A “Clinical Trial” Too Far

An interesting paper was published in the January 10 NEJM (Abiraterone in Metastatic Prostate Cancer with Previous Chemotherapy, Ryan et al). The study randomized 1,088 hormone-refractory prostate cancer patients to receive abiraterone plus prednisone, or placebo plus prednisone.

Abiraterone works by blocking the syntheses of testosterone (the critical survival factor for prostate cancer cells), both in the adrenal glands and within the tumor cells themselves. The drug had previously been approved for patients who had failed hormone therapy, but was only approved for those who had also failed Taxotere chemotherapy.

The results were so strongly positive in favor of the treatment arm, revealing a significant progression-free survival 16.5 versus 8.3 months (p < .001) and overall survival hazard ratio 0.75 (p = .01) that the monitoring committee invoked early stoppage rules. Virtually all of the other markers of disease also strongly favored the treatment arm. All of this speaks for an effective therapy in hormone-refractory prostate cancer and we applaud their success.

The question remains: Did we really need to conduct this study?

On a biochemical level, abiraterone represents an effective mechanism for androgen ablation. The drug has been established to work well in patients who have failed prior hormone and Taxotere chemotherapy. In that prior exposure to Taxotere would not be expected to substantively influence abiraterone efficacy, the wisdom of committing 1,088 hormone-refractory patients to a “placebo controlled” randomized trial to prove its efficacy in the Taxotere naive population seems questionable.

Prostate cancer generally afflicts older men. While most patients respond to hormonal ablation, hormone-refractory disease develops in virtually all patients over time. A comparatively mild oral therapy like abiraterone represents a demonstrably superior alternative to a comparatively toxic alternative intravenous cytotoxic drug like taxotere. Did we need to marshal a multi-million dollar trial to prove that abiraterone worked in people who had not received Taxotere, when there was absolutely no reason to believe that it wouldn’t?

The reason that this trial was conducted was to meet an increasingly onerous regulatory environment that demands that every use of every drug in every situation be proven with a large and enormously expensive clinical trial.

Registration trials cost between $10,000 and $20,000 per accrued patient. Using these figures, we can guess that this clinical trial cost between $10,000,000 and $20,000,000 to conduct. Those costs must now be recouped from patients and insurers. Thus, the very agency whose purpose is to protect patients and limit the inappropriate use of drugs has created an environment that adds to those expenses and it can be argued, prevents the appropriate use of drugs.

To put this into perspective, let’s examine the female counterpart – breast cancer. Once aromatase inhibitors showed activity in postmenopausal women, they were rapidly incorporated into clinical therapeutics. Dovetailing nicely with the established antiestrogen tamoxifen, these drugs became second line hormonal therapies. While these drugs naturally assumed their roles in hormonal management of breast cancer, no one would ever demand that a breast cancer patient with ER positive cancer first receive chemotherapy before being allowed to use the well-established aromatase inhibitors. Had the FDA demanded that no one could receive anastrozole, letrozole or Aromasin until they had had Adriamycin, there would have been a march on Washington to reverse the policy. It was obvious to all those engaged in the field that these drugs worked and that they would work at different points in hormonal management of the disease.

The physiology of and clinical experience in breast cancer management allowed smart scientists with the approval of the regulatory agencies to “crosswalk” the application of these important agents. It is time for the American public to demand that clinical trials be conducted (and resources allocated) when the questions they address can only be answered through the expenditure of these vast financial and human resources.

Stalking Leukemia Genes One Whole Genome at a Time

An article by Gina Kolata on the front page of the July 8, Sunday New York Times, “In Leukemia Treatment, Glimpses of the Future,” tells the heartwarming story of a young physician afflicted with acute lymphoblastic leukemia. Diagnosed in medical school, the patient initially achieved a complete remission, only to suffer a recurrence that led him to undergo a bone marrow transplant. When the disease recurred a second time years later, his options were more limited.

As a researcher at Washington University himself, this young physician had access to the most sophisticated genomic analyses in the world. His colleagues and a team of investigators put all 26 of the University’s gene sequencing machines to work around the clock to complete a whole genome sequence, in search of a driver mutation. The results identified FLT3. This mutation had previously been described in acute leukemia and is known to be a target for several available small molecule tyrosine kinase inhibitors. After arranging to procure sunitinib (Sutent, Pfizer Pharmaceuticals), the patient began treatment and had a prompt and complete remission, one that he continues to enjoy to this day.

The story is one of triumph over adversity and exemplifies genomic analysis in the identification of targets for therapy. What it also represents is a labor-intensive, costly, and largely unavailable approach to cancer management. While good outcomes in leukemia have been the subject of many reports, imatinib for CML among them, this does not obtain for most of the common, solid tumors that lack targets for these new silver bullets. Indeed, the article itself describes unsuccessful efforts on the part of Steve Jobs and Christopher Hitchens, to probe their own genomes for effective treatments. More to the point, few patients have access to 26 gene-sequencing machines capable of identifying genomic targets. A professor of bioethics from the University of Washington, Wiley Burke, raised additional ethical questions surrounding the availability of these approaches only to the most connected and wealthiest of individuals.

While brute force sequencing of human genomes are becoming more popular, the approach lacks scientific elegance. Pattern recognition yielding clues, almost by accident, relegates scientists to the role of spectator and removes them from hypothesis-driven investigation that characterized centuries of successful research.

The drug sunitinib is known for its inhibitory effect upon VEGF 1, 2 and 3, PDGFr, c-kit and FLT3. Recognizing the attributes of this drug and being well aware of C-KIT and FLT3’s role in leukemias, we regularly add sunitinib into our leukemia tissue cultures to test for cytotoxic effects in malignantly transformed cells.  The insights gained enable us to simply and quickly gauge the likelihood of efficacy in patients for drugs like sunitinib.

Once again we find that expensive, difficult tests seem preferable to inexpensive, simple ones. While the technocrats at the helm of oncology research promise to drive the price of these tests down to a level of affordability, everyday we wait 1,581 Americans die of cancer. Perhaps, while we await perfect tests that might work tomorrow, we should use good tests that work today.

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.”

Breast Cancer and Avastin, the Ongoing Saga

As many are now aware, in November of 2011, the United States FDA withdrew approval for bevacizumab (Avastin) for the treatment of breast cancer. Medicare and the National Comprehensive Cancer Network  (NCCN) are now re-examining their guidelines. In the interim, reimbursement for Avastin is a patchwork of approvals and denials across the country.

Into this mix comes an interesting concept apparently floated by Roche’s European affiliates. Described in a brief press release was the suggestion that Roche might be prepared to attach Avastin reimbursement to its efficacy. That is – Roche would only demand payment from patients and third party payers if the treated patient revealed objective evidence of response. This is an interesting idea!

The concept of conditional reimbursement is extremely intriguing. Contrary to contemporary reimbursement policy, the purveyors of therapy would only receive compensation if they could prove benefit, not mind you, benefit in the broad brush Phase III tiny statistically significant result (e.g. the FDA approval of erlotinib plus gemcitabine in pancreatic cancer for a median survival advantage of 10.6 days!), but instead very real benefit on a patient-by-patient basis.

We use erlotinib plus gemcitabine, as well as Avastin combinations, to great benefit for many of our patients and applaud the availability of these drugs and combinations. But we never, just give them. Were the federal government, major payers or HMOs to be prepared to reimburse novel therapies predicated on their efficacy, we might envisage a meaningful advance in cancer therapeutics.

Today, few small laboratories, start-up companies and early stage biotech firms have the resources to marshal multi-million dollar clinical trials to test new therapies. This may in part be why advances in cancer therapy are moving so slowly forward.  The barriers to entry are insurmountable, causing many good ideas to fall by the wayside for lack of the hundreds of millions of dollars required to achieve FDA approval and Medicare reimbursement. But what if on an individual basis, reimbursement policies reflected the most meaningful of all endpoints – individual patient response and survival. Even the largest pharmaceutical companies are now coming to realize that despite their clout they too are suffering under the guidelines forced upon drug developers in this era of ever increasing regulation.

This is a concept worth pursuing. Let’s see where it goes.

English Patients Denied Access to Ipilimumab

Among the more interesting discoveries in recent years have been two breakthroughs in the management of malignant melanoma. One drug, vemurafenib, a tyrosine kinase inhibitor, acts specifically in patients who carry the BRAF (V600E) mutation. The second drug ipilimumab, offered commercially from Bristol-Meyers Squibb as Yervoy, is a monoclonal antibody that acts by blocking CTLA-4, thereby enhancing T-cell response to tumor antigens. While vemurafenib has a somewhat narrow target population, ipilimumab targets may extend to a broader range of melanoma patients and will likely find a role in other cancers.

The data supporting ipilimumab’s use in advanced melanoma was reported in a 2010 Phase III trial, which provided a superior median survival for those treated with the drug over those who received a placebo. Superior one and two-year survivals were also reported. Unfortunately, this did not rise to the level that met the standards of the English watchdog organization, National Institute for Health and Clinical Excellence (NICE). The chief executive of NICE did admit that the drug could “potentially be very effective for a small percentage of patients.” Unfortunately, under current NICE guidelines, that small percentage of patients will not have access to the drug.

This is not the first time that a drug, found effective for the treatment of a subpopulation of patients has been denied approval based upon cost efficacy and the comparatively limited population of patients who stand to gain.

The role of Avastin in breast cancer represents a similar dilemma for those patients who might benefit but cannot afford the out-of-pocket expenses. Indeed, NICE originally denied approval to bortezomib, a highly active drug for the treatment of multiple myeloma, based upon similar cost considerations.

What ipilimumab, Avastin and bortezomib have in common is that they are harbingers of the coming conflict between patients-in-need and society’s capacity to cover the increasing costs of cancer therapy. Cost efficacy questions will only be resolved when we have the capacity to identify likely responders prior to therapy, enabling us to use drugs only in those patients with the highest expectations of response. Marginal overall benefits that come at high price will continue to fail until we redouble our efforts to refine the process of drug selection for individual patients. Janet Woodcock, MD, from the FDA once said, that we need “a critical path” from bench to bedside to guide clinical decisions. The human tumor primary culture functional analyses that we employ can provide that critical path and we would hope limit the need for the broad-brush policy decisions that are being handed down by NICE and similar entities both here in the U.S. and abroad.

Is Rationed or Rational Medical Care In Our Future?

We are witness to a sea change in medicine. Doctors and nurses are being replaced by “healthcare providers;” medical judgment is being phased out in favor of therapeutic algorithms; and the considered selection of treatments is giving way to rigid therapy guidelines. All the while, the regulatory environment increasingly precludes the use of “off label” drugs. It is understandable why insurers, governmental entities and hospital chains might welcome these changes. After all, once therapies have been reduced to standardized formulae, one can predict costs, resource allocations and financial exposures to the twentieth decimal place. For many medical conditions, these approaches will provide adequate care for the majority of patients.

But, what of the outliers? What of those complicated disease entities like cancer, whose complexity and variability challenge even the best minds? How do we bang the round peg of cancer therapy into the square hole of formulaic care?

There are several answers. The first is the least attractive: In this scenario, predicated upon cancer’s incidence in an older population, at the end or beyond their productive (and reproductive) years, we simply don’t allocate resources. Most civilized modern societies haven’t the stomach for such draconian measures and will seek less blunt instruments.

The second is a middle of the road approach. In this scenario, standardized guidelines that provide the same treatment to every patient with a given diagnosis are developed. Every medical oncologist knows the drill: FOLFOX for every colon cancer, Cytoxan plus Docetaxel for every breast cancer and carboplatin plus paclitaxel for ovarian cancer. The treatments work adequately well, the schedules are well established, the toxicities are well known and no one is cured. The beauty of this approach is that the average patient has an average outcome with the average treatment. By encompassing these regimens into standardized algorithms, we may soon be able to eliminate physicians entirely — first, with nurse practitioners and physician’s assistants and, ultimately, with computers. What is perhaps most surprising about this scenario has been the willingness of the medical oncology community to embrace it, a sort of professional self-induced extinction. At the time of this writing, this is the predominant model and is becoming increasingly entrenched under the auspices of NCCN and related guidelines. The operative term being guidelines, in as much as these “guidelines” are rapidly becoming “dictates.”

The final approach, and the one I find most appealing, is that which utilizes the clinical, scientific, laboratory and technical acumen of the physician to the maximum. Combining diagnostic skill with scientific insight, the physician becomes the captain of the ship, who must assume control from the autopilot once the vessel has entered the tempest and use his/her experience and training to guide the patient to a soft landing. This requires the capacity to think and demands an up-to-date knowledge of many disciplines. The judicious application of laboratory-directed approaches can further enhance the skillset, introducing objective data that is then used to guide drug and treatment selections. Predicated upon an understanding of the patient’s tumor biology, cancer therapy becomes an intellectual exercise that draws upon literature, and a knowledge of pharmacology and physiology. Adding the wealth of newly developed signal inhibitors to the mix only enhances the odds of a good outcome.

This approach improves responses and eliminates futile care. It provides patients the opportunity to participate in their own management. Correctly delivered, it would make available to every patient any FDA-approved drug. While it would seem to some that this would open the floodgates of drug use, I would strenuously disagree. It would instead limit drug administration to those patients most likely to respond, a goal currently pursed by virtually every major institution, yet accomplished by none. While a handful of targeted approaches have come to fruition in the last few years — erlotinib for EGFR mutation, and sunitinib in kidney cancers — most of the molecular profiling being done today doesn’t aid in the selection of therapy but instead provides negative information (e.g. RAS in colon cancer, ERCC1 over expression in lung) enjoining the physician against the use of a given agent but then leaving the unfortunate patient to fend for themselves amidst a panoply of randomly chosen options.

This is the approach that I have chosen to adopt in my own care of cancer patients. Our rapidly growing successes in ovarian, breast, lung, melanoma, leukemias and other diseases could and should serve as a model for others.

The False Economy of Genomic Analyses

We are witness to a revolution in cancer therapeutics. Targeted therapies, named for their capacity to target specific tumor related features, are being developed and marketed at a rapid pace. Yet with an objective response rate of 10 percent (Von Hoff et al JCO, Nov 2011) reported for a gene array/IHC platform that attempted to select drugs for individual patients we have a long way to go before these tests will have meaningful clinical applications.

So, let’s examine the more established, accurate and validated methodologies currently in use for patients with advanced non-small cell lung cancer. I speak of patients with EGFR mutations for which erlotinib (Tarceva®) is an approved therapy and those with ALK gene rearrangements for which the drug crizotinib (Xalkori®) has recently been approved.

The incidence of ALK gene rearrangement within patients with non-small cell lung cancer is in the range of 2–4 percent, while EGFR mutations are found in approximately 15 percent. These are largely mutually exclusive events. So, let’s do a “back of the napkin” analysis and cost out these tests in a real life scenario.

One hundred patients are diagnosed with non-small cell lung cancer.
•    Their physicians order ALK gene rearrangement     $1,500
•    And EGFR mutation analysis     $1,900
•    The costs associated $1,500 + $1,900 x 100 people =    $340,000
Remember, that only 4 percent will be positive for ALK and 15 percent positive for EGFR. And that about 80 percent of the ALK positive patients respond to crizotinib and about 70 percent of the EGFR positive patients respond to erlotinib.

So, let’s do the math.

We get three crizotinib responses and 11 erlotinib responses: 3 + 11 = 14 responders.
Resulting in a cost per correctly identified patient =     $24,285

Now, let’s compare this with an ex-vivo analysis of programmed cell death.

Remember, the Rational Therapeutics panel of 16+ drugs and combinations tests both cytotoxic drugs and targeted therapies. In our soon to be published lung cancer study, the overall response rate was 65 percent. So what does the EVA/PCD approach cost?

Again one hundred patients are diagnosed with non-small cell lung cancer.
•    Their physicians order an EVA-PCD analysis    $4,000
•    The costs associated: $4,000 x 100 people =    $400,000
•    With 65 percent of patients responding, this
constitutes a cost per correctly identified patient =     $6,154

Thus, we are one quarter the cost and capable of testing eight times as many options. More to the point, this analysis, however crude, reflects only the costs of selecting drugs and not the costs of administering drugs. While, each of those patients selected for therapy using the molecular profiles will receive an extraordinarily expensive drug, many of the patients who enjoy prolonged benefit using EVA/PCD receive comparatively inexpensive chemotherapeutics.

Furthermore, those patients who test negative for ALK and EGFR are left to the same guesswork that, to date has provided responses in the range of 30 percent and survivals in the range of 12 months.

While the logic of this argument seems to have escaped many, it is interesting to note how quickly organizations like ASCO have embraced the expensive and comparatively inefficient tests. Yet ASCO has continued to argue against our more cost-effective and broad-based techniques.

No wonder we call our group Rational Therapeutics.