Synta- The Signal Looks Real

So what does the market really think about Synta’s (SNTA) lung cancer data?  2 weeks ago, the stock lost 33% in 1 trading session following interim results from the phase II trial for the company’s lead agent, ganetespib. Since then, Synta regained most of the fall, as the market digested the data with the help of supporting analysts from Jefferies and Roth Capital.

Looking at the clinical results, it is easy to understand the market’s bi-polar reaction. One the one hand, there are multiple promising efficacy signals and a good safety profile. On the other, the data set was less mature than what investors had expected.

The GALAXY trial design

 Synta evaluated ganetespib in combination with chemotherapy (docetaxel) for 2nd line NSCLC (non-small cell lung cancer).  The trial is a large (240 patients) randomized phase II study designed as a “signal searching” trial for identifying specific patient populations that are more responsive to the drug. The trial is big enough to detect a signal even in a subset of 20% based on progression-free survival (PFS). Based on the signal in the phase II portion, Synta plans to take ganetespib to phase III in the relevant patient populations.


Originally, there were 2 subsets in which ganetespib had already shown an efficacy signal: ALK mutants and KRAS mutants. As the drug is already being studies in dedicated trials for ALK mutated tumors, the GALAXY  trial focused on other subsets, primarily KRAS mutants (based on early clinical experience) and high LDH (based on preclinical evidence and scientific rationale).

Initial signs of activity

At the interim analysis, the database included 183 patients, with an efficacy signal across three subsets:

1.       Adenocarcinoma subtype (114 patients, 62% of overall population)

2.       Adenocarcinoma subtype with high LDH (31 patients, 17% of overall population)

3.       Adenocarcinoma subtype KRAS mutants (20 patients, 11% of overall population)

In the adeno subset, ganetespib generated a signal in PFS and overall survival. Patients who received chemo+ganetespib had a median PFS of 4.2 months vs. 2.9 months in the control arm. Response rate was also higher in the ganetespib arm (15% vs. 8%). The most striking signal was in the preliminary overall survival analysis, which showed a clear separation between the two arms, which started from day 100. This analysis should be treated with cautious given the low number of events but the trend looks very promising. 


In the high LDH and KRAS mutant subsets, adding  ganetespib led to an impressive signal in progression-free survival (PFS). LDH-high and KRAS mutant patients in the control arm had a median PFS of 1.4 and 1.6 months respectively. Patients in these subsets who received chemo+ganetespib had a PFS of 4.2 months, representing a 3 and 2.6-fold increase, respectively. Responses were also more common in the combination arm for both subsets.


Are the signals real?

Subset analysis relies on several factors including sample size, numerical difference, prospective definition of subset and type of endpoint. The 3 different subset analyses presented by Synta look compelling although they vary in terms of data maturity and reliability.

The adeno subset included a large sample size (114 patients, half of whom experienced progression) but the PFS difference was modest and was not pre-defined as a co-primary endpoint. The overall survival signal in adeno patients is early but the separation of the curves looks very promising.

 The extent of PFS difference in the adeno group (1.3 months, 45% improvement) might not look impressive at first glance. However, PFS often under-represents the survival benefit of targeted agents like ganetespib. Two examples in lung cancer are Tarceva and Avastin, both of which are approved based a survival advantage. Avastin led to 1.7 month (38%) improvement in PFS with Tarceva adding only 0.4 months (25% improvement).

The LDH and KRAS subsets were small but the magnitude of PFS was impressive (2.5-3 fold increase) and they were prospectively defined. One encouraging sign is the fact that effect size was maintained as the data matured during the past 3 months, according to Synta’s CEO. Although the KRAS subset is the smallest, it is the only one relying on a molecular characteristic of the tumor with a clear rationale and clinical activity for ganetespib in an earlier trial as monotherapy.     

No statistical measures were provided by the company, due to the early stage of the data set. Nevertheless, Synta’s decision to proceed to phase III implies that there are at least statistical trends.

Synta vs. Array

In KRAS mutated lung cancer, the most relevant comparator for ganetespib  is AstraZeneca’s (AZN)selumetinib, which I wrote about in my ASCO 2012 summary. Originally licensed from Array Biopharma (ARRY), selumetinib was also added to docetaxel for NSCLC patients with KRAS mutants.

An indirect comparison between the two agents shows a similar PFS benefit over docetaxel, with a ~2.5-fold improvement. Response rate for selumetinib appears higher, but it is unclear whether responses were defined in the same way (confirmed vs. unconfirmed).


Selumetinib’s data set is larger and more mature, automatically making it more reliable.  The difference in PFS and response rate were also statistically significant with selumetinib, whereas there was simply not enough data to evaluate statistical significance for ganetespib. Lastly, the selumetinib trial was a double blind study in contrast to the ganetespib trial, where physicians knew which patients were receiving the drug or placebo. This could have created an investigator bias in evaluating PFS and response rate. Needless to say, updated results for ganetespib could change this comparison to either direction.

Both drugs are expected to enter phase III in KRAS mutants later this year. Since they have distinct modes of action, they could be synergistic in combination. It is unlikely that evaluating the two drugs in combination will occur before they reach the market, as they are running neck and neck towards approval. The only company with an Hsp90 inhibitor and a MEK inhibitor in clinical testing is Novartis.


The PFS benefit across the 3 different subsets looks reliable thanks to the large sample size for the adeno subgroup and the fact that KRAS and LDH sub-analysis was prospectively defined by the company. The biggest surprise was the preliminary survival trend in the adeno group, which represent a large commercial opportunity ($1.5B in the US alone). Even if only one of the smaller subgroup analysis is corroborated by larger studies (LDH or KRAS), ganetespib is still looking at a $0.5B opportunity, excluding the ALK opportunity.

Still, one cannot help wondering if Synta should have waited 2-3 more months to provide the investment community with the complete picture. The next update is expected at the ESMO meeting (starts Sep 28th), which is expected to include more patients and longer follow up.

Portfolio updates

We are initiating a position in Genmab (GEN.CO) following positive data with its CD38 antibody, daratumumab (discussed here). We are also selling our Onyx (ONXX) position at a profit of 84%, as high chances of accelerated approval for carfilzomib are already factored in.




60 thoughts on “Synta- The Signal Looks Real

  1. Good post on Synta and Array but suggest you missed a few things:

    a) For Array you made no comment on the fact that the OS curves crossed (and possibly the PFS as well) in what was probably a clinically meaningful way. Given that they do not appear to have collected further subgrouping data this may make it challenging to define a high reliability ph iii. And, in addition, if the cross-over is severe enough it may make the path to regulatory approval more difficult.

    b) Minor point: The adeno group is almost the same as the NOT-squamous group and the company did prespecify squamous as one of the subgroups. (Since even before the June 28 announcement I have treated the NOT groups as part of the pre-specification – see posts on iHub.)

    All that said, and FWIW, I think your post was the best I’ve seen on Synta to date – and just generally well thought out. (e.g. you made the first comment I’ve seen on the tendency of kinase actors to exaggerate effect between PFS and OS – the opposite of what traditional chemo does.)

  2. Clark,

    First, thank you for the kind words.

    a) Imo the signal they have is very robust, there is a limit to what we can get with such a sample size. The OS curves crossed once at a later stage and did not affect medians, could be resolved with longer follow up (or not). All their patients were KRAS mutants, what other subgroups should they look into?

    b)They obviously looked at histology and accounted for that in the randomization process but from what I understand, it was not part of the pre-defined co-primary endpoints.

    Wrt to PFS/OS effect, this is certainly a characteristic of many targeted therapies although that in cases where there is a clear molecular driver (Gleevec for Bcr-Abl, Xalkori for ALK fusion) a PFS difference is also very robust.


  3. ARRY – Have you actually seen the curves? I looked on the ARRY site and didn’t find them – and I would be interested.

    As for the robustness – I do not mean to argue that they shouldn’t take it forward. But given that kinase inhibiting drugs often (always?) actually accelerate disease in some patients I would suggest that the crossover is likely not an artifact. And thus their path to approval will be more difficult and risky than kinase inhibitors with well understood target populations (well understood wrt kinome profile) – e.g. MetMab.

    As for what subgroups they should look at – I haven’t done much research on MEK inhibitors per se. But so far as I know every Wow! result in a kinase inhibitor (and I include even the old ones for which we now know the correct population) was found to be related to either a mutation in the target or high levels of the target protein (in this case MEK). Has this already been checked in some previous trial? – and note that I wouldn’t count checking MEK Gene Copy Number as the same as checking protein levels. (If MEK doesn’t pan out I’d check ERK protein levels (downstream))

  4. “every Wow! result in a kinase inhibitor (and I include even the old ones for which we now know the correct population) was found to be related to either a mutation in the target or high levels of the target protein (in this case MEK).”

    That is not true. I don’t think you can generalize kinase inhibitors like that. It depends on the pathways. MEK inhibitors had showed really good results in BRAF and/or NRAS melanoma, so it shouldn’t be surprising MEK inhibitor would work in KRAS mutant NSCLC.

  5. —>>MEK inhibitors had showed really good results in BRAF and/or NRAS melanoma, so it shouldn’t be surprising MEK inhibitor would work in KRAS mutant NSCLC<<—

    First, I would agree that:

    1) they are showing results. And so have such drugs as Gefitinib and Sorefinib. But I wouldn’t call them great results… and that was my point. OS HR=0.8 is fairly anemic and the cross-over suggest that there is a wild card in there. Array needs to hope they can control the wild card in the ph iii.

    2) filtering for mKRAS patients might help get the right patient population (I haven’t looked at the pre-clinical data – but I don’t see any reason why this shouldn’t work). I am not disputing this – only suggesting it appears not to be enough by itself.

    3) I even agree that it might not be as simple as just checking the levels of the target protein or target mutation status – but I was asked where I might check (my bad for answering – apparently -g-).

    HOWEVER I am also pointing out that:

    A) Three of the four really knock-your-socks-off kinase inhibitor OS HRs (i.e. OS HRs under 0.4) for solid tumors in randomized trials have been in patients with a kinome profile that exactly matches their MOA (Zelboraf, a mBRAF inhibitor, in BRAF-V600E patients; Crizotinib, an ALK inhibitor, in ALK+ patients; and MetMab, a Met inhibitor, in Met+ tumors). (the only knock-your-socks-off results in solid tumor without kinome profiling appear to be XL184 for MTC – it would be interesting to know the kinome profile for MTC.)

    B) Surprisingly there is very little reliable human data on most other kinase inhibitors – for instance, Gefitinib shows some hints of the same extra benefit in a randomized trial limited to EGFR mutations (PFS HR<0.4) but the OS HR was completely contaminated by virtually complete cross-over to Gefitinib.

    Given both #A and #B you can see why I suggested that actually looking at the kinome profile around the inhibitor seems like a good place to start. Certainly I know of no data for a kinase inhibitor where it was shown that no aspect of the local kinome profile (i.e. mutations in target kinase gene, levels of target kinase) didn’t predict efficacy in a meaningful way in humans. Instead no one seems to actually look (in human results).

  6. Clark

    Yes I have seen the curves if you want send me an email.

    The only case I am aware of in which kinase inhibitors accelerate disease is BRAF inhibitors. I haven’t seen any evidence pointing to that with MEK inhibitors.

    Array’s MEK inhibitor (developed by AZN) was evaluated in a genetically defined population – KRAS mutants. The biologic rationale is clear if you look at the signaling of KRAS. MEK mutation are very rare in cancer.


  7. —>>The only case I am aware of in which kinase inhibitors accelerate disease is BRAF inhibitors. I haven’t seen any evidence pointing to that with MEK inhibitors.<<—-

    See MetMab ph ii for the cleanest data – but it is dead certain that it is also true in Gefitinib (Gefitinib HR is close to 1.0 overall in nsclc, but in some sizable kinase profile subgroups (certain mutations and probably EGFR high protein levels) the HR is under 0.4. Therefore it is accelerating disease in others. You can also see it in the Gefitinib ITT KM curves for OS. And so on – the only kinase treatments on the market for which I cannot find such evidence is Nexavar and Sutent – perhaps because the effect doesn’t exist (or more likely IMO because no one really looks.).

    As for evidence of that with MEK inhibitors – see ARRY curves (speaking of which – thanks for volunteering to send me the curves. I’ll send you an email.). Not incontrovertible (small sample, possible confounders, …) but still evidence, even if in need of confirmation.

  8. Ohad – thanks for curves, and agree that the crossing is less dramatic than I had thought from the description, and thus not proof of accelerating the tumor in some patients. But mote that, FWIW, neither is the curve a disproof since not all it’s-accelerating-some-tumors subgroups can be seen in the ITT curves – e.g. for MetMab the drug was definitively (OS HR~3.0) hurting about 1/2 the patients, but it wasn’t seen on the ITT curves since they never crossed.

    So, I’d still make the wager that in 10 years it will be found that the MEK inhibitor is, in fact, accelerating the tumor in some patients in a clinically meaningful fashion. But I certainly can’t claim victory on that predict right now.

  9. Last post – I found a definitive study on Gefitinib proving it accelerates disease in some patients while helping others dramatically. See:

    Results: in the 59% of asian patients with EGFR mutation the PFS HR was 0.48 (p<0.001) while in wt EGFR the PFS HR was 2.85 (p<0.001). OS results were substantially more muted but still showing clinically relevant acceleration in wt albeit with fairly small event count (more muted response in OS perhaps due to cross over – cross over was a HUGE problem in the similar Maemondo trial)?

    That said, there is a weird amount of noise in all of these results since other randomized trial data I’ve seen (Maemondo) had stronger results in mEGFR – my guess being because of different ‘assay’ since that can make a substantive difference. But it could be other factors as well (e.g. ethnicity, prior treatments)

  10. hi Ohad,

    CD19 is well known to you. What do you think about MOR208 (MorphoSys/Xencor)?



  11. Hello Ohad,

    also a question to Morphosys. Do you see a great disadvantage for the anti-CD38 antibody of Morphosys because they are behind Genmab in the clinical trials?

    Thanks for your great blog.


  12. I believe morphosys is well positioned with both programs although no data were released. This is based on medimmune’s cd19 and genmab’s cd38 programs.

    The cd19 market is very crowded but in cd38, the 3 clinical stage programs are in phase 1. I think morphosys’ antibody had good cross reactivity with primates which allowed them to start from a high dose so they shouldnt be that far behind.

    Again, assuming mor’s antibodies show comparable efficacy, which is still unknown…


  13. Ohad,

    What do you make of SNTA’s offering today? Think they are buying time until more data is available and therefore can strike a better deal with a partner? Looks like a positive to me as all the stock is being bought by insiders.

    Thanks, as always.


  14. I also view it as a positive, however, data is expected later this year already good results and a partnered drug. I guess since snta has an unpartnered drug that management appears to be worth more than the market is value the drug…would you start a position in thld or in snta if you were to only choose one? I wonder when a hedgefund would take a large position in snta.

  15. What is your take on Exel and arry’s move? Also what do u think about CLdx, can it follow SGEN and imgn? Also thinking about immu, it seems the market likes these adc companies. Thanx as always

  16. Sam – I would choose Synta, although I am long both. THLD will probably present OS data towards year end so the potential is definitely there (they didn’t have a lot of crossovers)

    Robert –
    Re EXEL and ARRY, hard to interpret their move.
    CLDX – I am waiting to hear their p3 plans. I wonder if they should try to do a single arm p2 in high GPNMB pts to get accelerated approval.
    IMMU- their ADC technology is old an ineffective imo.


  17. Hi Ohad,
    Do you think PGNX at its current pps is a buying opportunity?

  18. The news on Exel is pleasing, looks like Cabo is being taken seriously…added more today….r u adding or pausing for potential secondary?

  19. Will be nice to have FDA approval already this year although this is more symbolic. We plan to stay with the current positions.


  20. Hello Ohad,
    What’s your opinion on ARRY -797 pain data? The stock lost $1 after hours. Any thoughts?
    Thanks as always,

  21. The efficacy data was quite positive, with comparable efficacy and much better tolerability.
    Don’t know how to interpret the QTc signal. Opioids have nasty side effects but QTc signal is something that makes everyone very nervous.


  22. Per OxfordJournal: Consequently, values of QT greater than 500 ms should cause concern…per Arry 797 No subject in either trial exhibited an absolute QTc interval >500 msec or a change from baseline >60 msec

  23. Not an expert on this but 2 obvious questions would be what happens if you dose patients for longer than 28 days and/or what happens in larger patient populations.


  24. The AP crushed the arry comeback rally, sold some today will wait for base to form…bought some Thld on the dip

  25. Looking at getting into INCY, it looks like the sales projection may be inflated now that they are changing their reporting from sales to pharmacys to actual sale of drug. What are your thoughts.

  26. chris – I follow CLVS. They have an interesting pipeline but the pancreatic cancer program from Clavis is very risky imo. I like their PARP program.

    jh – Still didn’t have a chance to delve into this.


  27. Ohad is Exel attractive at this price or do u think the company pulled a fast one and just pissed a lot of people off so let’s wait?

  28. Hi Ohad, got some large chunk of cash on a real state deal. Any new entry you can suggest….as always thanks…..all your entries worked very well….only one still lagging is ymi

  29. Robert – Personally I bought more shares earlier this week, i don’t want to recommend a specific stock to a specific individual as everyone should make their own decisions.

    Roy – Again, it’s hard to bet on a single name, that’s why i publish the whole portfolio.


  30. Roy I have to believe there will be somewhat of an Exel run up prior to priority review in nov. u could play this angle…and I believe CLdx is due for a partner for CLdx- 011….. This could pop it up nicely…or pgnx bounce if it’s oversold

  31. Hi Ohad, yesterday I bought some BMY. Because of the non-essential (in my opinion) HEP-C program the share price has fallen. The PD-1 antibody this year begins the PIII trials. Thank you for your eye-opening contribution to this project! What is your opinion about BMY? Thank you.

  32. Hallo Ohad,

    beside Morphosys there’s another interesting Biotech in Germany: Evotec. They have multiple partnerships and are adding more and more because they invest heavily in new technologies every year. They are profitabel. In my opinion they closed excellent contracts with relativ high milestone payments for compounds in early stage of development. Do you have an opinion?


  33. Ohad do u have any opinion of the higher rate of death in the control arm vs. placebo arm for xl184 in the MTC study….is stating that this is just a vegf thing enough to appease…does this compare to similar death rates in other vegf drugs? Thanks for your time

  34. Ohad,

    Did you have a chance to listen to or read ARRY’s CC yesterday? Seemed like a lot of positives and a lot of potential. What’s your take?



  35. Hello Ohad! Your observations and selections in the biotech field have been VERY impressive! I have been investing in Biotehnology Companies since 1995.I am interested in your insights in a company with the symbol of IMUC…traded on the NASD. It appears that they have made some important University collaborations,and are presently in control of some valuable tehnology assets.Your comments are greatly appreciated!

  36. Hello Ohad! Your observations and selections in the biotech field have been VERY impressive! I have been investing in Biotechnology Companies since 1995.I am interested in your insights in a company with the symbol of IMUC…traded on the NASD. It appears that they have made some important University collaborations,and are presently in control of some valuable technology assets.Your comments are greatly appreciated!

  37. Robert – There’s definitely increased rate of mortality vs. placebo. This is observed with other VEGF inhibitors but cabo’s numbers look slightly higher than historical data.
    This is a risk going into the FDA’s decision but I believe the drug will be approved eventually.

    Bouschka3 – I know the company but not intimately familiar with them.


  38. Hi Ohad,
    CRIS has been down about 30% since July. Is it a good entry point in your opinion or does the current PPS already reflect its value?
    Thanks as always

  39. Hi Ohad,

    Do you think there are chances of lead trial of arql failing towards this yr end coz they haven’t checked for met levels?


  40. Chris – We plan on holding on to our position in CRIS. They have a solid cash position, approaching EU approval and sales are building up.

    Mike – That’s always an option although the assumption is that they’ll have enough met positive pts in the adeno subgroup. ARQL could have an issue going forward if Metmab demonstrates a better effect using a biomarker defined population. btw, Roche probably saw a signal in met+ gastric cancer in their p2 since they are about to start a p3 in met+ gastric cancer.


  41. Great article on SNTA.
    This stock has risen an extra 50% (!!) since this article was published, particularly because of the good phase 2 results. Gotta love the pharma stocks.

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