Todays FDA hearing on Avastin,news from Genentech..

[Soccermom]

http://www.gene.com/gene/products/information.html

[StephN]

Hi -
I got a notice on this decision that had a link to Genentech's press release:
http://www.gene.com/gene/news/press-...etail&id=13528

The recommendation was for disuse with Taxol in HER2 negative patients.

The final decision will be made at a later date.

"the FDA's Oncologic Drugs Advisory Committee (ODAC) recommended that the FDA withdraw its approval of Avastin® (bevacizumab) in combination with paclitaxel chemotherapy for previously untreated (first-line) HER2-negative metastatic breast cancer. The committee's recommendation is not the final decision and Avastin plus paclitaxel is still FDA approved for women with HER2-negative metastatic breast cancer. The FDA Commissioner will make the final decision on whether Avastin should remain approved for metastatic breast cancer. The FDA has not announced when the Commissioner will make the final decision."

Need some clarification as to the standing for HER2 positive patients.

[Soccermom]

Stinks that for those that have Metastatic disease and have been on AVASTIN successfully to even have to spend their days FIGHTING the gov't instead of enjoying the time AVASTIN has affoded them!
Hugs to you Steph,
Marcia

[chrisy]

Hear,hear. Very disappointing. I'm not optimistic that the final decision will change. True, the indication was for her2-/taxol so technically any other use would be "off label", I think it will just make it more difficult for breast cancer patients to get it (paid for) "off label" in the future despite the fact it is FDA approved for other cancers.

[Rich66]

"recommended that the FDA withdraw its approval of Avastin® (bevacizumab) in combination with paclitaxel chemotherapy for previously untreated (first-line) HER2-negative metastatic breast cancer."

Does that mean that 2nd line etc are still in the mix?

[gdpawel]

Dr. Len Lichtenfeld of the American Cancer Society, blogged about his experience at the hearing, on June 28th and 29th, held by the FDA on the question of whether or not Avastin should retain approval for the treatment of metastatic breast cancer.

http://www.cancer.org/AboutUs/DrLens...d-Emotion.aspx

When the votes were in, the FDA Advisory Committee voted 6-0 that the risks, being substantial, outweighed the benefits associated with a slight slowing of the pace at which metastatic breast tumors progress. Thus, for the Avastin indication granted accelerated approval in 2008 — metastatic breast cancer — Avastin is considered unsafe, according to ODAC.said unanimously that the approval of Avastin for the treatment of metastatic breast cancer should be withdrawn.

http://www.cancer.org/AboutUs/DrLens...-The-Pain.aspx

Avastin combined with chemotherapy has improved the survival of some lung cancer patients. Avastin plus folfox has improved survival for some colon cancer patients. Avastin plus chemotherapy improves the survival of some breast cancer patients. The problem is that it doesn’t improve the survival of all cancer patients.

Roche has reported that women with breast cancer who were treated with Avastin in combination with chemotherapy followed by the continued use of single-agent Avastin demonstrated a significant improvement in progression-free survival. It’s unclear if Avastin can help increase the overall survival rate in this indication.

I remember a clinical oncologist involved with real-time studies under real-world conditions of drugs like Avastin, telling me when the FDA rules on the clinical utility of a drug, they use a broad-brush approach that looks at the global outcomes of all patients, determining whether these glacial trends reflect a true climate change.

The problem is that while Bethesda, Maryland may not be noticing significant changes in ocean levels, people who live on the Maldives are having a very different experience. As these scientists ponder the significance of Avastin, some cancer patients are missing out on a treatment that could quite possibly save their lives.

One breast cancer patient’s life saving therapy is another’s pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another.

The solution to this problem is to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s outcome.

In regards to Avastin side effects, any chemotherapeutic has its range of side effects. With Avastin though (and probably most other agents), it was reported in JCO that emerging evidence shows many of the drugs like Avastin may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses. The dose being used for Avastin is 15 milligrams per kilogram of body weight, despite research showing it may work with 3 milligrams per kilogram.

There are selected groups who will benefit from Avastin, if they knew who they were. Genentech/Roch (or whatever flavor of the month they are) researchers have been looking for tests to help predict how patients will respond to Avastin. Some have suggested that they should use the cell-based functional profiling platform (AngioRx Assay) to identify a potential targeted population of cancer patients that it thinks will benefit from Avastin, and then conduct a randomized clinical trial among this group.

However, unlike some genetic assays that look whether an individual has a particular mutation or amplification, and therefore tests for “theoretical” candidates for a particular targeted drug, the functional profiling technique may find Avastin not synergistic (cooperative) and finds some other VEGF-targeted (or multiple VEGF-targeted) drug may work better in an individual cancer patient and then put that individual into the clinical trial. I can understand they may not want some other drug tested on their dime.

There are a number of new classes of drugs that target VEGF, at the protein level (Avastin), at the tyrosine kinase level (Nexavar, Sutent) and at the intracellular metabolic pathway mTOR (Afinitor, Torisel). However, responses to any individual mechanism occurs in the miniority of patients. It is unclear why some patients repond to these interventions while others fail. In cell function analysis, it has found unexpectedly good response to conventional cytotoxic drugs following a failure to respond to these targeted agents.

This reinforces the need for cancer therapies to be individualized. It remines us that it is the good outcome of the patient not the therapy applied that constitute successful therapy. There is really nothing wrong with Avastin. It’s a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman. There are not perfect drugs. There are simply drugs that work for certain patients. But that’s not what pharmaceutical companys like to hear. They like to produce drugs that apply to a broad base of patients. To make the most out of a drug, not just some subsets of patients.

[Rich66]

"emerging evidence shows many of the drugs like Avastin may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses."

Have to wonder how many drugs are either discarded or approved in a limited benefit dose due to bias towards "more is better". Phase one is usually focused on determining how much is physiologically tolerable..only after they determine that amount do they determine how well the drug works. There is now significant suggestion that drugs can sometimes be used at highest dose and metronomic dose with benefit in each instance..i.e. 2 for 1.

[gdpawel]

In reading one of Dr. Nagourney's lastest blog postings "So What Happened to the PARP Inhibitors in Breast Cancer Anyway? ASCO 2011," I was struck by his comments about the dosage of gemcitabine in Dr. O'Shaughnessy's clinical trial (1000 mg/ml2 vs 800 mg/ml2 vs 600 mg/ml2). It reminds me of the dosages with Avastin brought up by Dr. Haines.

Nagourney originally reported the carboplatin plus gemcitabine combination in breast cancer, as a split-dose doublet in 2008 (Nagourney, Clin Breast Cancer Research, 2008). He observed, in that original clinical trial, that even a lower starting dose of gemcitabine (i.e. 800mg/ml2 vs. the O’Shaughnessy 1000 mg/m2) resulted in significant toxicity and in his concluding comments in that paper, he suggested 600mg/ml2. At 1000 mg/m2, Dr. O’Shaughnessy’s trial nearly doubled his recommended dose in this patient population.

Bottom line: more is not always better. How the role the drug delivery schedule plays in the disease control.

[Rich66]

There is a lot to suggest that time of day of dose can influence efficacy and toxicity of chemos. Studies at this point are probably giving doses according to convenience. Hrushesky feel sthat a tNF therapy was dismissed due to toxicity that could have been lessened by appropriate chronotherapy. so..amount of dosage and time of dosage may be wild cards in this process...only one of which is addressed by functional profiling.

[Rich66]

Let me add the issue of sequence. There has been some variable info on sequencing Zoledronic acid 24 hrs after a chemo infusion. Here's one that combines metronomic dosing with sequence in usually unsuccessful chemo treatment of prostate cancer:

Cancer Biol Ther. 2010 Sep;10(6):543-8. Epub 2010 Sep 8.
Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial.

Facchini G, Caraglia M, Morabito A, Marra M, Piccirillo MC, Bochicchio AM, Striano S, Marra L, Nasti G, Ferrari E, Leopardo D, Vitale G, Gentilini D, Tortoriello A, Catalano A, Budillon A, Perrone F, Iaffaioli RV.

LINK

Source

Genito-Urinary Department, National Cancer Institute Fondazione G Pascale, Naples, Italy.

Abstract

BACKGROUND:

Docetaxel (DTX) and zoledronic acid (ZOL) are effective in patients with hormone resistant prostate cancer (HRPC) with bone metastases. A phase I clinical trial of metronomic administration of Zoledronic Acid AN d TaxoterE combination (ZANTE trial) in 2 different sequences was conducted in HRPC.
RESULTS:

The maximum tolerated dose was not achieved with sequence A. Two patients at third level of sequence B developed dose limiting toxicity. A disease control was obtained in six out of nine patients treated with sequence A, where a decrease of biological markers and PSA were also observed. No evidence of anti-tumor activity was observed in patients treated with sequence B.
PATIENTS AND METHODS:

Twenty-two patients enrolled into the study (median age: 73 years; range: 43-80) received one of three escalated doses of DTX (30, 40 and 50 mg/m(2)) in combination with a fixed dose of ZOL (2 mg), both administered every 14 days in two different sequences: DTX at the day 1 followed by ZOL at the day 2 (sequence A) or the reverse (sequence B). Patients were evaluated for adverse events and serum IL-8, MMP-2 and MMP-9 were evaluated prior and after therapy with the two sequences of administration of DTX and ZOL.
CONCLUSIONS:

The bi-weekly combination of DTX (50 mg/m(2)) followed by ZOL was feasible and show promising anti-tumor activity.

PMID:20657175 [PubMed - indexed for MEDLINE]

[gdpawel]

Rich

In regards to your "time of day of dose" comment. The earlier in the day concept has some basis in cancer biology. Apparently, this "circadian" issue is talked alot in medical oncology. This is the first heard of it in radiation oncology recently.

Circadian physiology highlights the basic processes and latest research findings in circadian biology and describes how this knowledge applies to the timing for effective administration of medicines. The formal study of biological temporal rhythms is called chronobiology.

According to Wiki, photosensitive proteins and circadian rhythms are believed to have originated in the earliest cells, with the purpose of protecting the replicating of DNA from high ultraviolet radiation during the daytime. As a result, replication was relegated to the dark.

Circadian rhythms allow organisms to anticipate and prepare for precise and regular environmental changes; they have great value in relation to the outside world. The rhythmicity appears to be as important in regulating and coordinating internal metabolic processes, as in coordinating with the environment.

Many more genetic components of the biological clock are now known. Their interactions result in an interlocked feedback loop of gene products resulting in periodic fluctuations that the cells of the body interpret as a specific time of the day.

Greg

[gdpawel]

[Dr. Robert A. Nagourney is medical director at Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine. He posted on his blog about the issue surrounding Avastin.]

We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patient’s response durability. It was hoped and believed that time to progression would be an early measure of survival.

Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastin’s indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs).

There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval — statistically significant survival — was not met.

The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), “I am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.”

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma.

The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 — providing her an additional five years of life — it wasn’t until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication.

We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test.

Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward.

The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma.

We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies.

We stand at the ready for the challenge.

[gdpawel]

According to Merriall Goozner (who occasionaly writes for the Journal of the National Cancer Institute), two clinical trials showed no improvement in mortality among women with metastatic breast cancer. Those trials didn’t even replicate the delay in progression of disease that had been shown in the original trial that led to accelerated approval in 2007. Now comes the firestorm from patient advocacy groups, who will use anecdotal stories to claim the drug works for some women.

Here’s the truth of those matters: Anecdotes are not science. Those who insist their use of the drug is the reason why they are remaining alive longer than average will still have access to the drug since most insurance companies and Medicare will continue to follow the National Comprehensive Cancer Network guidelines.

NCCN’s guideline writing committee, a third of whom have financial ties to Roche/Genentech, has said it will not withdraw Avastin’s use in metastatic patients. A few years ago, CMS passed a rule that said it would reimburse any use of a cancer drug, even if the FDA had not approved it for that use, if it was included in the NCCN guidelines and accompanying formulary.

http://www.fda.gov/NewsEvents/Newsroom/UCM279485

One breast cancer patient’s life saving therapy is another’s pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another.

The solution to this problem is to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s outcome.

[Rich66]

Of course, all this likely without investigating continuation past progression...potentially a key to any antiangiogenic therapy. RECIST we much....

[gdpawel]

I was reminded for the record, the formal indication that the FDA revoked involved Avastin used in combination with the cancer drug paclitaxel (Taxol) for those patients who have not been treated with chemotherapy for their form of metastatic breast cancer known as HER2 negative.

Some industry-insiders have suggested the Compassionate Use Program could work for Roche, with Avastin. Now that the FDA has rejected Avastin for breast cancer, breast cancer now becomes a non-approved indication and therefore any investigator wishing to do a compassionate use trial would have to do so under a Treatment IND.

In 1987, the FDA enacted regulations that provided increased access to experimental drugs for patients with life-threatening or seriously-debilitating diseases when no alternative treatment exists. These guideline, commonly called Treatment IND (Investigational New Drug), provide for rapid review of new therapies even when clinical trial results proving efficacy have not been established.

Typically Treatment IND applications are made for drugs that are in Phase III trials; however in rare cases the FDA approves a Treatment IND for a drug that has not yet progressed beyond Phase II. In order to stay compliant with the protocol, the drug developer must continue to collect safety and efficacy data on test subjects in order to better establish a drug's therapeutic benefit to patients.

Additionally, it must continue to make a good faith effort to win final approval from the FDA; if the drug developer stops working on the product, the Treatment IND can be rescinded and patients may lose access to the drug.

The company would have to write the protocol with prettly strict inclusion/exclusion criteria and thus Roche has to ask the question as to whether it's worth it since they can't sell it for this purpose.