One of the most interesting sessions I attended at this year’s American Society of Clinical Oncology (ASCO) annual meeting in Chicago was the Clinical Science Symposium (CSS) on the next generation of EGFR inhibitors.
We’ve previously written on the blog about the data for AZD9291 and CO-1686 presented at ASCO, but the CSS also featured an informative discussion by Larry Schwartz, MD, Professor of Radiology at Columbia University Medical Center which raised questions about how we should evaluate new lung cancer drugs.
In a presentation entitled, “Getting the Right Drug to the Right Patient Faster,” Schwartz who is a diagnostic radiologist, discussed and critiqued abstract 8012 by Dr Gideon Michael Blumenthal and colleagues at the U.S. Food and Drug Administration (FDA).
A meta-analysis of fifteen trials involving 12,534 patients (median N = 698) from nine experimental agents (tyrosine kinase inhibitor = 5, chemotherapy = 2, monoclonal antibody = 2) submitted to the FDA for treatment of metastatic non-small cell lung cancer (NSCLC) cancer in initial or supplemental New Drug or Biologics License Applications since 2003 was performed by Blumenthal and colleagues.
Their analysis showed a strong correlation (R² of 0.89) between overall response rate (ORR) and progression-free-survival (PFS) but only a weak or no correlation between ORR and overall survival (OS) (R² of 0.07) or between PFS and OS (R² of 0.09).
Dr Blumenthal noted in his conclusion that further work is ongoing to corroborate these findings given the lack of correlation between OS and ORR could have been due to high cross-over, under-power and long post-progression survival.
He went on to note that what the findings do show is that “a drug with a large effect on ORR is likely to have a large effect on PFS, conversely a drug with a small ORR may have a small effect on PFS.”
The debate around objective response and outcomes is a very interesting one, as is the drive to find better biomarkers of response to improve chances of clinical trial success.
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Our ASCO 2014 conference coverage continues with more gems from the poster sessions; it’s where we believe you find the promising gems that offer hints of future promise (or not) as the case maybe.
Sometimes a failure with one agent can help another company design a more optimal trial for their own new product in development, thus moving the field on. Other times, a surprising result can emerge that teaches us something new about the science and increasing our body of knowledge about pathways or biomarkers.
The other thing to understand about phase I trials is that they are generally conducted in the salvage situation where patients are refractory to most current treatments. The disease burden is high and the patients much sicker than when they were newly diagnosed. What companies are looking for is to characterise the side effect and PK profiles while looking for possible hints of where the agent might be efficacious. Given that most cancer therapies are given in combination, it’s very rare to see a home run in phase I, especially in solid tumours.
Here are a triplet of interesting posters from small companies looking at moving the needle in solid tumours with early phase I studies:
Companies mentioned: Nucana, OncoMed, Celldex
Agents mentioned: Acelarin, OMP–59R5, varlilumab
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Post ASCO 2014, many journalists and commentators have hotly declared the third-generation EGFR inhibitor CO-1686 from Clovis Oncology to be a “loser.”
AstraZeneca have a competitor compound AZD9291 also in early stage development. We’ve been keenly following both compounds on the blog over the past year.
While the Clovis share price has dropped, we are certainly not declaring Clovis CO-1686 to be a loser at ASCO 2014, nor are we declaring AZD9291 to be winner – with no median survival data mature yet, it’s far too soon to call it either way.
For this piece, we interviewed Dr Pasi Jänne (DFCI) who presented the AZD9291 data at ASCO and Dr Lecia Sequist (MGH) who presented the CO-1686 data. We also gained perspectives from Dr Ross Camidge (Univ of Colorado), who has participated in both trials.
You can login to read why I think CO-1686 was not a loser at ASCO 2014.