test the combination in patients.

Liver cancer is resistant to many chemotherapies and to cell-death inducing agents. Last year, however, the U.S. Food and Drug Administration approved sorafenib (Nexavar®) as a treatment for liver cancer after a clinical trial showed that the targeted agent prolonged survival in some patients.

Unfortunately not all patients respond to sorafenib and the drug does not cure the disease.

Therefore, Wafik El-Deiry, MD, PhD, Professor of Medicine, Genetics, and Pharmacology, and co-Program Leader of Radiation Biology in the Abramson Cancer Center, and colleagues have tested other targeted agents in combination with sorafenib.

They found that treating liver cancer cells with sorafenib and an antibody or the natural ligand that stimulates programmed cell death via the TRAIL pathway, dramatically increases the rate of cell death.

"Sorafenib by itself causes a little cell death, but not that much," Dr. El-Deiry said. "Now you combine sorafenib and TRAIL, and all of the sudden you get massive cell death. It is a real synergistic interaction. It is very profound killing."

The combination works regardless of whether the researchers use a monoclonal antibody that stimulates the TRAIL receptor, which resides on the surface of the cancer cells, or the receptor's natural ligand, a small protein called TRAIL. Both the antibody and the TRAIL ligand are currently being tested as single agents in patients.

Within the next several months, Dr. El-Deiry's team expects to announce the details for a trial testing the combination in patients.

In a healthy individual, the immune system uses the TRAIL pathway to rid the body of unwanted cells, including precancerous ones. Once cancer develops, however, the cells often become less responsive to TRAIL activation, in part because of an overabundance of a protein called Mcl-1, according to Dr. El-Deiry. His team found that sorafenib reduces the amount of Mcl-1 in the cancer cells, restoring their sensitivity to TRAIL-induced cell death.

Although the Penn investigators focused their current report on liver cancer, they discovered that the sorafenib-TRAIL combination also kills colon cancer cell in vitro and in animal models.

...

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2. http://www.medicalnewstoday.com/articles/97792.php

Nexavar Dropped From Lung Cancer Trial

by Catharine Paddock, PhD19 Feb 2008 - 3:00 PST

Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals have stopped a late stage trial of their cancer drug Nexavar (sorafenib) in patients with nonsmall-cell lung cancer (NSCLC), because it was not showing the hoped for increase in survival.

Following a planned interim analysis, the trial's independent data monitoring committee (DMC) concluded that the drug was not going to meet the trial's main goal of improving overall survival.

In the phase 3 trial, a group of patients with squamous cell carcinoma of the lung who took the drug in combination with chemotherapy drugs carboplatin and paclitaxel showed a higher rate of death than a group that received chemotherapy alone.

The trial, which is called ESCAPE (Evaluation of Sorafenib, Carboplatin And Paclitaxel Efficacy in NSCLC), was otherwise showing safety events generally in line with those previously reported, said Bayer in a press statement.

The two drug companies are giving the DMC information to health authorities and other investigators studying the effects of Nexavar and will also be presenting the findings of the trial at a forthcoming scientific meeting.

The companies will also be reviewing the findings of this trial, including the DMC review, to see if they impact any other ongoing lung cancer trials using Nexavar.

Vice president of Therapeutic Area Oncology at Bayer HealthCare Pharmaceuticals, Dr Susan Kelley said that they were disappointed with this result, but the two companies were still very much committed to widening the scope of Nexavar in treating as many cancers as possible and will continue to extend trials to other cancers.

"Nexavar has proven significant clinical benefit for patients with liver cancer and advanced kidney cancer and we will continue to investigate its potential across a wide variety of tumors," said Kelley.

The ESCAPE study was a multicentre, randomized, double-blind, placebo controlled phase 3 trial involving more than 900 NSCLC patients at over 140 clinics in North and South America, Europe and Asia.

The main outcome sought was overall survival, but secondary endpoints included progression-free survival, tumour response, quality of life, and drug safety.

The participants had not received any systematic anti-cancer treatment for lung cancer before the trial, which was open to patients with all types of NSCLC, including squamous cell carcinoma or adenocarcinomas.

The patients were randomized to a drug group and a control (placebo) group. The drug group was given 400 mg of Nexavar, orally, twice a day, while the control group had a placebo. Both groups also had two chemotherapy drugs, carboplatin and paclitaxel. Both groups continued with the drug or placebo alone, after chemotherapy had finished (maintenance phase), until symptoms of tumour progression or side effects showed.

Nexavar (sorafenib) attacks both the tumour cell and the blood vessels that feed it. In studies before clinical trials, the drug showed ability to target kinase proteins thought to be involved in cell growth and development of blood supply, two essential cancer enablers. The kinases involved include: Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.

Nexavar is approved for the treatment of liver cancer in over 30 countries and for the treatment of advanced kidney cancer in over 60 countries. It is being evaluated for use with many other cancers such as breast cancer, metastatic melanoma, and as an adjuvant therapy for kidney cancer and liver cancer.

...

[gpawelski]

It's a shame about the Nexavar clinical trial. It reminds me of the Iressa debacle. It actually did work miracles in some patients. Cell function analysis has found that a cellular signal for response to the drug can identify some responders, but this limits Iressa's market profile significantly.

To the manufacturer, what good is the drug if it cannot be used by a broad base of the population? How will drug companies respond when studies show their drug to be highly effective, but only in 10-15% of the potential patient population? A failure? No, not by a long shot!

Combination chemotherapy has not always produced greater degrees of clinical benefit than single agent therapy, as this clinical trial illustrates. When two or more drugs are given, there is a greater probability that at least one of the drugs will be active. There is then the potential for true synergery, where the whole is greater than the sum of the parts.

But most drug combinations are only additive or at most, minimally synergistc. However, some newer combinations show greater degrees of synergy, although apparently not in this study. True synergy is rather uncommon in most adult solid tumors. Most drug combinations in diseases are merely additive, where the whole equals the sum of its parts, and not synergistic. In hematologic neoplasms (leukemia, lymphoma, multiple myeloma), true synergy is very common.

In cases like this study, where drugs are only additive and not synergistic, nothing is learned by testing the drugs in combination compared to what is learned by testing them separately. Therefore, drugs in combination are only tested in cases where there is the realistic possiblitiy of seeing true synergy.

The best combinations are those in which there is true synergy and in which the toxicities of the drugs in the combination are non-overlapping, so that full doses of each drug may be given safely.

The era of empiric, aggressive, multi-agent cytotoxic chemotherapy for first-line/recurrent/refractory adult solid tumors should come to an end. More emphasis should be put on matching treatment to patient, through the use of individualized genetic and cellular pre-testing.

[CaroleHammett]

Hi, G, and thanks for posting.

Like Avastin, at this point Nexavar is still considered a viable option as a second line treatment for NSCLC patients with other than squamous cell.

The article does not specify the predominant cause of death for squamous cell patients, but in the case of Avastin, it was hemorhages, a possibility in the case of Nexavar, too, based on an earlier article at onctalk's website:

http://onctalk.com/?p=99

Thanks again for your comments. I fully agree.

Carole

[gpawelski]

You'd be surprised, Avastin or Nexavar can be a viable option as first line treatment, but not for everybody. It actually works miracles in some patients. But it may be hard to tell a medical oncologist to ratchet back on the anti-VEGF drug they're using when the disease setting is stage IV lung, ovarian, or pancreatic cancer. More circulation epithelial cells are found preoperatively in patients with squamous cell carcinoma than in those with adenocarcinoma.

Pharmaceutical companies seem to be attracted to studies looking at the maximum tolerated dose of any treatments. Cancer patients are taking doses of treatments that are possibly well in excess of what they need. Many of them may be just as effective and produce fewer side effects if taken over shorter periods and/or in lower doses. Avastin, for example, the dose being tested is 15 milligrams per kilogram of body weight, despite other research showing it may work with 3 milligrams per kilogram.

http://jco.ascopubs.org/cgi/content/full/25/25/e31

[CaroleHammett]

Excellent article. Really makes one think.

Thanks very much.

Carole

[CaroleHammett]

Hi, G.

Re pharmaceutical companies and maximum doses, an interesting article found taking same position as you but in re nutrition and taking too high a dosage of various herbs and vitamins:

http://www.democratandchronicle.com/app ... 032/LIVING

Carole

[gpawelski]

Thanks! The one part of the article popped out at me about the intuitive thinking that if the disease can be corrected with vitamins and minerals, then consuming a larger amount of them will be better.

That was virtually the same issue with the anemia drugs. If the patient felt better with the anemia drugs, then taking a larger amount of the drugs will be better. It turns out not to be the case either. They are a "growth" factor. Scientists at The Weizmann Institute of Science seemed to have found the control mechanism.

http://lchelp.org/l_community/viewtopic ... highlight=

I do have to say Vitamins, minerals and phytonutrients, although not entirely replicated in supplement form, are badly depleted in our American "processed" foods, and can be a necessary complement to what is lost by these foods.

And last year, research on epigenetics at Johns Hopkins is proving orthodox oncology wrong about supplements. Evidence from their research suggests that the epigenome can be influenced by the environment which means that epigenetic modifications that lead to carcinogenesis may be reversible by changing the environment.

What is meant by environment? The environment is the totality of surrounding conditions - the milieu of the cell. What affects the milieu of the cell? Toxins, viruses, carcinogens, diet, essentially everything that our cells are exposed to. Detoxification followed by the creation of a healthy milieu with appropriate diet and supplements benefits cancer patients.

Such a concept is heresy to the orthodoxy within the oncology community that determines research priorities. The viability of detoxification (removing toxins, viruses, carcinogens and other biological contaminants from the body) followed by improving what a patient consumes (organic, whole, vegetarian foods, vitamin supplements, etc.) as a cancer therapy has been summarily rejected by the cancer establishment for decades (most cancer patients are offered artificially colored, sugared and preserved foods during their hospital stays).

Despite the growing empiric and anecdotal data that demonstrate that these factors do play a role in distinguishing long-term cancer survivors, the orthodoxy within the oncology community has rejected such treatment approaches as worthless. Part of their reasoning has included that there are no biological mechanisms to support such a modality. However, epigenetics is providing a plausible biological mechanism.

Is detoxification and diet a viable cancer modality by itself or in combination with other approaches? There are many long-term survivors who swear it is and offer their existence as proof. What is clear is that our body and the environment are one, as epigenetics proves, the environment can effect how our genes work within our cells.

As epigenetics has become an accepted science perhaps it is time researchers took the next step and asked what role epigenetics may play in reversing cancer and what lifestyle decisions and exposures may impact such a role. Perhaps some resources focused on the mechanistic, reductionist and overwhelmingly failed gene therapies can be redirected.

[CaroleHammett]

gpawelski: ...The one part of the article popped out at me about the intuitive thinking that if the disease can be corrected with vitamins and minerals, then consuming a larger amount of them will be better...

G: I changed my diet (organic, vegetarian, etc.) upon completion of my chemo last Spring and at the same time added numerous herbs, vitamins and minerals.

After reading your response and then re-reading the original article, I am now wondering if I may not have "overdone" (i.e., "more is better") the latter and have decided to "re-review" my current herbal/vitamin/mineral regimen.

Thanks for the input!

Carole