Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Human beings use 20 mg of iron each day for the production of new red blood cells, much of which is recycled from old red blood cells.

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Erythropoeitin stimulating agents (ESA's) such as Epogen, Aranesp and Procrit sold by Amgen and J&J have been under scrutiny by the FDA for over a year, with data from several phase III trials suggesting that the drugs may stimulate the growth of tumours in some cancer patients.  They are primarily used to treat anemia, or low red blood cell count, and protect against the need for blood transfusions, but concerns linger about the risk-benefit profile.

A new study presented at ASCO indicated that activity in certain tumour genes, the same ones
the drugs target on red blood cells, was correlated with bad outcomes. The researchers tested whether measuring Epo receptor (EpoR) mRNA levels in head
and neck cancer
could identify patients susceptible to Epo induced
tumour growth.  They also examined whether endogenous Epo might stimulate
tumour growth.

The preliminary findings suggest that adverse effects of Epo on tumour progression may depend on tumor
EpoR expression.  Whether a relationship exists between other C20
targets and Epo induced tumor progression may need further investigation. Their findings present clear hypotheses that could be tested in archival
tumours from other Phase III trials.

If research bears this link out, ESA's could then be
targeted toward the patients whose tumours don't show that activity.  Amgen have, however, steadfastly maintained that there's no link between the drugs and tumour progression and noted that tumour samples were not routinely collected in prior trials, but would do so going forward.

At ASCO, it was clear that a new trend is emerging in oncology using biomarkers to determine which patients should and shouldn’t
receive certain cancer therapies.  If sufficient data emerge to suggest that ESA's
are indeed risky for cancer patients, it might be prudent to identify those cancer patients at lower risk for anti-anemia treatment, rather than a one drug fits all approach.

{UPDATE – recent data in The Lancet suggested that:

"Treatment with erythropoiesis-stimulating agents in patients with
cancer increased mortality during active study periods and worsened
overall survival. The increased risk of death associated with treatment
with these drugs should be balanced against their benefits.

The question is are some patients more or likely to benefit and are there any factors that predict which responses are most likely?  Looking at the study definition;

"Mortality
during the active study period was defined as death from any cause
between the date of randomization and 28 days after the end of the
study phase, and overall survival was defined as death from any cause
between the date of randomization and the last available follow-up."

So how did the separate out natural death from cancer or other factors and treatment-related deaths due to ESA's?  It is probably hard to determine on that basis alone.

If you at the data closely, assessment of mortality during the active study period, median
follow-up of ESA patients was 3.7 months and that of control patients
was 3.9 months.  However, assessment of overall patient survival showed that the median follow-up of ESA
patients was 6.2 months and that of control patients was 8.3 months,
for a combined hazard ratio of 1.06 (95% CI 1.00 to 1.12, P=0.046).
 

What struck me though, what that as only recently as December 2008 in a press briefing at the ASH meeting, the lead author was claiming the exact opposite and that there was no reason to change the guidelines!  This debate will no doubt continue in earnest with the FDA and ASCO throughout 2009.}

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2 Responses to “ESA's and tumor proliferation – do they or don't they make cancer worse?”

  1. drsteventucker.wordpress.com

    The answer to this puzzle is going to be a nightmare. A recent report in JCO by Glaspy et al (JCO May 20, 2009) found no increased risk of death or association with progression with ESA’s. On the other side you have guys like Charlie Bennett at Northwestern (who wrote the JAMA paper in February) stating categorically the risk of death is increased.
    In daily clinical experience we never see any overt progression attributed to these drugs (nor could we on an individual basis) and they are so ingrained in the patient experience and in the supportive care literature, that removing them will be difficult.
    Further, if they are in fact, conclusively found to hasten death, then we are all in for some really stinging black eyes. Trust in “Bio-Pharma” and oncology will be shot. Trust in journals and peer-review will be shot. All will ask, how did we let this get by? And not the least of whom will be congress, as the people foot the bill for these drugs to the tune of 7-8 billion USD annually.

  2. Sally Church

    Very good points indeed, Steven. It is a very tricky question.
    The challenge for me with the Glaspy study (http://jco.ascopubs.org/cgi/content/abstract/JCO.2008.19.1130v1) is that he is a well known spokesperson for Amgen on the topic, so whether any bias creeps in, I don’t know.
    The Bohlius Lancet paper declared the various authors conflict of interest with Amgen, J&J, Roche etc yet still found a negative outcome.
    The Bennett paper (http://jama.ama-assn.org/cgi/content/abstract/299/8/914?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1=Bennett%2C+CL&andorexacttitle=and&andorexacttitleabs=and&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT) appears to be an update of the Cochrane data, which Bohlius et al., are already expressing concerns about methodology of the re-analysis in letters to JAMA.
    Who knows which study is accurately reporting the real effect? The ASCO guidelines were updated in 2008 and no doubt there will be further revisions after much debate!
    I wouldn’t like to be the FDA and ODAC atrying to sort this one out.

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