Drug approvals: Are we in a new age yet?

BY DEBU TRIPATHY | AUGUST 28, 2011

With all the news of cancer drug shortages and the FDA's controversial decision to withdraw approval of Avastin (bevacizumab) for breast cancer, we are also getting some positive developments.

Just recently (on Aug. 26), the FDA granted accelerated approval to Xalkori (crizotinib), the newest member of an emerging generation of "niche" drugs. These are drugs that work in very defined subsets of patients, based on certain biological characteristics.

In the case of Xalkori, this is confined to the approximately 3 to 9 percent of patients with non-small cell lung cancer (NSCLC) who carry a chromosomal translocation that results in overexpression of the ALK protein (anaplastic lymphoma kinase). In fact, the approval of this drug is accompanied by the approval of a gene-based test to detect this translocation in tumor tissue. This approval comes on the heels of the approval of Zelboraf (vemurafenib) just eight days earlier for advanced melanoma, and again, only for the subset who harbor a mutation in the BRAF gene, and also approved with a diagnostic kit called the cobas 4800 BRAF V600 Mutation Test. In this case, the mutation is more common, seen in about half of all melanomas.

The big question is whether these two approvals herald the new age of personalized drugs. The now old story of Herceptin that many regard as one of the first targeted therapies, was spread out over 17 years from discovery of the gene to drug approval (or 11 years if you go from the discovery of HER2 amplification in breast cancer).

The new generation of drugs is being developed in a just a few years based on our exponentially growing body of data on mutations carried in cancers and new clinical trial designs that rapidly test drugs and verify biomarkers that predict response. Moreover, they seem to be quite effective with a higher percentage of patients responding, but not to the point that permanent cures are expected.

One can only hope that we are truly in the new era – and there are several indicators that this is the case. The Cancer Genome Atlas (TCGA) program is one of several worldwide that is collaboratively sequencing tumor genomes. Drug companies are investing more effort into biomarker analyses and integrating them earlier in the clinical trial process. Healthcare reform is demanding that drugs have a larger impact and that they not be used indiscriminately. Finally, the public's expectations are rising – they want more information about their cancers and access to clinical trials.

While it is possible that the initial wave of "low-hanging fruit" of "druggable" gene targets will soon be exhausted, it is more likely that we will have more targets and drugs than we can test. The bottleneck will really be in the patient clinical trials and how quickly and widely they can be deployed and fully enrolled. There will still be negative trials and other disappointments, but perhaps we are entering a new era where the bar of success is being raised.

• More trail mix
• When the cancer comes back
• Two new drugs approved, one pulled from the pipeline
• Emerging treatment option for myeloma presented at hematology meeting
• The big news from the American Society of Hematology

Do the FDA Avastin hearings mark the end of an era?

BY DEBU TRIPATHY | JUNE 29, 2011

The Avastin public hearings, which were organized by the FDA, began yesterday as part of Genentech's appeal to reverse the FDA's plan to withdraw the drug's accelerated approval.

This temporary approval, which was pending more data, was granted back in 2008. The approval came despite a recommendation for disapproval by the Oncologic Drugs Advisory Committee, which cited a lack of survival benefit. Although there was nearly a doubling of progression-free survival, it came with significant, albeit infrequent, serious toxicities and even excess treatment-related deaths. We have previously covered the background and controversies surrounding this topic in Hurdles on the Faster Track.

Now as two more trials have been analyzed -- neither showing a survival benefit -- the FDA stated that in the balance, the benefit did not outweigh the harm. The public hearing has taken on a circus-like atmosphere despite the seriousness of the topic and the emotional testimonies of patients whose disease has improved or been stable on Avastin.

On the other hand, several patients and advocacy groups have lobbied against approval, saying that giving this drug the nod despite the lack of scientific evidence of benefit is counterproductive to the whole field -- attention must be focused on developing survival-enhancing therapies.

How can such divergence in opinions exist? Actually, both sides of the argument have some merit. There probably are individuals who are clearly benefitting from Avastin. However, we do not know how to identify them, so the impact from the small number of "super-responders" is diluted.

The average effects in large trials then look rather small or nonexistent. This is probably true of many drugs we use today. We could probably get more dramatic effects, but only if we treat that fraction of patients who would benefit--if only we had tests to guide these decisions.

Avastin affects a complicated process -- angiogenesis, which involves tumor blood vessel formation that includes numerous receptors, enzymes and biological pathways. So called "predictive biomarkers" have been particularly elusive for Avastin.

There is no right answer to this wrenching issue that has dominated the headlines this week. Many patients and doctors want "freedom to operate" and the ability to do what they believe is best for their patients. Others don't want health care dollars (and in some cases, patient safety) expended for the kind of benefit seen in the trials so far.

The process of testing new cancer agents has forever changed because of this. It is now necessary to define predictive factors at the same time a drug is initially being developed. Not only is FDA approval in jeopardy, but drug companies can no longer afford the cost of huge trials to show a tiny difference in outcomes. The FDA hearings mark a milestone in this turn - the end the old era of cancer drug development.

• Make a difference
• For the Cure to a broken heart
• An update on the Cancer Genome Atlas for breast cancer
• Video blog: Test could spare some DCIS patients from radiation
• Video blog: HER2-targeted agents

A preview of ASCO – The new way of doing clinical trials

BY DEBU TRIPATHY | MAY 31, 2011

For decades, we have used the same system of testing and ultimately approving new treatments for cancer. The starting point of new drugs has become sexier--by targeting genetic lesions and avoiding some of the poisonous effects of older drugs. But the rest of the sequence of trials toward the road to approval is stale. It still starts by demonstrating safety (phase 1 trials), then some sense of effectiveness in shrinking tumors (phase 2) and ultimately a large trial comparing it with "standard" treatment or to adding the new drug to standard treatment (phase 3). Drug companies are focused on meeting the metrics by the FDA for approval--usually improving survival or time to recurrence or delaying progression. This used to mean showing a statistically significant improvement in a large number of eligible patients, even if the overall improvement was small--just a couple of months of extra survival.

This model is no longer working well because as we discover that cancer is broken down into small subsets that are biologically distinct, with only some subsets responding to targeted drugs. Given the side effects and spiraling costs of newer drugs, what might work for a cheaper and safer hypertension drug will certainly not apply for cancer therapies. Having to treat hundreds of patients for only a few to benefit is not sustainable, especially when newer technology is available to improve the situation. This year at ASCO, you will read our blogs about exciting updates on the cancer front, and a common theme will emerge. A much greater effort is being made to understand what subset of patients might respond even before a new agent is ready for human testing. Sometimes it is not clear what tissue tests should best qualify a clinical trial subject, so even in phase 1 testing, analysis of tissue is not built into the study in hopes of refining eligibility criteria for future trials.

Another innovative trial design we use when we do not know what patient population might best respond is called a "randomized discontinuation trial." It is based on the notion that only a small fraction of patients might respond. A large number of patients are initially tested (after basic safety is established). A very small number of patients might actually have shrinkage of tumor and they stay on treatment, while those who progress are taken off the study. However, those who have neither growth nor shrinkage after a defined period of time (termed "stable disease") are randomized to either continue or discontinue therapy. If those who stop therapy exhibit tumor growth after some time more so than those who continue, it proves that the drug is effective and may even shed some light on the tumor characteristics that predict response in the small fraction of cases. Of course, the trial can be designed to allow the "randomized discontinuation" group to restart therapy with the assumption that they might derive a benefit.

Another approach is called "adaptive trial design" where the results of the trial are analyzed in real time, and the randomization scheme (the fraction of patients randomized to standard vs. experiment treatment) changes over time to maximize the efficiency of the trial. While these ideas are not exactly new, they are being applied more often, especially for biologically targeted drugs since we have tools newly made available, such as rapid whole genome sequencing that can be feasibly done for at least part of the genome and are standardized to the point that they can be used for both pilot and large definitive trials. This will no doubt be a part of the major overhaul of the clinical research process currently under way in the government and drug industry sectors--the transformation of cancer clinical trials has just begun.

• Two new drugs approved, one pulled from the pipeline
• Cancer screening rates low
• A call for more pancreatic cancer research
• An introduction to cancer: From a father and his daughter
• The cushion of silence

Chemotherapy shortage: A symptom of a bigger problem

BY DEBU TRIPATHY | JANUARY 17, 2011

You may have heard about the chemotherapy shortage over the past few weeks whereby the supply of certain drugs is limited and even causing some infusion centers to reschedule appointments or change treatment plans.

While this is not a major disaster and will be fixed shortly, it is emblematic of our country's whole medical system. We really don't have a shortage of drugs as a looming problem – it is more a matter of supply temporarily not meeting demand due to production, transport and inventory. But the bigger problem is coordination. Because our health care is decentralized and insurance coverage is spotty, you will get a wide spectrum of opinions about our nation's health care – from "best in the world" to "bloated, expensive, inefficient and unfair."

I see incredible wastage of resources in my everyday practice of medicine – tests that are repeated because earlier results are unavailable or not felt to be reliable. Treatments or diagnostics that are "long shots" and made by both doctors and patients in haste without much reflection. State-of-the-art facilities and equipment that are not used to capacity.

There is much talk about electronic medical records (EMRs) as the savior for all of these problems, although the verdict so far is that these systems have not really made much of an impact on quality or efficiency of care. However, we are really only on "version 1.0" of EMRs, and further integration and standardization of these systems do hold the potential to improve many aspect of medical care, particularly the coordination of care and other activities (like chemotherapy availability) that are essential in the very complicated arena of cancer management. I believe that the public needs to be very engaged in the debate regarding EMRs and coordination of care because quality and affordability, especially in oncology, is at stake.

An informed and vocal public can steer the health care debate from the rancorous halls of Washington to a discourse with the public and ultimately the enactment and adoption of a coordinated information network, including patient portals and a seamless transfer of information across medical practices and hospitals. These advances have had huge effects in commerce, banking, entertainment and even social networking and dating, so why is medicine being left behind?

• Two new drugs approved, one pulled from the pipeline
• Cancer screening rates low
• A call for more pancreatic cancer research
• An introduction to cancer: From a father and his daughter
• The cushion of silence

A disquieting moment: Two steps backwards?

BY DEBU TRIPATHY | DECEMBER 12, 2010

Just about all of us attending the San Antonio Breast Cancer Symposium were disappointed and puzzled by two negative studies that went counter to all the early clinical data and biological theories in two important areas. While we recognize that this can sometimes be the normal course of science, it is never what we expect when we attend a meeting amid all the buzz about the latest news.

The first was in the area of personalized medicine--more specifically, the field called pharmacogenomics, which refers to the analysis of gene variants in drug metabolism enzymes to customize recommendations for specific drugs and doses. We all inherit different versions of the gene that encodes an enzyme called CYP2D6, which metabolizes the hormonal therapy tamoxifen into a more active form called endoxifen.

While preliminary studies showed that those who inherit a low activity version of this gene might have a higher risk of recurrence or progression on tamoxifen, it appeared that a new method to steer patients to the right therapy might be emerging. However, these early results were on smaller groups of patients.

More recent and much larger updates presented on Thursday showed no difference at all based on CYP2D6 genotype, even though tests are already commercially available and used by some oncologists. The consensus from the presenters, including the commentator, Dr. Matthew Goetz from Mayo Clinic, (one of the original investigators to observe differences in clinical outcomes), is that for now, doctors should discuss the controversy with patients, but not use CYP2D6 testing routinely to make decisions about tamoxifen. However, it is still recommended that drugs that inhibit CYP2D6, notably certain anti-depressants, should be avoided in patients taking tamoxifen. This is not really a big step backwards for patients because it doesn't necessarily take any benefits or options away. But it is an unexpected turn in the road where all the pieces of the puzzle were starting to fall together, only to be contradicted for the moment.

Another negative confirmation, however, was really a setback. Every indication was that bisphosphonates (a class of drugs used to protect the bone from both osteoporosis and bone metastases) might also prevent metastases. Several studies had suggested this earlier. In a smaller study of premenopausal patients receiving hormonal therapy, the drug Zometa had already been shown to lower the risk of recurrence. The supposition was that it made the bone a less fertile ground for breast cancer cells to colonize and use it as a springboard to metastasize elsewhere. But after a long anticipated wait, a much larger study yielded absolutely no difference in patients who received Zometa compared with those who did not. A secondary analysis hinted that in postmenopausal patients, there might be a benefit, but this was not statistically significant and no recommendations can be made at this time to use Zometa as a way to further reduce recurrence risk above what chemotherapy and hormonal therapy can achieve.

A large North American study was recently completed, but the results of this one are not expected for several years. The good news is that these studies took longer to analyze because fewer women are recurring after early-stage breast cancer than ever before. Still, we would like to get this down to zero and still have a ways to go. Progress is just never linear, but even negative data helps us create better experiments and trials for the future.

• Breast cancer research in 2010 and the Breast Cancer Deadline 2020
• Where are we in breast cancer research?
• Another SABCS comes to a close
• Why is the San Antonio Breast Cancer Symposium so unique and special?
• Confessions of a two-time survivor

Finding the Perfect Prevention Drug

BY DEBU TRIPATHY | NOVEMBER 30, 2010

Using drugs to prevent cancer has long been sought, as many clues from the laboratory and observational population studies have pointed to several clues and candidate drugs. Testing these in the clinic requires huge numbers of subjects (well over 10,000) that have to be randomized to placebo or the active drug and then followed for many years, an expense that few companies or the government will take on. The first prevention drug, tamoxifen was approved in 1998 to lower the risk of getting breast cancer (lowered the rate from about 2% to 1% over 5 years). However, this drug is rarely used, in part because of bothersome side effects, but also more serious ones like an elevated risk of uterine cancer and blood clots.

A cousin of tamoxifen, raloxifene (Evista), with a lower risk of both these side effects was approved in 2007. This class of drugs, known as selective estrogen receptor modulators (SERMs), also improves bone mineral density--Evista is actually approved for osteoporosis. Since the estrogen receptor pathway mediates many different physiological processes ranging from breast cancer to clotting to bone density, SERMs have been engineered, through slight chemical alterations in their structures, to be the perfect women's health drug--with the potential to lower cancer risk and to improve bone and cardiac health.

Evista was designed to not produce stimulation of uterine cells as to avoid a known complication of tamoxifen--an increased risk of uterine cancer. While it did achieve that goal, its breast cancer risk-attenuating activity is not as good as tamoxifen's, and it still raises the risk of blood clots. Another SERM called lasofoxifene has come a little closer, with a recent update of a large randomized trial now showing a lowering of breast cancer rates by nearly 80%--that is from 1 in every 114 women to 1 in every 550 women over 5 years. It also lowered the bone fracture rate and even the stroke rate without increasing endometrial cancer risk. However, it did increase blood clotting--the one SERM side effect that we cannot seem to "engineer out." Still, the FDA earlier rejected lasofoxifene as a preventive drug because the overall death rate (from non-cancer causes) was higher in the low-dose arm compared to placebo even though it was not in the high-dose arm. This turn of events reflects the frustration by all parties--doctors, patients, researchers and the FDA itself.

We have prevention drugs that can lower cancer risk with side effects that are much lower in number than the cancers prevented. So far, no drug is free of rare but serious side effects--and coupled with the less dangerous but still bothersome side effects, such as hot flashes and a myriad of less characterized symptoms, it is understandable why only a fraction of eligible patients opt for FDA-approved breast cancer prevention drugs. Also, there is no statistical difference in the overall death rate in prevention studies, in part because they were not designed to be large enough to detect them, but it may also be that we are preventing the less dangerous estrogen receptor-positive breast cancers.

The field of cancer prevention is still very active but could use a shot in the arm. While the science behind it is very elegant, it appears that, like many other things in life, it comes down to a popularity contest. Doctors and patients will vote with their feet--with prescribing and compliance hinging on both a better side effect profile, and a bigger impact on saving lives, not just lowering the number of cancer cases.

• Two new drugs approved, one pulled from the pipeline
• Cancer screening rates low
• A call for more pancreatic cancer research
• An introduction to cancer: From a father and his daughter
• The cushion of silence

Is a new anti-angiogenic strategy on the horizon?

BY DEBU TRIPATHY | OCTOBER 28, 2010

As both a clinician and scientist, I always look at new biological findings with a mixture of enthusiasm and skepticism. In the New England Journal of Medicine, a very provocative finding was published (the Journal prides itself on being the first to report something that just might be a game changer).

A new property of a well-known protein called the follicle stimulating hormone receptor (FSHR) was described – namely, its presence in the blood vessels of many different types of tumors in humans – breast, prostate, colon, and host of other cancers. Normally, FSHR is expressed in specific cells within the ovaries and testes, in keeping with its known roles in sex hormone production and menstrual cycle control. This was a very carefully done study, with multiple antibodies against FSHR and very careful analysis over the areas of many tumors and adjacent normal tissue. Staining for FSHR was seen in tumor-associated blood vessels within all of the tumor tissues in 1,336 cases, and in some cases of "precancerous" tissue. Its expression in blood vessels fell off progressively in moving away from the tumor into normal tissue.

Might this new finding represent a target for treatment against many types of cancer? Well, we have been down this road before – a tumor-specific antigen that is hailed as a way to develop the perfect magic bullet, only to lead to disappointment once tested in patients. Still, anti-angiogenic therapy - the targeting of tumor blood vessels that are necessary for tumor growth and spread, has been a successful strategy, with the drug Avastin showing improvements survival in colon and brain cancer, but not fully curative in advanced cancers.

In the case of breast cancer it delays progression without improving survival. Avastin does not only target tumor blood vessels, since the growth factor it targets is also involved in non-tumor blood vessel formation and other cellular functions – hence it has side effects.

In the case of FSHR, the investigators showed that they can deliver particles bound to antibody to tumor blood vessels using animal tumor models. This might therefore represent a promising therapeutic avenue, although there may be toxicity to the ovaries and testes that would need to be addressed. It remains unknown why FSHR is expressed on tumor blood vessels – but there is good reason why it made the "scientific front page."

• Two new drugs approved, one pulled from the pipeline
• Cancer screening rates low
• A call for more pancreatic cancer research
• An introduction to cancer: From a father and his daughter
• The cushion of silence

The ordinary drug that could

BY DEBU TRIPATHY | APRIL 23, 2010

The oral sugar-lowering drug metformin has been in the cancer news quite a bit as of late. This drug, which is now off patent, is very cheap and safe--used by millions of people with diabetes worldwide. In the last few years, it has been associated with lower rates of breast and pancreatic cancers.

A large database study of patients in the UK showed that patients on long-term metformin had about half the risk of developing breast cancer compared to non-users, including those with diabetes who took insulin or another class of oral sugar-lowering drugs called sulfonylureas. And in breast cancer patients, it seems to be associated with greater responses to chemotherapy.

This past week, at the American Association for Cancer Research meeting, researchers at the National Cancer Institute showed it can lower lung cancer rates in animals exposed to nicotine-like carcinogens.

Metformin inhibits insulin and insulin-like growth factors, both of which produce growth signals that can lead to cell growth. In contrast, insulin and other diabetes drugs can stimulate these pathways--in fact, insulin use has been implicated in slightly higher risks of breast cancer.

This is one of several examples of the anti-cancer potential of several older drugs used for other diseases. So far the story with metformin is very appealing in that it has a long and safe track record. Based on this background, The National Cancer Institute of Canada is planning a large early-stage breast cancer trial of standard therapy with or without metformin for five years. It will be interesting to see if an old drug that has no patent life can actually be developed for use in cancer.

• More trail mix
• When the cancer comes back
• Two new drugs approved, one pulled from the pipeline
• Emerging treatment option for myeloma presented at hematology meeting
• The big news from the American Society of Hematology

The evolving story of estrogen replacement and its effects

BY DEBU TRIPATHY | APRIL 17, 2010

As more and more information comes in from large-scale trials, it is clear that estrogen replacement therapy in the usual form of an estrogen plus a progesterone drug (E+P), commonly called hormone replacement therapy or HRT, increases the risk of breast cancer.

When the results from the "definitive" randomized trial, the Women's Health Initiative (WHI) study, were announced in 2002 and showed about 25 percent more breast cancers with E+P compared with placebo, the use of HRT plummeted. A few years later, this became evident with fewer breast cancers diagnosed, reversing a longstanding trend of rising rates.

However, the estrogen receptor is expressed in many other tissues besides the breast, so further analyses of this trial looking at other cancers showed interesting effects--such as a higher death rate from lung cancer with E+P, but interestingly, a lower risk of colorectal cancer.

Just this month, a group at the University of North Carolina, using a less reliable case-control design, found the lower end of colon and rectal cancer risk has halved with any HRT use. However, on further follow-up of the WHI study, it turns out that the colorectal cancer cases on E+P were of higher stage, so that there were actually more deaths from colorectal cancer on replacement therapy. Finally, E+P also increased the risk of stroke and blood clots in the lung and appeared to raise the chance of heart attacks, especially in the first year of therapy. It did lower hip fracture rates, in keeping with its bone density-enhancing properties.

So clearly, E+P causes more cancers and does not, as initially thought, protect the heart. Even though there are still detractors who criticize the trial design--the age at which patients were started on therapy and the exact form of therapy--one wonders if there is at all a silver lining in this story.

Well, there might be--and that is therapy with estrogen alone. This therapy can only be given to women who have had their uterus removed. In women who do have a uterus, estrogen-only therapy can cause a build-up of the uterine lining and raises the uterine cancer risk. (Women with a uterus receive E+P because adding progesterone reduces that risk of uterine cancer).

The WHI study also randomized more than 10,000 women who had prior hysterectomy and gave them either estrogen alone or placebo. In this trial there were actually fewer cases of breast cancer, not quite statistically significant, though. There was no effect on colorectal or lung cancers. There were also slightly fewer stokes and heart attacks, but more clots to the lung; however none of these were statistically different.

So, it is possible that estrogen might be a useful drug in women without a uterus, but clotting problems are still a concern. We have seen the emergence of designer anti-estrogen drugs like raloxifene (approved for breast cancer reduction and osteoporosis), and more recently lasofoxifene, an investigational drug found to lower fracture, breast cancer, stroke, heart attacks, but increased clots.

Manipulating the hormonal milieu is a tricky proposition, but future generations of "estrogen modulators" might just strike the right balance for multiple health effects.

For more on HRT and the risk of breast cancer, read "The HRT Connection" from Fall 2007.

• Two new drugs approved, one pulled from the pipeline
• Cancer screening rates low
• A call for more pancreatic cancer research
• An introduction to cancer: From a father and his daughter
• The cushion of silence

Preventing breast cancer: What's next?

BY DEBU TRIPATHY | MARCH 23, 2010

Assessing the risk of getting breast cancer and acting on this risk is a very complicated and controversial topic. The 27th Miami Breast Cancer Conference, held earlier this month, focused on bringing together a multidisciplinary approach to breast cancer, including surgery, medical, and radiation therapies.

The first day of the meeting focused on several key questions. What are the risk factors? Who should get genetic testing? What type of screening is best, depending on one's risk? What is the best prevention measure for those at high risk?

Experts in each of these fields provided us with some answers, but much is still unknown. Breast cancer risk is multi-factorial--with genetic predisposition being the highest risk factor. However, only about one in 200 or 300 people carry the breast cancer risk gene, and only about 5 to 10 percent of all breast cancers are due to this. Other risk factors such as alcohol use, physical inactivity, using estrogen and progesterone replacement, or early onset and late cessation of menstrual periods only raise the risk by a small amount. The majority of cancer cases occur in people with no clear risk factors.

So it makes sense to universally recommend exercise, healthy diet, moderation in alcohol, and avoiding more than a few months of estrogen replacement therapy if needed for symptoms of menopause. Those with a family history of breast, ovarian, and other cancers should check with their doctors to see if genetic counseling and testing would be in order. For very high-risk patients (such as BRCA1 or 2 mutation carriers), it is becoming clearer that MRI is the most sensitive test--although we are not sure that it saves lives yet. Based on lives saved by mammograms in the general population (over age 40), one might extrapolate that a more sensitive test would be better, but only in high risk patients --because otherwise, there may be too many false alarms.

What about prevention? We know that both tamoxifen and raloxifene (Evista) are approved for this, but very few doctors actually prescribe it because of side effects and the very small number of cancers prevented for every 1,000 people treated. A new drug, lasofoxifene, was recently found to not only prevent breast cancer, but lower the rate of bone fractures, heart attacks, and strokes, but it also caused more blood clots. The drug will be evaluated by the FDA in the near future. However, we do not quite know how to identify the people whose benefit-to-risk (serious ones and nuisance side effects) ratio tips in favor of taking the drug--that would be a big step forward because the FDA-approved indications for prevention include just about everyone over age 60 and quite a few people that are younger than that.

• For the Cure to a broken heart
• Two new drugs approved, one pulled from the pipeline
• Drug approved specifically for treating myelofibrosis
• Erbitux Approved for Metastatic Head and Neck Cancers
• Perfume me