As the sun rose last Saturday morning in Orlando, I wondered what this year’s ASCO meeting would bring, especially after a very interesting and stimulating AACR recently, where lots of new pathways and novel inhibitors appeared to be emerging.
No, I never did make it to the pool, as the conference was far too busy but some lobsters were spotted beside it on the last day, the red British variety, that is.
Anyway, I was hopeful that some of the TKI’s, now in the clinic, might herald a new
area for targeted therapies. You can tell a lot from phase I and II
data – what the potential side effects might be and whether the
compounds may evolve as a viable single agent or combination therapy,
for example. In addition, ASCO had made a big splash with their pre-meeting press briefings, so it would be interesting to see if the final data presented at the meeting would hold up.
Over the next few days I’m going write a series of blogs summarising positive and negative data by pathway. These are based on my observations and also from talking informally to experts in the fields at the convention center. Today’s topic is PI3 kinase inhibition, which also includes mTORC1, AKT and MEK inhibition. It is particularly interesting because a third mTOR inhibitor, Afinitor (Novartis) has recently been approved, this time in renal cancer. The mTOR class evolved from the approval of rapamycin, a drug developed by Roche for immunosuppression in transplants. It seems to have found a home for the new generation versions in oncology though.
This pathway (PI3K through to the downstream mTOR) has recently garnered much attention because sanofi-aventis and Exelixis signed a licensing deal for not one, but two inhibitors, XL147 and XL765. Exelixis released a stirring press release prior to Monday mTOR/PI3K session announcing, “Exelixis Reports Encouraging Phase 1 Data To Be Presented at ASCO for XL765, a Dual Inhibitor of PI3K and mTOR” and similarly for XL147. During the ASCO meeting, AstraZeneca and Merck also announced an unusual joint collaboration to develop their compounds in this area, a MEK and an AKT inhibitor, the background to how the deal emerged is reported in the InVivo blog.
So what did the data actually amount to, you may well be asking?
Without going into too much detail, I’ve linked the actual abstracts with each of the compounds, but here is a topline summary of the 4 abstracts presented in the PI3K/mTORC1 session on Monday, ignoring the extravagant press releases and carefully written abstracts:
Company Responses
XL147 Exelixis/sanofi-aventis 1 PR, 1 PSA response in AIPC, 16/43 still on study
GDC-0941 Genentech None, 1 reduction in CA125
XL765 Exelixis/sanofi-aventis None
MK-2206 Merck None
While walking out of the freezing cold auditorium, I don’t think I have ever been more flat or disappointed after all the hype and excitement prior to a session. “Encouraging”, my foot; if that is the best companies can do, there isn’t much hope for the future. Certainly, if I were sanofi-aventis and had purchased 2 compounds in a billion dollar deal I would be expecting much more than that. Perhaps I am a little British here after getting used to the Gleevec phase I results that resulted in 31/31 patients responding and calling that ‘promising’ in a somewhat understated way.
One of the major challenges with this pathway, as shown in the graphic below, is that inhibition of one portion of the pathway may still lead to a feedback mechanism with insufficient inhibition of other areas of the pathway, ie inhibition of mTOR or PI3K still leaves MEK/ERK, RAS and Notch exposed, for example, as well as the potential for loss of PTEN expression:
Source: Nature Biotechnology doi:10.1038/nbt0706-794
This particular area is, however, rich with compounds in the clinic, including four mTOR inhibitors, sirolimus, temsirolimus, everolimus and ridaforolimus (formerly deforolimus). It is likely that these agents may well work better in combination with a RTK inhibitor of EGFR, IGFR or VEGF as opposed to simply blocking mTORC1, judging by the new clinical trials popping up in combination on Clinicaltrials.gov.
There are a number of other PI3K inhibitors being tested in phase I trials, in addition to those mentioned above. They include PX-866 (Oncothyreon), CAL-101 (Calistoga) and SF1126 (Semafore). Merck’s MK-2206 is probably the leading AKT inhibitor at the moment, but there are others in phase I and II development including perifosine (Keryx) and PBI-05204/Oleandrin (Ozelle Pharmaceuticals), a pan inhibitor of Akt, FGF-2, NF-Kb, and p70S6K.
C-MET inhibition is also another possible pathway in this family. Two leading compounds with data at this meeting included Arqule with ARQ 197 in combination with erlotinib for NSCLC and Pfizer’s PF-02341066, where a couple of responses have been observed in sarcoma and NSCLC.
The other subclass is serine/threonine inhibition, lead by Lilly’s enzastaurin, which is being tested in combination with other therapies in glioblastoma and NSCLC with mixed results.
All in all, my sense is that while the mTOR class has had some initial success in renal cancer, their future development will depend upon working in combination with RTKI’s in other cancers and the PI3K-AKT-MET-MEK inhibitors still have aways to go. Ultimately, reducing drug resistance will mean blocking multiple pathways or targets downstream of the RTK, but the leading question is still which ones will be important, nay, critical targets cuasing aberrant activity and which are just simply overexpressed as part of
the changes induced by the tumour.
The jury is still out on that one.
Workman, P., Clarke, P., Guillard, S., & Raynaud, F. (2006). Drugging the PI3 kinome Nature Biotechnology, 24 (7), 794-796 DOI: 10.1038/nbt0706-794
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