Do We Need Phase III Randomized Controlled Trials for EVERYTHING?

Posted by Judi Space on Thu,Aug 29, 2013 @ 09:00 PM

Targeted therapy agents

Phase 3 randomized controlled trials - time to drop in some cases?In clinical trials of targeted therapy agents, sometimes the target is such a crucial driver of the neoplastic process, that its inhibition is able to stop the growing tumor in its tracks. This appears to be the case for some recently approved agents such as vemurafenib for BRAF V600E melanoma and crizotinib for ALK+ NSCLC. Careful screening of patients for these mutations ensures the likelihood of improved progression free survival (PFS) and longer survival times. Unfortunately, because patients are switched from the control regimen in the Phase III trials, the chances of proving better survival are greatly diminished, if not completely eliminated.

In a recent opinion piece in Nature Reviews: Clinical Oncology, Robert Doebele argues that when patients are screened for the relevant oncogene "the burden of proof for approval should be adjusted for oncogene-targeted therapy in biomarker-selected patients....There might be oncogenes that will not follow this paradigm, but that should not deter us from trying to extend the benefit of this precision medicine approach to patients that may fall into one of these uncommon oncogene categories." 

Crizotinib for ALK+ NSCLC

One example is crizotinib, a tyrosine kinase inhibitor (TKI) for the treatment of ALK gene rearrangement-positive (ALK+) non-small-cell lung cancer (NSCLC), which was approved by the FDA in 2011 based on the results of phase I and phase II clinical trials. Phase I observed an objective response rate (ORR) of 61% and a PFS of 9.7 months.  Phase II observed an ORR of 53% and a PFS of 9.1 months.

Considering the estimated ORR and PFS for most single-agent chemotherapy drugs in pretreated patients with lung cancer is 10% and 3-4 months respectively, was there really a need for a Phase III RCT in this case? 

The outcome of a phase III randomized trial, PROFILE 1007, of crizotinib in patients with ALK+ lung cancer merely provided further proof that cizotinbin is superior to standard chemotherapy for these patients that included a better quality-of-life and physical and emotional function.  Based on the results of this study, it seems reasonable to argue that the burden of proof for approval should be adjusted for oncogene-targeted therapy in biomarker-selected patients, especially in lung cancer. 

Not limited to TKI

Calls for the elimination of Phase III trials are not limited to TKI. During the presentation of a melanoma Phase II trial of a combination of two immunomodulators, ipilimumab and nivolumab at ASCO this year, one of the questions from the audience was, "Do we really need a phase III trial?" The results of the trial being presented were certainly impressive, with one year survival in the 80% range.

Time to shift the burden of proof?

Based on these examples, some feel that it may be time to eliminate the Phase III trial in targeted therapy agents when such overwhelming proof is given that a therapy induces remarkable tumor responses in Phase I and II.  This will allow studies to move along more quickly, minimize the need to switch patients from the control regimen, and provide more rapid approval for certain therapies.


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: Oncology, Targeted Therapy, Cancer Drug Development, Drug Development

Defining Success in Clinical Trials: Is Learning Something Enough?

Posted by Judi Space on Thu,Jul 25, 2013 @ 06:00 PM

Avastin discussed at ASCOAt last month’s ASCO conference, rapt attention was given to a presentation on the clinical trial results for the drug Avastin for patients recently diagnosed with an aggressive form of brain cancer, glioblastoma multiforme (GBM), according to an article by Clinton Leaf appearing in the New York Times, which is summarized below, with our comments added. The presentation by Dr. Mark R. Gilbert, professor of neuro-oncology at the University of Texas M. D. Anderson Cancer Center, revealed earlier clinical trial results that were encouraging:  tumors shrank and the disease appeared to stall for months in two smaller single-arm studies.

No Difference

However, Dr. Gilbert’s larger double blind study of over 600 brain cancer patients found no difference in the survival rate for patients given a placebo with standard treatment vs. those given Avastin with standard treatment.  In effect, the larger, more reliable double blind study eliminated doubt as to the general effectiveness of the drug.   In other words, the trial was “a success” because it had a clear result, but we learned that the drug has no statistically significant impact on the disease as a whole. But is that enough for the trial to truly be deemed a success?

It depends on how you define success. On one hand, doctors have no additional information on how to successfully treat brain cancer as a result of the study. On the other, one possible solution has been eliminated, so doctors and pharmaceutical companies can continue their quest for an effective drug armed with the knowledge from the study.

Not so Fast

The problem is that it is not quite as cut and dried as all that. Some patients who take Avastin do significantly better than those who do not. However, the trial failed to reveal the responders that make this result possible. Despite 400 clinical trials over 16 years, no correlation has been made as to why Avastin works or fails to work in certain patients. Again, given that we don’t know, can we deem the trial a success?  

Individualized Factors May Hold the Key

Researchers are learning that individualized pathology and physiology may be significant factors in developing effective drugs for treating certain diseases.  The variability of tumors and cancers at the genetic level can be great, as can the way our genes affect our response to drugs. So the solution to some diseases may lie in identifying the drugs that best align with the individualized factors associated with a given disease.

Failure rates in clinical trials tend to increase significantly as the drug moves from phase I to phase II. In the final phase it is not unusual for trials to wholly contradict earlier trials, or for the benefits to be far less than what was first reported, according to a 2005 paper published in the Journal of the American Medical Association by Dr. Ioannidis, an authority on statistical analysis.

The Difficulty of Matching Clinical Trial Populations to Patients

Rules governing statistical trial enrollment typically produce trial populations of younger and healthier members than those likely to use the drug. In addition, trial populations typically have had far less medical treatment. These factors combine to form somewhat of a mismatch between the trial population and patients. Given that the vast majority of drugs that enter clinical testing fail to get approved (95%), finding ways to match clinical trial participants with the appropriate genetic or molecular signature may be paramount to finding drugs that work.  

That’s the approach taken by Genentech in developing Herceptin, a breast cancer drug that targets tumor cells with an abundance of the HER2 protein. Small clinical trials were designed that enrolled only those with the required molecular or genetic signature. 60% of the new drugs in development at Genentech/Roche are being developed in concert with a diagnostic test to determine patients most likely to benefit. They did not go that route when they developed Avastin and tested it in patients with GBM.

Back to the Question at Hand

So, is it enough to simply learn something from a clinical trial, even if we don’t find a solution to treat a disease? Given that there is so much riding on finding drugs that improve and extend the lives of those suffering, anything that moves us forward, even if only eliminating what was thought to be a potential solution, is a step in the right direction.


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: FDA, Oncology, Targeted Therapy, Cancer Drug Development, Oncology Clinical Trial Design, Breast Cancer, Breast Cancer Drug Development, Breast Cancer Oncology, Glioblastoma, ASCO

Breakthrough Therapy Opens Door to Streamlined Drug Development

Posted by Rebecca Levine on Wed,May 15, 2013 @ 07:51 AM

The FDA's New Breakthrough Therapy Designation

What does the FDA's new Breakthrough Therapy designation mean for pharma and biotech firms? Commentary by Pennside Partners, consultants to the pharmaceutical and biotechnology industries.The FDA recently added a new designation, ‘Breakthrough Therapy’, to its roster of pharmaceutical regulatory terminology in order to ensure that truly innovative compounds get to the patients who need them most as soon as possible.  This new designation was enacted as part of the 2012 FDA Safety and Innovation Act (FDASIA).  The Breakthrough Therapy designation will provide companies with the opportunity for a streamlined developmental process, which could greatly shorten the development timeline. 

How the Breakthrough Therapy Request Process Works

A company can request the designation from the FDA at any time after the original IND submission, but is under no obligation to publicly announce the request.  Once the FDA grants the compound the Breakthrough Therapy designation, the process for approval becomes abbreviated.  The FDA representatives effectively form an advisory panel with the company, in order to determine the most efficient trial designs.  The review time will also be shortened due to the rolling NDA / BLA submission. 

Oncology Likely to Benefit Most

While the language of the bill does not specifically refer to oncology as a primary source of Breakthrough therapies, it is likely that a majority of these designations will apply to oncology compounds.  Other diseases that have already received Breakthrough Therapy status include the rare genetic disease epidermolysis bullosa, hepatitis C and cystic fibrosis. 

Flexible Approval Standards

These new breakthrough therapies must show early clinical evidence of a substantial improvement over existing therapies for serious or life-threatening diseases.  The bill purposefully left the approval standards vague, so that a judgment call can be made by the reviewers at the FDA.  There is no efficacy bar set; however officials warn that if a company wonders if their drug is in a grey area, it is unlikely to be a true breakthrough. 

Rigorous Data Requirements Remain

The data requirements for Breakthrough Therapies will be as rigorous as other submissions, but other faster trial designs may be possible for these compounds.  The options could include a phase Ib expansion or single-arm pivotal trial for diseases states where there is no standard of care.  A phase IIb randomized controlled trial with a modest-sized population might also be an option for some of these compounds where substantial efficacy benefit is seen over the standard of care.  Both these options and others could lead to either full or accelerated approval.

50% Breakthrough Therapy Approval Rate So Far

Over a dozen companies have already sought the Breakthrough Therapy designation, with approvals being granted to approximately half.  One of the compounds recently granted Breakthrough Therapy status is Pfizer’s palbociclib, an oral inhibitor of cyclin-dependent kinases (CDK) 4 and 6.  The designation was granted based on preliminary data from their phase II trial in first-line post-menopausal patients with ER+, HER2- locally advanced or metastatic breast cancer.  Interim data presented at the 2012 San Antonio Breast Cancer Symposium showed that women treated with the combination of palbociclib plus letrozole achieved a statistically significant improvement in median progression free survival (PFS) compared to women who received letrozole alone (26.1 months and 7.5 months, respectively).

Official FDA Guidance Set for July 2013

The official master guidance will be released by the FDA in July of 2013; however it is clear that this new designation will provide a significant benefit to qualifying extraordinary therapies. 

Pharmaceutical Industry Hurdles

What remains unclear at this time is how the already underfunded FDA will manage to provide even more time and attention to these compounds and how much the designation will actually streamline the regulatory pathway. 


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: FDA, Oncology, Cancer Drug Development, Drug Development, Breakthrough Therapy, FDASIA

Heads up for ASCO: Our List of Key Oncology Presentations

Posted by Judi Space on Tue,May 07, 2013 @ 06:00 PM

Expect the biggest data dump of the year at this annual cancer mega-conference

ASCO Oncology and Drug Development Conference Highlights May June 2013

 

 

 

For those of us taking an interest in Biotech and Drug Development the largest release of new clinical data is just around the corner at the annual American Society of Clinical Oncology (ASCO) meeting to be held in Chicago starting on May 31. In ASCO’s preliminary press release, the organization revealed what it thought were the key presentations to be presented at the meeting.  The actual abstracts will be posted on the ASCO website on May 15th, but the titles of the presentations are available now.

Pennside always sends a large team to ASCO to review the data and discuss its implications with experts in the field.  After reviewing the entire program, we have a hit list of what we believe are the most important studies to be presented at the meeting, especially regarding development of targeted therapies for a number of cancer indications.

Breast Cancer:

    • Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3). (Abstract #505)

One of the most important data releases this year at ASCO in Breast Cancer will be the preliminary results from the BOLERO-3 trial of Afinitor in combination with Herceptin and vinorelbine in HER2+ metastatic Breast Cancer patients.  Results were expected at the San Antonio Breast Cancer Symposium in 2012; however there had not been enough events to report at that time.  This trial should clarify whether Afinitor can be used to reverse resistance to HER2 therapies as well as it does with hormonal therapies.  If successful, this will expand the reach of Afinitor into the 2nd line of HER2+ Breast Cancer therapy, where its side effect profile will not cause the hesitance that it has in the ER+ populations.

  • A phase II trial of an oral CDK 4/6 inhibitor, PD0332991, in advanced breast cancer. (Abstract #519)

Interest remains extremely high for the anti-CDK4/6 inhibitor palbociclib from Pfizer.  More data from the Phase II trial will be released during a poster discussion session at ASCO.  The preliminary data seen at SABCS in 2012 was very significant and if these further results support it, the approval of this compound will dramatically affect the 1st line treatment of advanced ER+ Breast Cancer.   Since the FDA granted palbocicllib the designation of Breakthrough Therapy, the oncology community is very focused on how this will affect it’s developmental pathway. 

Colorectal Cancer:

  • Analysis of KRAS/NRAS, BRAF mutations in the phase III PRIME study of panitumumab plus FOLFOX versus FOLFOX as first-line treatment for mCRC (abst# 3511)

ASCO granted an exception to its abstract policy so that data from this analysis could be released early (17 April) because it shows that patients with certain RAS mutations beyond KRAS may have a negative outcome from treatment with Vectibix. ASCO and Amgen strongly believe oncologists need this information now in order to make informed decisions about choosing effective treatments for their patients.

  • Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type mCRC: German AIO study KRK-0306 (FIRE-3) (Abst# LBA3506)

Outcome of this trial may determine if patients truly benefit from this class of drugs in the first line setting.

Non-Small Cell Lung Cancer (NSCLC):

    • A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1) (Abst# CRA8007)

This is Synta’s lead product for 2nd line NSCLC. Previous interim results from GALAXY-1 have been positive, which leads us to suspect that this interim analysis will continue in a positive trend.  Final data (PFS/OS) for GALAXY-1 should be ready in time for EMSO2013 in Amsterdam or WCLC2013 in Sydney. The key for ganetespib’s initial success lies in any additional toxicity in combination with docetaxel. Note that GALAXY-2 (Phase III 2nd line NSCLC with docetaxel) has recently began enrolling patients. Clinicians will clearly contrast ganetespib with nintedanib (see below).

    • Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial. (Abst# LBA8011)

This is Boehringer Ingelheim’s second foray into the NSCLC. Their lead agent, afatinib is currently under regulatory review with both the FDA and EMA. Like ganetespib above, the key issue for nintedanib is toxicity in combination with docetaxel (provided the data is positive).Nintedanib clearly has the early lead when compared to ganetespib for becoming the newest agent in 2nd line NSCLC. Positive data in  LUME Lung-1 would be the second shot in the goal for Boehringer Ingelheim and their NSCLC franchise.

Prostate Cancer (PrCa):

  • Abstract #5016: A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): Immune results (Abst# 5016)

With the increasing number of approved treatments available for prostate cancer the biggest challenge is how to best sequence the drugs to maximize efficacy and minimize toxicity.  Because Provenge does not alter PFS but does improve survival, there has been much discussion regarding the optimal place for its use.  This abstract may offer some guidance or at least improve understanding.

 

    • Abstract #5004: ERG rearrangements and association with clinical outcome in patients (pts) receiving abiraterone acetate (AA) (Abst#5016)

Results from the COU-AA-302 study in chemotherapy (chemo)-naïve metastatic castration-resistant prostate cancer (mCRPC): The increasing number of targeted cancer therapies in development has necessitated the need for biomarkers to aid in determining patients most likely to respond to and benefit from each treatment.  Biomarkers will be increasingly valuable for patients and physicians in the decision making process.   ERG rearrangement in prostate cancer at the time of diagnosis, are markers for predicting subsequent tumor behavior and can help in better predicting the clinical outcome.

Kidney Cancer (RCC):

    • Record-3: Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in mRCC (abst# 4504)

Trials evaluating sequencing of targeted therapies are always important in RCC, although mTOR use is uncommon in the first line setting. 

    • Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in mRCC (Abst# 4505)

This is early data, but it will be interesting to see how this agent compares to BMS’ nivolumab (anti-PD1), which is already in Ph III for RCC.

Melanoma:

    • Long-term follow-up data on the safety and efficacy of singe-agent nivolumab (an anti-PD-1 antibody) in patients with advanced melanoma (Abstract #CRA9006)

Nivolumab (BMS) , a new immunomodulator, made a big splash at last year’s ASCO and BMS has lost no time in fleshing out its development program across a number of tumor types.  Since its debut last year companies with other agents like nivolumab have sprung into action, with clinical data presentations for quite a few of them on the schedule.

    • Findings from a Phase III trial exploring the effect of the anti-PD-L1 antibody drug MPDL3280A in patients with locally advanced or metastatic solid tumors (Abstract #3000)

This study of MPDL3280A (Roche) in patients with solid tumors will be presented by Roy Herbst (Yale). It is most unusual for a Phase III trial to include patients with many different tumor types, and we are intrigued by what Roche plans to do with the data (should the study be positive).

    • BRAF inhibitor (BRAFi) dabrafenib in combination with the MEK1/2 inhibitor (MEKi) trametinib in BRAFi-naive and BRAFi-resistant patients (pts) with BRAF mutation-positive metastatic melanoma (MM). (Abst#9005)

Interest is high here for this combination of TKIs from GSK. Phase II data was very promising at last year’s ASCO, and NDA has been filed with the FDA, so any updates will be followed very closely by all stakeholders.

Glioblastoma (GBM):

    • RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab in newly diagnosed GBM (Abst# 1)

ASCO’s top abstract. Presentation of results from this trial, along with the previously-reported AVAglio trial, will help determine the benefit of adding Avastin to standard chemo and radiotherapy in newly-diagnosed GBM.

    • Bevacizumab, irinotecan, and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT-nonmethylated GBM: First results from the randomized multicenter GLARIUS trial (Abst# LBA2000)

GBM patients with non-methlyated MGMT are resistant to treatment with the current standard of care chemotherapy (temozolomide), so if Avastin/irinotecan proves useful in this setting, it will be an important option for this group of patients who are currently without effective therapy.

Thyroid Cancer (ThyCa):

    • Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The Ph III DECISION trial (Abst# 4)

Another top Abstract at ASCO: Earlier this year, Bayer announced that DECISION met its primary endpoint, so it will be exciting to see just how effective Nexavar is in this difficult setting in thyroid cancer.

    • Phase II study of everolimus and sorafenib for the treatment of metastatic thyroid cancer (6024)

It will be interesting to see if the addition of Afinitor to Nexavar (which is known to be effective in thyroid cancer) will add any additional benefit.

Liver Cancer (HCC):

    • Sorafenib alone versus sorafenib combined with gemcitabine and oxaliplatin (GEMOX) in first-line treatment of advanced HCC: Final analysis of the randomized Ph II GONEXT trial (UNICANCER/FFCD PRODIGE 10 trial) (Abst# 4028)

The GONEXT trial will show if the addition of Nexavar to chemotherapy can improve outcomes in HCC, where chemotherapy alone is not very effective. HCC is a difficult disease, and many patients have difficulty with the side effects of Nexavar alone—this combination will have to overcome the potential for increased toxicity with some significant benefit in survival in order to be successful.

    • Ph II trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, followed by sorafenib in patients with advanced HCC (Abst# 4122)

Oncolytic viruses are a novel approach in oncology, particularly in HCC. This Ph II data will hopefully be the first indication of whether Pexa-Vec will be effective and well-tolerated.


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: Oncology, Cancer Drug Development, Drug Development, Breast Cancer, Breast Cancer Drug Development, Breast Cancer Oncology, Kidney Cancer, Liver Cancer, Thyroid Cancer, Glioblastoma, Melanoma, Prostate Cancer, Lung Cancer, Colorectal Cancer, ASCO

Molecular Testing in Trouble from Medicare. Who’s on First?

Posted by Judi Space on Tue,Apr 02, 2013 @ 06:00 PM

Only a Bureaucracy as Inefficient and Unwieldy as Medicare Could Create a Mess This Bad and Then Walk Away Whistling, Hands in Pockets

Medicare's decision to stop reimbursing labs for molecular testing threatens both the labs and the patients who badly need these potentially life-saving testsI’m referring to Medicare’s decision to stop paying bills for molecular testing and other diagnostic tests that are transforming the way many life-threatening diseases are being treated.  This is a decision affecting hundreds of labs, including labs performing proprietary tests that target treatments for cancer patients and other serious conditions. To be clear, this is not a decision to permanently stop paying, but to withhold payments until a favorable alternative has been found to the current system of reimbursement.

Could this have come at a worse time, a time at which significant medical and diagnostic gains are being made by molecular testing?

What began as an honest effort to reduce costs has devolved into a quagmire of indecision, with no one taking charge of resolving the mess.  In the meantime, bills from hundreds of labs and health care companies are going unpaid, with no clear resolution in sight. Just how long labs and health care companies will continue to perform these expensive services without being reimbursed is anyone’s guess, but the situation should be causing alarm bell to go off inside Medicare and the Obama administration. 

Here’s How the Medicare Reimbursement System for Molecular Testing Broke Down

First, Medicare, in a much-needed effort to address an abuse-prone billing and reimbursement system, decided to seek an alternative to the billing process known as “code stacking”, a system whereby the costs and reimbursements for diagnostic tests are determined by identifying the codes and associated costs for each step in performing a particular molecular test.  Rather than paying based on the true value of the test, the code stacking system paid for the steps, I.e., the complexity of a test. This of course opened the door to abuse and inconsistency, with some labs identifying and charging for additional steps.

116 New Codes Went Into Effect in 2011, but Medicare Sat Them Out

In order to replace this with a system of paying based on what was being tested form, in 2010 Medicare asked the American Medical Association to create codes for the most critical and common molecular tests. 116 new codes went into effect in 2011, but Medicare decided to wait until 2012 to use the new system, and until then to continue using the old code stacking method until it could set pricing for the new codes.  In the year since, Medicare has done virtually nothing, and (stunningly) has instead decided to have local Medicare carriers assign prices to each of the diagnostic codes! Now, at the last minute, instead of a unified pricing and reimbursement standard, the local Medicare carriers are forced to determine pricing.

Tests Going Unpaid, at Least for Now

As a result, many prices have not been established, and many tests are going unpaid. The market for the development of new tests is being hammered with uncertainty, with many investors sidelined until the pricing issues are resolved. To get by, some contractors are beginning to mirror the pricing charged by the Medicare contractor for California, the only carrier who has managed to set rates. One can question whether a state as large and unique as California should be driving the rates for the US as a whole.  That said, other contractors are not following the California model, and are not getting paid.

On April 30, Medicare contractors are scheduled to submit their 2013 pricing, including their prices for molecular testing. Once this occurs, it is possible that the labs will get paid after the fact. However, this is not guaranteed, and the deadline is not firm.

Is it Fair for Medicare to Delay Payments for Molecular Testing?

One must ask, is it fair for Medicare to refuse to pay for molecular testing simply because they bungled their own deadline for producing a viable reimbursement system? Should the agency be permitted to walk away from the problem by throwing it into the hands of the Medicare contractors, while in the meantime testing labs go unpaid and patients run a growing risk of having to do without potentially life-saving diagnostic testing?

For more information on this timely issue, see the full article that inspired this post on Forbes.


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: Oncology, Targeted Therapy, Molecular Testing

Will Oncology and Pathology Unite on Molecular Testing?

Posted by Judi Space on Wed,Mar 27, 2013 @ 07:00 PM

For more than a decade, we have been listening to the leaders in cancer research tell us that in order for targeted therapy to work, we must be able to identify who will benefit from it through the use of predictive biomarkers. This is the essence of personalized medicine.

Is molecular testing the key to targeted therapies and a solution to a one-size-fits-all approach?Molecular testing (MT) is becoming the new paradigm for determining an individual cancer patient's course of treatment. Although it is fairly widespread in large academic cancer centers, community hospitals and cancer clinics, where most cancer patients are treated, are often completely out of the loop.

Recently the Association of Community Cancer Centers has sought to better understand the scope of this problem through a survey of its members (1). This survey polled the member institutions' administrators, oncologists, pathologists nurses, and pharmacists (N=52 institutions) about policy, practices, and proceedure related to MT as well as reimbursement issues.

Implementing Molecular Testing: Education of Stakeholders is Key

There are many challenges to the implimentation of MT in the community oncology setting(1).  Chief among them is unwillingness of various stakeholders to work together to make MT a routine proceedure for all newly diagnosed cancer patients. The reality is that testing is already being done on a very limited basis for breast cancer patients (HER2, and ER/PR), but the cancer centers appear to balk at the expansion of similar testing in other cancer indications.(2)

It also represents a great new opportunity to improve the coordination between pathologists and oncologists.

In order to implement MT, The ACCC survey indicated that there should be "champions" that drive the institution toward a coordinated testing program. Most often these champions come from the ranks of the oncologists. They must educate their peers and the institution's administration about the necessity for having a MT policy/proceedure to decide how and when specific tests will be implemented.

Will Oncology & Pathology Come Together Over MT?

Can oncology and pathology unite over molecular testing?The lack of collaboration between pathologists and oncologists is one of the things that's holding molecular testing programs back. Many physicians can't seem to agree on whether MT is necessary, and when. Some don't see the value in personalized medicine, while cancer center administrators see it as simply a line in the budget and are unwilling to spend the time and money in an environment of competing interests.

However, there is safety in numbers. By uniting on the molecular testing issue, oncologists and pathologists will have a greater chance of convincing administrators its necessity.

Is Molecular Testing Costly or Cost Effective?

One of the drawbacks to molecular testing programs is the cost of testing. The decision for doing MT may lie with the payer, rather than the patient's specific needs.  Each assay can run as much as $7,000, which can make insurance companies unwilling to cover the cost in many cases.

However, most oncologists and pathologists agree that molecular testing can actually save money in the long run. The detailed, personal information that it provides can guide an otherwise uncertain treatment plan. A negative test result can save a lot of money on expensive, targeted therapies.

In order for progress to take place, continuing education is essential. This is true of both the medical oncologists and the pathologists. In the rapidly evolving world of cancer drug development, new molecular tests will emerge on a regular basis which will help choose new options for treatment where there were none before.  Pathologists and oncologists must work together to use the test results to guide treatment by identifying who will benefit from specific targeted therapy regimens. 

References

(1)http://accc-cancer.org/education/molecularTesting-Overview.asp

(2) http://obroncology.com/obrgreen/article/Molecular-Testing-Preparing-for-the-New-Normal-in-Community-Oncology


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: Oncology, Predictive Biomarkers, Targeted Therapy, Drug Development, Molecular Testing, Personalized Medicine

NCI Improvements: Drug Development Opportunity for Pharma and Biotech

Posted by Judi Space on Tue,Mar 12, 2013 @ 06:00 PM

Three years ago the Institute of medicine declared that the nation’s cooperative group system for conducting clinical trials was so moribund as to not be an effective vehicle for the generation of scientific data in a timely fashion. In a report generated in 2010, the IOM recommended that the number of cooperative oncology groups be reduced from 10 down to 5[1], improve speed and efficacy of the trial processes as well as incorporate new scientific discovery into clinical protocols. Along with this, the report said it was critical to create a data platform that would assist in the administration of trials across all of the remaining cooperative groups. This would be a system to which both large academic centers and community cancer centers could adhere.

NCI Less of a Barrier; More of a Facilitator

To a large extent, the NCI was  a barrier to the conduct of clinical trials due to their role of providing oversight. The IOM report urged that NCI become part of the solution by helping to prioritize and design trials as well as directing patients to relevant studies so that enrolment could proceed more rapidly. In addition, CMS was tasked with removing barriers to enrollment by supporting appropriate costs associated with patient treatment during the trials.

Efforts Bearing Fruit

Now, nearly three years later, we can see the effects of this report. In a two day workshop[2] that took place in Washington last month, improvements in the national cooperative group trial system were documented[3]. Among the improvements noted:

  • The time between concept and activation of phase II trials sponsored by NCI has shrunk by more than a third. Trials not meeting timelines will be terminated!
  • Time to activation for phase III trials has been halved since the overhaul process began
  • The number of cooperative groups has actually been cut in half – now there are only 5
  • A common enrollment and data management system has been put into place
  • Patients can enroll 24/7 and they may participate in ANY Ph III trial in the system regardless of origin
  • There are now  standardized agreements for industry collaborations
  • A new  review process has been launched for grading the quality of trials
  • Integrated biospecimen banks are being created

Still to come are more innovative Ph II trials based on molecular biology of the tumors and the extensive use of biomarkers and genomic profiling.

Ecology of Clinical Trials

Community Cancer Centers are Key

The key to moving clinical research forward more rapidly will be enhanced participation of community cancer centers. Investigators at these sites are often hesitant to take part as many of the costs associated with the trials are not covered.  After more provisions of the Affordable Care Act go into effect, next January, this may no longer be a barrier. Federal law will require insurers cover the cost of routine patient care in clinical trials.

Design and Conduct of Trials Improving in UK As Well 

Interestingly, the US is not the only place that has had a sea change in the way it conducts clinical research for cancer. Over the same period, the UK’s National Health Service has recognized that clinical research is an important part of its mission, and therefore has provided incentives for patients to participate in trials. The key here is that cancer patients do not get access to novel agents unless they participate in the trials. The result is a trials network that rivals anything in the US but existing in a much smaller country.

 

Implications for Drug Development:

Drug approval process improving in the UK as well as the US

Pharma  and biotech companies can harness the power of the NCI to get things done faster than they have become accustomed to in the past, and the improvements will continue into the foreseeable future. This is also good news for cancer patients who will be able to access more cutting edge clinical trials no matter what part of the country they are from.

 


[1] http://www.iom.edu/~/media/Files/Report%20Files/2010/A-National-Cancer-Clinical-Trials-System-for-the-21st-Century-Reinvigorating-the-NCI-Cooperative/NCI%20Cancer%20Clinical%20Trials%202010%20%20Report%20Brief.pdf

[2] http://www.iom.edu/~/media/Files/Activity%20Files/Disease/NCPF/2013-FEB-11/Agenda%20-%20IOM%20ASCO%20Implementation%20Workshop.pdf

[3] http://www.nap.edu/catalog.php?record_id=18273


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: FDA, Drug Developers, Oncology, Predictive Biomarkers, Targeted Therapy, Data Standardization, NCI, Cancer Drug Development, Oncology Clinical Trial Design

Breast Cancer Drug Development - Targeting HER2 Activating Mutations

Posted by Judi Space on Thu,Jan 10, 2013 @ 09:00 AM

A Possible Development Pathway for Biotech Companies with PanHER Inhibitors?

Many Breast Cancer Patients Not Helped by Herceptin

For more than ten years oncologists have been aware of the role that Herceptin (trastuzumab, Roche/Genentech) has played in extending the lives of women with HER2 overexpressed breast cancer. Herceptin works by blocking the HER2 receptor from receiving activating stimuli from outside of the cell. In addition there is a second agent, Tykerb (lapatinib, GSK) which is able to block signaling from the tyrosine kinase domain of the receptor, inside the cell. Still, there are many patients who are not helped by these agents. These targeted therapies work when the receptor is overexpressed, but may not work when the receptors are mutated.

Breast cancer drug development - exposure to neratinibSomatic Breast Cancer Mutations Identified

At December’s San Antonio Breast Cancer Symposium, there was a talk given by Ron Bose from Washington University, about other perturbances of the HER2 receptor[1][2]. Over the last year, the Cancer Genome Atlas Breast Cancer has conducted genome sequencing of breast cancers. This endeavor has identified several somatic mutations that appear on the HER2 receptors in some breast cancers. A majority of the mutations were found in the kinase domain of the receptor. Most of the lesions analyzed were considered HER2 negative as they did not achieve the 3+ score in IHC testing.  

Ph II Trial of Neratinib in Breast Cancer Patients

Because the mutations cause constitutive activation of the receptor (it is always turned on), Herceptin cannot block its signaling from outside of the cell. The mutations are rare, and it is estimated that only about 5000 women in the US with breast cancer would have them. In cell line studies, Tykerb has some effect on cells with these mutations, but the agent that appears to have the most activity is neratinib (Puma), a “pan-HER” inhibitor. To that end, there will be a fairly large Ph II trial of neratinib in breast cancer patients who test negative for HER2 amplification but positive for these somatic mutations.

Breast Cancer Drug Development - Targeting Somatic Cancer Mutations

There is precedent for targeting somatic mutations in malignant lesions. Even in the same family of receptors, there are three agents with activity against EGFR: Iressa (gefitinib, AstraZeneca), Tarceva (erlotinib, Roche/Genentech) and afatinib (Boheringer Ingleheim). This has implications for the larger world of breast cancer biotech drug development targeted at the EGFR family of receptors as there are many “pan-HER” inhibitors in development that could potentially be used to treat tumors with these mutations.

Barriers to Breast Cancer Drug Development

The biggest barriers for development would be working up accurate testing systems to detect the mutations as predictive biomarkers of drug efficacy, and then getting these tests included in the battery of diagnostics used to analyze both primary breast tumors and recurrent disease.     


[1] Bose, R Activating HER2 mutations in HER2 gene amplification negative breast cancers, SABCS December 2012, S5-6


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: Oncology, Predictive Biomarkers, Targeted Therapy, Breast Cancer, Breast Cancer Drug Development, Breast Cancer Oncology, Breast Cancer Therapy

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