Practicing Clinical Oncologists to the Rescue

Cancer patients and their physicians can find themselves at the wrong end of many scientific discoveries. For example, the drug capecitabine, sold commercially as Xeloda, was originally marketed at a daily dose of 2500 mg/m2 given for two weeks.

This schedule developed by the pharmaceutical investigators, is known as the maximum tolerated dose (MTD) and it performed well against other regimens for breast and colon cancer. With an FDA approval in hand, oncologists began administering the drug on the recommended schedule.

MTD2It did not take long before physicians and their patients realized that 2500 mg/m2/day was more than many patients could tolerate. Hand-foot Syndrome (an inflammation of the skin of palms and soles), mucositis (oral ulcers) myelosuppression (lowered blood counts) and diarrhea were all observed. Immediately clinical physicians began to dose de-escalate. Soon these astute practitioners established more appropriate dose schedules and the drug found its rightful place as a useful therapeutic in many diseases.

What was interesting was that activity continued to be observed. It appeared that the high dose schedule was simply toxic and that lower doses worked fine, with fewer side effects.

Modern targeted agents have been introduced over recent years with dose schedules reminiscent of capecitabine. The drug sunitinib, approved for the treatment of renal cell carcinoma, is given at 50 mg daily for four weeks in a row, followed by a two week rest. Despite good activity, toxicities like mucositis and skin rash often set in by the third week. What remained unclear was whether these schedules were warranted. A recent report in the Annals of Oncology examined this very question. In a retrospective analysis of patients with kidney cancer the physicians found that lowering the dose of sunitinib preserved activity but reduced toxicity.

As a practitioner, I have long reduced my patient’s schedule of sunitinib to two weeks on, one week off or even 11 days on, 10 days off. In one patient that I treated for a gastrointestinal stromal tumor (GIST), I achieved a durable complete remission with just 25 mg/day, given seven days each month, a remission that persists to this day, seven years on.

We are in a new world of targeted therapy, one in which very few people understand the kinetics, pharmacodynamics and response profiles of patients for novel drugs. In our laboratory, favorable dose response curves often suggest that many agents could be administered at lower doses. More interestingly, some patients who do not carry the “targets” for these drugs nonetheless respond. This has broad implications for multi-targeted inhibitors like sunitinib that can influence multiple targets simultaneously.

As so often happens, it is the nimble clinical physicians with their feet on the ground, confronting the very real needs of their patients who can outmaneuver and outthink their academic colleagues. The trend toward consolidation in medicine and the absorption of clinical practices into hospital groups all using standardized algorithms has the risk of stifling the very independence and creativity of practicing oncologists that has proven both effective and cost-effective for our patients and our medical system at large.

Of Cells, Proteins and Cancer Drug Development

Our recent presentation at the American Association for Cancer Research meeting reported our work with a novel class of compounds known as the HSP90 inhibitors. AACR 2015-HSP90 Abstract

The field began decades earlier when it was found that certain proteins in cells were required to protect the function of other newly formed proteins hormone receptors and signaling molecules. Estrogen and androgen receptors, among others, require careful attention following their manufacture or they will find themselves in the cellular waste bin.

230px-Geldanamycin.svgAs each new protein is formed it risks digestion at the hands of a garbage disposal-like device known as a proteasome (named for its protein digesting capabilities). To the rescue comes HSP90 that chaperones these newly created proteins through the cell and protects them until they can assume their important roles in cell function and survival.

Recognizing that these proteins were critical for cell viability, investigators at Sloan-Kettering and others developed a number of molecules to block HSP90. The original compounds known as ansamycins underwent clinical trials with evidence of activity in some breast cancers. The next generation of compounds was tested in other diseases. Though the clinical results have been mixed, the concept remains attractive.

We compared two drugs of this type and showed that they shared similar function but had different chemical properties and that the concentrations required to kill cells differed. What is interesting is the activity of these drugs seems to be patient-specific. That is, each patient, whether they had breast or lung cancer, showed a unique profile that was not directly connected to the type of cancer they had. This has important implications.

Today, pharmaceutical companies develop drugs by disease type. Compounds enter Phase II trials with 30 to 50 lung cancer patients treated, then 30 to 50 breast cancer patients treated and so on. This continues until (it is hoped) one of the diseases provides a favorable profile and the data is submitted to the FDA for a disease-specific approval. As home runs are rare, most drugs never see the light of day failing to provide sufficient response in any disease to warrant the enormous expense of bringing them to market.

What we found with the HSP90 inhibitors is that some breast cancers are extremely sensitive while others are not. Similarly some lung cancers are extremely sensitive while others are resistant. This forces us once again to confront the fact that cancer patients are unique.

Pharmaceutical companies exploring the role of targeted agents like the HSP90 inhibitors must learn to incorporate patient individuality into the drug development process. Failing to do so not only risks the loss of billions of dollars but more importantly denies patients access to active novel agents.

The future of drug development can be bright if the pharmaceutical industry embraces the concept that each patient’s profile of response is unique and that these responses reflect patient-specific, not diagnosis-based drivers. Clinical trials must incorporate individual patient profiles. Drugs could be made more available once Phase I studies were complete by using biomarkers for response, such as the EVA-PCD assay, which has the capacity to enhance access and streamline drug development.

The Cost of Chemotherapy Comes Home to Roost

NY TImes rotatedMedical care in the United States is a $2.7 trillion industry. That translates into almost $8,000 per person per year. One of the most expensive aspects is cancer care. This has caught the attention of the medical oncology community. A highly touted editorial in the October, 2012 New York Times described the unwillingness of physicians at Memorial Sloan Kettering Cancer Center to add a new and expensive drug to their formulary. The authors opined that the new drug provided outcomes similar to those for an existing drug, yet cost twice the price.

A subsequent editorial in the Journal of Clinical Oncology from MD Anderson (Cancer Drugs in the United States: Justum Pretium – The Just Price) further examined the cost of cancer therapy, profit margins and some of the drivers. Among the points raised was the fact that the monthly cost of chemotherapy had more than doubled from $4,500 to $10,000 in just one decade. Furthermore, of twelve anticancer drugs approved in 2012, only three prolonged survival and for 2 of 3 by less than two months. Despite these marginal benefits, nine of the twelve drugs were priced at more than $10,000 a month.
60 Minutes
This caught the attention of the media with 60 Minutes recently conducting an interview with the authors of the New York Times editorial. While Lesley Stahl pointedly decried the rather marginal 4 – 6% markups that many physicians apply to cover their costs of chemotherapy drug administration, there are in fact much darker forces at work.

The cost of cancer drug development reflects the expense of human subject trials, cost of R & D, the regulatory burden, as well as an extraordinary new drug failure rate. Fully 50% of new agents fail at Phase III (the last and most expensive type of study). Phase III trials cost tens to hundreds of millions of dollars. An article in Forbes magazine stated that the average drug approved by the FDA now costs, not the one billion dollars often cited but instead five billion dollars when one factors in the failures against the rare successes.

Drug development begins with a novel idea, a small molecule and a few preliminary results. At this point the expenses are low but the drug is of little commercial value. As one moves from cell lines to animal models, the price goes up but the value remains low. The cost of formulation, toxicology and animal studies continue to add up but doesn’t influence interest in the agent. Then come human studies as the Phase I trials begin. Specialized institutions across the United States accept contracts with the pharmaceutical industry to examine the tolerability of the drug. I use that term advisably as the intent of Phase I trials is only to determine safety not efficacy. If the drug proves tolerable, it then moves to Phase II to explore it’s activity against cancer. This is where the money starts flowing.

Phase II clinical trials are conducted by university medical centers. Each patient accrued costs the pharmaceutical sponsors from $25,000 to more than $50,000 per patient. As drugs are tested in many schedules against many diseases it can take hundreds or even thousands of patients for statistical analysis. Nonetheless, a successful Phase II trial showing meaningful benefit in a cancer population generates a buzz and the drug’s value begins to gain traction. With hundreds of millions already expended, the final testing pits the new drug against an existing standard in one or more Phase III trials. Endpoints like progression-free-survival must then fold into overall survival if the drug has any hope to gain full approval by the FDA. These registration triaus-money-with-black-backdrop-1024x640ls at the national or international Phase III level cost up to $100,000 per patient and most of the participating institutions are university-based medical centers or their affiliates.

So, why do chemotherapy drugs cost so much? While it may be convenient to point fingers at the pharmaceutical industry, private practitioners or the smaller institutions, the university medical centers and their affiliates have added greatly to the costs of drug development as have the increasingly byzantine regulatory standards that have so encumbered the process that it is now increasingly only a rich man’s game.

We applaud the investigators at Memorial Sloan-Kettering for focusing attention upon this important matter. We applaud 60 Minutes and the authors of the Journal of Clinical Oncology editorial for their exploration of the same. While the willingness of these physicians to raise the issue is laudable, the solution may be somewhat more complex than these authors have been willing to admit. Before we vilify private practitioners who have time and again proven to be more efficient and less expensive purveyors of cancer care than their university brethren we should examine other drivers.

To wit, a review of one of the NY Times editorial author’s conflicts of interest statement listed in the 2012 American Society of Clinical Oncology proceedings revealed that his co-presenters at this national meeting disclosed fully 16 separate pharmaceutical affiliations for employment or leadership positions, consultant or advisory roles, stock ownership, honoraria, research funds, expert testimony, or other remuneration. With the research community enjoying these levels of compensation, it must be surmised that the costs of clinical trials reflect in part these expenditures. When one adds to this, the increasingly burdensome regulatory environment, the cost of cancer chemotherapy development appears to have plenty of blame to go around.

New Cancer Drug: Breakthrough or Just Hype?

Having just passed through Ontario’s Pearson International airport on route from eastern Canada, I was struck by an email from one of my patient’s mothers who shared with me a 6/20/2013 article from the Toronto Globe and Mail, “Take news of cancer breakthrough with a big grain of salt,” by staff writer André Picard.

The author describes an announcement by two prominent cancer researchers, Tak Mak, PhD, of Princess Margaret Hospital Toronto, CA and Denis Slamon, MD, from UCLA, who reported the results from a new class of compounds known as “polo-like kinase 4 inhibitors.” Picard goes on to note, “This seemingly miraculous ‘breakthrough’ drug has not been tested on a single person. The experimental drug CFI-400945 has ‘prevented cancer growth’ in a bunch of mice.”

What troubles the author (and should probably trouble us all), is the lack of substance in this report. After all, many drugs reveal activity in animal models, yet most seemingly promising drugs fail to provide clinical benefit. Only 8 percent of cancer chemotherapy drugs that enter the earliest form of human clinical trials (Phase I) ever achieve FDA approval. According to a study published in the New England Journal of Medicine, fully 50 percent of drugs that make it to the final stage (Phase III) of clinical testing nonetheless fail to gain approval. Thus, there is ample reason for concern when “breakthrough” drugs achieve this level of public recognition, because it is distinctly unlikely that they will ever deliver on their promises.

When I attend the AACR meetings, I’m impressed by the level of scientific discovery. When I then attend the ASCO meetings, I’m even more concerned by the lack of clinically relevant progress. The divide between clinicians and scientists seems to grow ever wider. While TIME magazine and The New York Times (to use Andre Picard’s term) genuflect before these scientists’ reports of dramatic advances, most cancer patients continue to suffer through largely ineffective toxic therapies. The disconnect is becoming painfully evident. What we need is a better pathway from discovery to clinical application. What we don’t need is more hype.

Cancer and the Great Divide

There are two types of cancer patients: those we can treat and those we can’t. As I reflect on this year and the years past during which we have applied the process of laboratory-guided treatment, I am reminded of this fact.

The EVA-PCD functional profile enables us to choose active treatments for patients, but I have sometimes wondered whether we are, in fact, choosing patients for the available drugs.  While the end result may not be all that different, e.g. superior clinical outcomes over randomly administered (standard) therapies, the path to that outcome, leaves room for interesting discussion.

I first pondered this issue at the time of completion of our earliest study. That study was conducted in childhood acute lymphoblastic leukemia (ALL). Recognizing that the corticosteroids were among the most important drugs for ALL, we exposed freshly isolated lymphoblasts from ALL patients to dexamethasone (ex vivo). At the fourth day we measured the degree of cell death and separated the patients in “sensitive” and “resistant “ subgroups. Strikingly, those children whose lymphoblasts died in the laboratory following exposure to dexamethasone (ex-vivo), virtually all survived without relapse, while those children whose lymphoblasts did not die in the laboratory following dexamethasone exposure (ex-vivo) relapsed at an alarming rate with only 25 percent still alive at the sixth year of follow up (p=0.009).

What we had succeeded in doing by Day 4 of diagnosis was something that all the known prognostic factors, like age, WBC and male vs. female could not do, namely accurately identify the responders and survivors.

Today, when I test patients in our laboratory, I consistently double or even triple the response rates over standard protocols, yet a subset of patients are not found sensitive to the available therapies. Patients who do not respond to chemotherapy are today known, in the oncologic vernacular, as “failing therapy.” If we view these “non-responders” as a biologically distinct group (not unlike the dexamethasone-resistant ALL patients above) then our role, in the field of functional profiling, is to quickly segregate the responders (to available drugs) from the non-responders and move those “non-responders” immediately to something that will work for them. In this light, patients no longer “fail therapies” but instead “therapies fail patients.” It is then our mandate to use the ex-vivo platforms to find (and yes, discover) novel therapies and combinations that will meet their unmet need.

As the New Year is upon us I am filled with the expectation that 2013 will be one of discovery and innovation. Never before have so many interesting compounds been available for study. If we are fortunate enough to succeed in our efforts to collaborate with members of the drug development community and have the opportunity to intelligently apply functional profiling, for drug discovery, 2013 could be a very good year indeed.

A Tale of Two Trials

As I read through the November 10 issue of the Journal of Clinical Oncology there were two very different but highly instructive reports.

They first examined the impact of gemtuzumab ozogamicin for patients with acute myeloid leukemia. The second involved the incorporation of bevacizumab and erlotinib into the treatment of Stage III NSCLC in combination with radiation.

By way of introduction, gemtuzumab ozogamicin (GO) is an anti CD33 antibody linked to the highly toxic chemical calicheamicin. Calicheamicin, a member of enendyne class, is among the most toxic substances known to man. By linking this poison to an antibody directed against leukemia cells, it was reasoned that this novel conjugant would provide an effective therapy for leukemia. And indeed it did. But despite compelling science and what appeared to be initially good results (particularly in older patients with AML), and FDA approval for the agent, the drug was withdrawn from the market. Now, with the publication of a new study from the United Kingdom, GO is once again in the limelight as its inclusion in induction therapy resulted in a statistically significant three-year relapse-free survival advantage (p=.0007) and three year overall survival advantage (p=.05).

It appears, with regard to GO, that the clinical trial process failed to identify the clinical utility of an active and novel form of therapy for a potentially lethal disease.

The second article of interest regards a pilot study that incorporated an anti-VGEF antibody (bevacizumab) with EGFR TKI (erlotinib) along with chemotherapy and radiation. In this trial the objective response rate of 39 percent, median progression-free survival of 10.2 months and median overall survival of 10.4 months, were not demonstrably superior to contemporary results, yet toxicity was significantly enhanced. The investigators recommended against further exploration of this combination. Here the aggressive integration of targeted and conventional therapies proved a misadventure.

While these two reports are very different, they represent similar failings of the contemporary clinical trial process. The GO experience reflects the failure to identify efficacy due to contemporary clinical trial’s dilution of the benefit in select candidates, mixed in the overall population, with limited responsiveness to the agent. The second trial represents clinicians’ desire to engage in theoretically attractive clinical trials only to find that they reflect ineffective and/or more toxic treatment regimens.

On one hand, laboratory models that accurately identify responders can segregate those most likely to benefit from those who will not. GO represents just one of many interesting new classes of drugs for whom selective methodologies could prove highly valuable. The lung cancer experience reflects the failure of the research community to dedicate adequate resources to predictive clinical models.

Combinations of chemotherapy with target therapies have been the subject of investigation in our laboratory for more than a decade. For example, we observed antagonism between platins and the EGFR antagonists (gefitinib and erlotinib) two years before publication of the unsuccessful INTACT I and II Trials and three years before the unsuccessful TALENT and TRIBUTE trials.

All four of these trials combined platin based doublets with EGF-TKI’s. More recently we successfully identified favorable interactions between erlotinib and VGEF inhibitors in individual patients that have provided durable responses in our NSCLC patients as first line therapy, now out to four and five years since diagnosis. These experiences represent opportunities to explore novel therapies and avoid inadvertent antagonisms and misadventures.  In the recent JCO, a good treatment was missed while a bad treatment was advanced.

Functional profiling through use of the EVA-PCD® assay may represent the “critical path” from bench to bedside that the deputy director of the Center for Drug Evaluation and Research at the Food and Drug Administration, Janet Woodcock has described as a crying need.

Do We Already Have the Tools We Need to Cure Cancer?

The rapid-fire sequence of the annual American Association of Cancer Research (AACR) meeting, held in May, followed by the annual American Society of Cllinical Oncology (ASCO) meeting, held in June, provides the opportunity to put scientific discoveries into perspective as they find their way from theoretical to practical.

Members of AACR, the basic science organization, ponder deep biological questions. Their spin-offs arrive in the hands of members of ASCO as Phase I and Phase II trials, some of which are then reported at ASCO meetings.

Many of the small molecules my laboratory has studied over the years are now slowly making their way from “Gee Whiz” to clinical therapy. At the ASCO meeting I attended many of the Phase I sessions, where alphabet soup compounds had their first “in-human” trials. As most of these compounds are familiar to me, I was very interested in these early, though highly preliminary, results.

Departing from one Developmental Therapy (Phase I) session, with visions of signal transduction pathways in my head, I attended a poster discussion on triple negative breast cancer. For those of you unfamiliar with the term, it refers to an increasingly common form of breast cancer that doesn’t mark for the usual estrogen, progesterone, or HER-2 features. Often occurring in younger patients, this form of breast cancer can be aggressive and unresponsive to some forms of therapy. Much work has gone into defining sub-types of this disease and slow progress is being made.

As I examined the posters, one caught my eye, “Clinical Characteristics and Chemotherapy Options of Triple Negative Breast Cancer: Role of Classic CMF regimen. (Herr, MH et al, abstract #1053, ASCO 2012.) What these investigators showed in a series of 826 breast cancer patients was that those treated with the oldest drug combination for breast cancer (CMF) did better than those who received the more modern and more intensive anthracycline or taxane-based regimens. CMF, originally developed by Italian investigators in the 1970s, was the principal therapy for this disease for two decades before it was replaced, first by anthracycline and later by taxane-based treatments. What struck me was the unexpected superiority of this old regimen over its more modern, toxic and expensive brethren.

I began to wonder about other modern therapies and their real impact upon cancer outcomes. One study in HER-2 positive patients revealed relative equivalency between weekly taxol, every three-week Taxotere and Abraxane-based therapy. Once again, the cheaper, older, less toxic Taxol regimen proved superior. While most of the attendees at the ASCO meeting were considering how the newest VEGF inhibitor Regorafenib, or the addition of aflibercept, might impact their practices, I was somewhat underwhelmed by the results of these statistically significant, but clinically marginal survival advantages, all associated with great expense.

As I pondered the implications of the CMF results in triple negatives and those of the taxol results in HER-2 positives, I considered other old-fashioned therapies with newfound potential. Among them, losartan, the angiotensin antagonist that influences tumor stroma or the results of an earlier published study that identified intraconazole (a widely available anti-fungal therapy), as an inhibitor of the hedgehog pathway. While the pharmaceutical industry promotes the use of vismodegib, a hedgehog inhibitor for basal cell skin cancer, and dozens of trials examine VEGF and FGF inhibitors, I wondered whether losartan or intraconazole or other simple compounds and combinations might not already provide many of the tools we need. Is it possible that effective treatments for cancer are at hand?

Lacking the tools to decipher the signals and combine the agents to greatest effect, are we destined to continue to blindly administer increasingly expensive, toxic, yet arguably no more effective therapies? With the myriad of drugs and combinations available today, might it be that we “can’t see the forest for the trees.”

Platinum Resistance is in the Eye of the Beholder

I was recently apprised of an online conversation surrounding the treatment of platinum refractory and platinum resistant ovarian cancer. To clarify our terminology, platinum refractory disease refers to cancer that progresses during platinum therapy. This would be considered the most platinum resistant of the ovarian patients. The term “platinum resistant” developed over the last two decades, by Markman and others, is used to describe patients who initially respond to platinum-based chemotherapy and then relapse within six months of treatment.

While platinum refractory seems intuitively obvious, it has been suggested that platinum resistance is somewhat more arbitrary.  That is, what if one relapses one month versus five months, or seven months after treatment. In fact, studies conducted by investigators at Memorial Sloane-Kettering under Dr. David Spriggs, suggest that platinum resistance is a continuum extending from six months continuing out to 24 months and beyond. The longer the “platinum-free interval” the better the chance of response to combinations like carboplatin plus Taxol. Within the scope of this discussion I am in general agreement. However, as I describe below, this is, by far, not the whole story.

I am composing this particular blog in response to a comment that I encountered in a recent chat room discussion. The individual took an extremely strong stance stipulating that no medical oncologist should re-challenge a patient with a platinum-based regimen if they fall within the category of platinum refractory or platinum resistant. This statement is absolutely, positively WRONG.

Platinum resistance is mediated by DNA repair enzymes. These enzymes recognize and respond to platinum adducts and excise the DNA residues, replacing them with the appropriate base pairs. While this confers resistance to single agent platins, a degree of resistance which is largely is unaffected by the addition of taxanes, platinum resistance actually opens up an Achilles heel for treatment of these patients. Drugs like the antimetabolites (Gemcitabine, 5-FU), as well as the topoisomerase inhibitors become collaterally more active in those tumors with the most active DNA repair capacities. This is the reason why we have consistently observed responses in both platinum resistant and platinum refractory patients utilizing the combination of cisplatin and gemcitabine, as we reported in the original paper describing this combination in 2003 (Nagourney, R et al, Gyn Onc, 2003). Our response rate of 50 percent in heavily pre-treated and platinum resistant patients was confirmed by investigators in Ohio who reported similarly good results in patients with p-glycoprotein positive/platinum resistant disease (Rose, P, Gyn Onc 2003).  To formally test this hypothesis we conducted a national clinical trial with the GOG, which treated platinum resistant and platinum refractory patients with the combination of cisplatin plus gemcitabine. This trial provided the longest-time-to-progression for this population (six months) in the history of the GOG (Brewer et al, Gyn Onc 2006). These observations were subsequently reported in our textbook (Deoxynucleoside Analogs in Cancer Therapy, GPeters [ed] Humana Press 2006).

Similar results have been reported for Folfox in recurrent ovarian patients by Greek investigators (Pectasides, D et al, Gyn Onc 2004). To examine this phenomenon, one of the great investigators of antimetabolite chemistry, William Plunkett, conducted an instructive series of experiments in which they showed that platinum resistant ovarian cell lines expressed high levels of the DNA repair enzyme ERCC1. When these investigators blocked the ERCC1 expression with siRNA, the cell lines became resistant to the cisplatin plus gemcitabine combination, indicating beyond a shadow of a doubt, that it is the cells’ own DNA repair capacity that makes it sensitive to this drug doublet.

I write this blog because it is critically important for patients and doctors alike, to understand the chemistry of these agents and their interactions. While platinum resistance may indeed confer clinical resistance to platinum, carboplatin plus Taxol and related combinations, platinum resistant tumors may actually be more sensitive to intelligently administered drug combinations. Using our laboratory platform to measure the chemosensitivity and synergy for drug combinations we have identified numerous platinum resistant and platinum refractory patients who have had dramatic and durable response to re-challenge with platinum based therapies that employ these synergistic combinations. This is why we are extremely interested to study platinum resistant patients. After all, platinum resistance is in the eye of the beholder.

What Exactly are the Targets of Targeted Therapy?

The term “targeted therapy” has entered common parlance. Like personalized medicine, targeted therapy is a generic description of drugs and combinations that inhibit specific cancer-related pathways. I am impressed by how quickly esoteric phenomena like the downstream signal in the insulin factor pathway have entered the lexicon of medical oncologists. With the advent of temsirolimus and everolimus, both rapamycin derivatives that target mTOR, we now have at our disposal agents that are every bit a part of the therapy repertoire. Unlike erlotinib that targets a specific tyrosine kinase, mTOR is a complex and multifaceted target.

There are actually two separate forms of mTOR, TORC1 and TORC2, and they sit at a critical point in cellular determination. Stimulated by the insulin growth pathway, cells must decide whether they will grow in size or divide. The mTOR proteins participate in this process by regulating protein synthesis and glucose uptake among other functions. In turn, the mTOR pathway is regulated by numerous other factors like AMP kinase and AKT. The current crop of mTOR inhibitors all target TORC1.

New classes of compounds are being developed that inhibit both TORC1 and TORC2. More interesting are the compounds that influence upstream signaling, including phosphoinositol kinase (PI3K) and AKT. What we are coming to learn, however, is that these are not targets but collections of targets. Indeed, the PI3K inhibitors themselves have influence on one, two or all of the distinct classes of phosphoinositol kinases.

Most of the studies to date have used compounds that affect all the classes equally (pan-inhibitors). Pharmaceutical companies are now developing highly selective inhibitors of this fundamental pathway. In addition, duel inhibitors that target both PI3K and mTOR are in clinical trials. What we are coming to realize is the complexity of these pathways. What may prove more vexing still is their redundancy. One well-established by-product of successful inhibition of mTOR (principally TORC1) is the upstream activity of AKT via a feedback loop. This has the undesirable affect of redoubling mTOR stimulation through the very pharmacological manipulation that was designed to inhibit it. Again, an unintended consequence of a well laid plan.

To unravel the complexities and redundancies of these processes, we have utilized the primary culture platform. It enables us to examine the end result of signal inhibition and dissect disease specific profiles. Using this approach we can partner with collaborators to define the specific operative pathways in each disease entity.

Biological complexity is the hallmark of life. We ignore it at our peril.

The Avastin Saga Continues

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.