- NVS and PFE both announced unexpected eye toxicity in their HSP90 inhibitors in 2h2010. AUY922 (NVS) exhibited 89% ocular toxicity in the MTD cohort. This is caused by the drugs inducing apoptosis in a specific cell layer of the retina known as the outer nuclear layer (Slide 13)
- Slide 19: HSP90 inhibitors target the chaperone protein rather than a specific oncoprotein. This means we need to ask 2 separate questions: 1) How addicted is tumor to oncoprotein? 2) How addicted to HSP90 is the oncoprotein?
- Highly addicted client protein require the constant presence of HSP90- believe these situations are driving single agent ganetespib activity seen to date (ie, inhibition of HSP90 leads to instability of oncoprotein and increased cell death). Combination of HSP90 inhibitor with other agents results in sensitization of the cells to these agents- this is rationale for combo trial with docetaxel (Slide 23)
- When they took the poll as to the best path forward, the most votes went to pursuing single agent and combo paths to registration in parallel (but they didn't really announce the detailed results on the webcast- were displayed on screen at the event..)
- SNTA has talked to large pharma individuals- some of these folks have said that the data and promise of ganetespib warrant proceeding directly into large phase 3 program. However, due to the size of SNTA, a derisked strategy of the p2b/p3 trial design is being employed
- Slide 33- four chemotherapy regimens for NSCLC, all give indistinguishable results
- Goal in NSCLC is to deliver a HR of 0.80 or so
- At this point, the histological subtype determines which first-line therapy the NSCLC pt gets
- Slide 64- shows the progress made in RR and survival since 1975, but also that there is such a long way to go in this field
- Slide 83 - conclusions from second speaker. "There is no blockbuster targeted drug for adenocarcinoma" instead, there can be blockbuster drugs for small % subsets of NSCLC pts
- Ganetespib diarrhea side effect- the pts that had grade 3 AE were largely those who did not pre-treated with medicine such as immodium to optimally manage this side effect. If well managed, generally is grade 1 diarrhea for only 24 hrs or so
- SNTA is "well underway" in characterizing the correlation between clinical activity and specific pt genetic profiles
- Slide 92 mentions some of these mutations such as ALK-EML4 (ganetespib and other HSP90 inhibitors), Her2-neu, PDGRFA-alpha (unique for GIST), BRAF (melanoma, lung, gastric cancers)
- Safety profile of phase 2 trial very similar to what was seen in phase 1
- Longest pt on therapy in NSCLC trial so far is 14 months
- 4th speaker- covered rationale for combining gantespib with docetaxel
- Docetaaxel has been approved in NSCLC for over 10 years, is now approved for first-line in combination with Pt-based therapies, is equally effective for all histological subtypes
- In refractory disease, docetaxel, pematrexib, and erlotinib produce similar results (Slide 107): response rate <10%, median PFS of 3 months, median survival of 6-8 months
- Slide 109- in several trials, lower HSP90 levels have been correlated with increased survival
- Docetaxel dose-limiting toxicity is bone marrow-related, so not overlapping with ganetespib, important for combination therapy
- Taxanes such as docetaxel induce mitotic arrest and apoptosis- cells induce AKT pathway to inhibit apoptosis- this is an HSP90 client protein, so inhibition of HSP90 in combination helps the anti-cancer activity of taxanes
- A phase 1 trial of 17-AAG with paclitaxel was completed- was well tolerated but not enough efficacy to move forward- ganetespib is more potent so hope would perform better- this trial was done by the same investigator who is leading current gan-doc combo trial
- Phase 1 ongoing of gantespib (150 mg/m2) plus docetaxel (75 mg/m2) combo, 13 pts so far, 7 still on study, expanding at the 150/75 dose level (Slide 119)
- Have seen activity in combo trial in a variety of tumors including NSCLC, majority of pts have seen some benefit
- Slide 121 shows p2b trial design for NSCLC
- Most competing HSP90 inhibitors are analogs of 17-AAG (including the Infinity compound). Ganetespib is based on a pharmacophore, designed for max inhibition of target with minimal toxicity
- Now that several competitors have failed (and even another one Motesanib from AMGN and Takeda since the presentation- see link), first panelist (Langer) thinks should take the time to maximize therapeutic window of sta-9090 and find out where it can be applied
- Patients are much more willing now to enroll in clinical trials requiring biopsy than used to be (see success of targeted therapies requiring genetic profiling)
- Ganetespib as single agent is closer to phase 3 than the combo (I didn't think much of this as the comment was made, but since the phase 3 portion of the docetaxel combo could start 1h2012, that means SNTA is confident they have/will identify a subpopulation with superior efficacy and could start a trial shortly)
- Moderators did not orally discuss the "after" poll on the preferred path forward of the attendees
- Question- why not 200 mg dose in combo? Answer: 150 gives basically the same efficacy, only used 200 dose in single agent trials due to PK variability
- Q: note importance of a comprehensive genetic profile at start of trial before randomization- or else imbalance in some unknown genotype could seriously confound results
- SNTA mentioned that they are looking at another set of biomarkers associated with response to ganetespib that are not genetic mutations- but not wiling to discuss these yet
- Partnering interest and form may depend on the elucidation of genotypes that the drug works best for (makes sense, this would determine the market size and time to approval)
- Pharma companies are very interested in the potential to develop combination therapies for cancer from within their own pipelines- this is reflected in partnering discussions
- The use of docetaxel in 2nd line NSCLC is actually increasing- this is because first line is moving away from docetaxel, so when pts fail the newer drugs (such as pem), they are more often going onto docetaxel
- Docetaxel will shortly go off patent, which is bad for SNY, but good for SNTA in developing the combo
- The expert panel does not foresee the approval of a new single agent therapy in the next 1-2 years. Several phase 3 trials on single agents in 2nd line vs docetaxel have failed recently
SNTA hosted a webcast to discuss non-small cell lung cancer (NSCLC) treatments and landscape generally and in regards to their HSP90 inhibitor ganetespib (aka STA-9090) specifically. Click here for the link to the very informative and highly recommended webcast as well as slides from each of the presenters. I'll copy my notes from the talks below- I don't intend to summarize everything that was said, just items of notes in my opinion. I'll make reference to particular slide #'s in the PDF file (126 slides of information total!)
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