Drugs to watch at ASCO 2012

Below is a list of drugs and companies which will have meaningful data at this year’s annual meeting of American Society of Clinical Oncology (ASCO). As I will be attending this year’s conference, I will try to write updates on a regular basis. Feel free to send me questions or post them as comments to this post.

 

PD1 antibodies – the next big thing in oncology

BMS’ (BMY) anti-PD1 antibody BMS-936558 is expected to steal the show with results across three indications (melanoma, lung and renal cancer). The abstracts report an objective response rate of 22% in melanoma, 18% in NSCLC (non-small cell lung cancer) and 25% in renal cancer. BMS-936558’s safety profile looks very good compared to Yervoy, which has a similar mode of action of promoting an immune response against cancer (as opposed to attacking cancer directly).

This type of response rate is impressive for any single agent drug in late stage patients, and even more so when it comes to immunotherapy drugs. Today it is clear that looking at response rate does not provide the full picture when it comes to immunotherapies, which tend to have a slow onset and long term effect compared to conventional drugs. For the sake of comparison, Yervoy, an immunotherapy which was the first drug to show an overall survival benefit in melanoma, has a response rate of only ~10% in melanoma. In addition, it appears that one of the doses is more effective (28% response rate in lung cancer) and this dose will probably be chosen for further studies.

At ASCO, investigators are expected to present updated results which are likely to be better due to longer follow up. It will be interesting to see whether responses are durable, an important hallmark of immunotherapies. Yervoy, for example, can lead to a remission of years in some patients. If BMS-936558 shows a ”Yervoy-like” response durability in deadly indications such as lung cancer and melanoma, this could be a major breakthrough.

Lastly, there might be biomarkers for patient selection, which could shorten the route to market and enhance likelihood of success in pivotal trials. In earlier trials, there were indications that certain markers on tumors correlated to clinical benefit but this will have to be corroborated at the data set at ASCO.

BMS is leading the field of PD-1 antibodies, but there are several competing programs at various stages. These include an anti-PD-1 antibody from Merck (MRK), which will also have data at ASCO. Other competing programs include PD-1 inhibitors from Curetech/Teva (TEVA) and GSK (GSK) as well as antibodies against PD-1 ligand (PD-L1) from BMS itself and Genentech.

I discussed PD-1 and why it is such a promising target in an earlier post.   

MEK inhibitors – AstraZeneca, Array, GSK and Novartis

For almost a decade MEK inhibitors have been regarded as an unfulfilled promise. Despite their wide therapeutic potential, MEK inhibitors could not generate a real clinical signal with a clear route to market. While BRAF inhibitors, which inhibit the same pathway, generated spectacular responses (which turned out to be short lived) in melanoma patients, MEK had only a modest effect as single agents.  2012 looks like the turning point for MEK as a target with encouraging results for 3 different inhibitors.

AstraZeneca’s (AZN) selumetinib, which was licensed from Array Biopharma (ARRY), generated excellent results in a phase II in NSCLC patients with KRAS mutations. When given in combination with Taxotere, selumetinib had a dramatic increase in response rate (37% vs. 0%) and PFS (5.3 vs. 2.1 months), both were statistically significant. There was also a trend in overall survival (9.4 vs. 5.2 months) that was not statistically significant, not surprising given the small sample size of 87 patients. This is the first and most robust clinical proof of concept for a MEK inhibitor and AstraZeneca is expected to start phase III in the near future.

Earlier this year, AstrzZeneca reported positive data with selumetinib from a single arm trial in heavily pre-treated ovarian cancer patients. The results compared favorably to historical data with approved agents.

GSK is presenting phase III results for its MEK inhibitor, trametinib, compared to chemotherapy in BRAF mutated melanoma. Although the company already announced the drug improved PFS, the magnitude of effect remains to be seen. Results will automatically be compared to those of Zelboraf, which also demonstrated an improvement over chemo in a similar patient population.

Another interesting trial is a phase I/II trial combining trametinib (MEK) and GSK’s BRAF inhibitor, dabrafenib. The combination led to a PFS of 7.4 months, slightly better than what Zelboraf achieved in its phase II (6.2 months). In patients who received the optimal doses of both drugs, PFS was 10.8 months, but the sample size was small. GSK recently advanced this combination to phase III, implying that updated results from the phase II portion are compelling.

Novartis (NVS) will present data for its MEK162, which it licensed from Array. In a phase II study in melanoma, the drug demonstrated some efficacy in patients with NRAS mutation (3 responses in 13 evaluable patients). These patients are not candidates for BRAF inhibitors, and can therefore serve as an attractive route to market.

Antibody drug conjugates –Roche, Immunogen, Seattle Genetics Sanofi, Celldex and Pfizer

Antibody drug conjugates (ADC) are another hot segment in oncology. The two most successful ADCs to date are Roche’s T-DM1, which is based on Immunogen’s (IMGN) technology, and Seattle Genetics’ (SGEN) Adcetris. At ASCO, investors will focus on T-DM1’s phase III data in breast cancer and Seattle Genetics’ efforts to expand Adcetris’ label. Although there will be data for additional ADC programs, next year’s conference should see a flood of data sets from ADCs that got to the clinic in the past 18 months.

T-DM1 (Roche/Immunogen)

Roche will present preliminary results from a phase III (EMILIA trial) where T-DM1 is compared to standard of care in 2nd line Her2+ breast cancer patients. The trial was successful in showing an improvement in PFS (progression free survival). Investors are expected focus on the extent of benefit as well as a potential trend for overall survival.

This will be the first ever phase III data set for an ADC (earlier ADCs such as Adcetris and Mylotarg were approved with phase II data), and should lead to an approval next year. Patients and physicians alike will be very receptive to T-DM1 for 2nd line patients as the currently approved alternative (Xeloda+Tykerb) is considered minimally effective and too toxic. In fact, even if T-DM1 had a comparable PFS to Xeloda+Tykerb, it would have become the gold standard due to safety and pricing issues.

EMILIA  is viewed as an appetizer to another phase III trial, in which T-DM1 is given to 1st line patients (MARIANNE study). In that therapeutic setting, the bar for efficacy is much higher and competition is expected to be stronger. The main competitor is another HER2-targeting from Roche, pertuzumab, which is expected to get approval based on excellent phase III results. Therefore, in the 1st line setting, T-DM1’s performance will be indirectly weighed against that of pertuzumab. Interestingly, the MARIANNE trial includes a combination arm for T-DM1+pertuzumab, which could become the new standard of care if proven effective. 

Adcetris (Seattle Genetics/Takeda)

After establishing Adcetris as an important treatment option for late stage hodgkin’s lymphoma (HL), Seattle Genetics is trying to broaden the drug’s use using several approaches. The first strategy is getting Adcetris approved in 1st line HL as well as re-treatment of late-stage patients. Other trials look at additional blood cancers, where Adcetris’ target (CD30) is known to be expressed. Lastly, the company initiated a “screen and treat” study where patients with a variety of cancers (except lymphoma) are screened for CD30 expression.

At ASCO, investigators will present data from the 3 initiatives:

In the re-treatment trial the abstract reports an impressive response rate of 65% and a duration of response of 11 months, which is encouraging given that these patients had already been treated with Adcetris. In the additional blood cancer trials (excluding HL), there are already signs of activity in CD30+ NHL patients. This complements the impressive activity the company reported earlier this year in 2 subtypes of NHL.  In the “non-lymphoma” trial, the abstract reports presence of CD30 across a wide range of tumors including ovarian and breast cancer, but with low incidence.

Additional ADCs  

Sanofi (SNY) is expected to present data on SAR3419, its anti-CD19 ADC based on Immunogen’s technology. Although phase I data for this program have already been reported, Sanofi decided to use an amended regimen with an improved safety profile in phase II. Results with this regimen will be presented at ASCO for the first time and according to the abstracts, the safety profile looks compelling with clear signs of efficacy in NHL. SAR3419 looks less potent than other CD19 therapies such as Micromet’s (now part of Amgen) blinatumomab or CD19-targeted T cells (referred to as chimeric-antigen receptor or CAR).

Celldex (CLDX) was hoping to present the long-anticipated phase II data for CDX-011 at ASCO, but a “clerical” error prevented them from getting accepted. As a result, the company already published the results, which were overall positive with several caveats. The trial was unique as it compared CDX-011 to “physician’s choice” (patients in the control arm could receive a drug based on their physician’s decision). In other words, CDX-011 was rigorously compared to an active drug , not to placebo.

The results were positive because CDX-011 had comparable activity in the overall patient population and appeared more effective in two prospectively defined subgroups (tumors with high GPNMB expression and tumors that are negative to ER, PR and HER2, aka triple negative). It is important to note that the subset analysis is reliable as it was pre-defined before seeing the data, making it more reliable. The main issue with the results is the low number of evaluable patients in each subgroup (33 patients).

Pfizer (PFE) will present results for its anti-CD22 ADC in acute lymphocytic leukemia (ALL). The abstract discloses a 40% complete response rate in advanced stage patients, which is impressive but pales in comparison to Micromet’s (now part of Amgen) blinatumomab. The latter will have updated results in ALL, with a reported response rate of 68% and encouraging overall survival.

MET inhibitors – Arqule, Amgen and Exelixis

MET continues to be a very hot target in oncology. The two leading selective MET inhibitors, Daiichi-Sankyo/Arqule’s (ARQL) tivantanib and Roche’s Metmab are in phase III in lung cancer based on positive phase II studies. Exelixis’ (EXEL) cabozantinib, which is a dual MET/VEGFR inhibitor, is in phase III in prostate cancer.

At this year’s meeting, Arqule will report phase II results for tivantinib in 2nd line liver cancer. The drug led to a negligible PFS improvement in the entire patient population, however, the effect was more profound in patients whose tumors had high MET expression. In these patients, tivantinib led to a statistically significant benefit (2.4 vs. 1.5 months). These results are somewhat disappointing and the decision to go for phase III in 2nd line patients will probably depend on an overall survival signal, which will be presented at the conference.  

Amgen is presenting data in gastric cancer for its anti-HGF antibody, rilotumumab, in combination with chemotherapy in gastric cancer (HGF is the ligand that activates MET). This program had been terminated by Amgen last year, but was recently re-activated based on a subset analysis in the trial. Although the drug had no effect in the intend-to-treat population, there was a near doubling of survival in patients with high MET expression.     

Exelixis will have multiple presentations for cabo, including phase III data in medullary thyroid cancer (MTC) and phase II data in prostate cancer and renal cancer. Investors’ main focus will be the effect on bone metastases, which appears to be a unique feature of the drug.

Cabo continues to demonstrate the bone effect across several indications, primarily in prostate cancer, where 60% of patients experienced a bone scan response. Resolution in bone scans was observed in breast cancer and lung cancer as well.

The drug continues to demonstrate more “traditional” anti-cancer effect on soft tissue solid tumors. Promising activity has been observed across the different studies, including a large PFS benefit in the medullary phase III trial (11.2 vs. 4.0 months) and impressive activity in heavily pretreated renal  and prostate cancer patients.

ALK/ROS1 inhibitors  – Pfizer, Novartis and Roche

Pfizer’s Xalkori is the only approved ALK inhibitor in the market. It is currently approved for patients with ALK mutated lung cancer, but data at ASCO could lead to label expansions. The most important data set is in lung cancer patients with mutated ROS1, another target inhibited by Xalkori. An abstract reports impressive clinical activity, similar to the one observed in ALK-mutated patients. Of 13 patients, 7 (54%) experienced objective responses, which appear durable. Another trial in various childhood cancers that are ALK-driven, Xalkori induced multiple responses.

I discussed ROS1 as a new indication for Xalkori in an earlier post.   

Other companies will report initial data with their ALK inhibitors. Both Novartis and Chugai (Roche) will report phase I results with their ALK inhibitors, both appear active in ALK-mutated patients. Interestingly, the abstract for Novartis’ drug mentions responses in Xalkori pre-treated patients.

 

Immunokinase inhibitors – Pharmacyclics, Celgene and Gilead

Pharmacyclics (PCYC) will present data for its ibrutinib, its Btk inhibitor in  elderly patients with CLL (chronic lymphocytic leukemia). The drug continues to demonstrate unprecedented activity with a 73% response rate and an excellent safety profile. Combination trials with approved agents also demonstrated robust efficacy.

Celgene (CELG) will present data for its own Btk inhibitor in CLL and NHL. The abstract includes very preliminary data, making it hard to interpret given the fact that Btk inhibitors take several months to reach full effect.

Gilead (GILD) will present combination data for its PI3K-delta inhibitor,GS-1101, which recently entered phase III in CLL. Initial data from a combination study with Arzerra demonstrated promising activity. Of note, Gilead is evaluating the combination in its phase III study in CLL.

In my previous post there is a full list of immunokinase drugs and licensing deals and acquisitions.

 

 

31 thoughts on “Drugs to watch at ASCO 2012

  1. I enjoyed reading your blog since your first article at a time when everyone was selling in 2008. I enjoyed your unbiased analysis. What biotechs are you long in your portfolio?

  2. Hi Ohad,
    Is PGNX with its current PPS undervalued in your opinion?
    Thanks
    Chris

  3. Hey Ohad
    Thanks for this great overview of ASCO 2012! Could you elaborate on CDX-011 results and the potential of GPNMP as a target beyond TNBC and BC. Also, I have seen information saying that CLDX may plan to also use the naked antibody (cdx-011) to inhibit the same target… what do you think the possibility and use of that may be compared to the ADC?

    Also, will PARP inhibitors be resuscitated (as alternative target for TNBC)?

    Finally, what do you think EXEL’s valuation should be, the stock seems to languishing in the $4.50 region…. what are investors waiting for? What’s your take?
    Thanks for your great coverage and insight!
    Seba

  4. hello Ohad,

    re CLDX another question: they have not disclosed response rates in patients with greater than 50% GPNMB. to be consistent, I guess we should see an at least as strong effect as in the 25% GPNMB patients – but we do not know.

    do you have any idea why they have not been disclosed?

  5. Sam – I particularly like Synta and Array at current levels.

    Chris – don’t have a smart answer to that. Results continue to be positive, here it’s a matter of execution and marketing.

    Seba – We know GPNMB is present in other indications but I haven’t seen any clinical results except the melanoma study which showed an effect. I don’t know about using the naked antibody, will probably be substantially less potent.

    Christian – I don’t know why this wasn’t disclosed, perhaps the numbers are too small and results are not conclusive.

    Ohad

    Re EXEL – I think the current price reflects a lot of skepticism. the current price barely represents the MTC approval and the out-licensed programs.

    Personally I believe PARP inhibitors should have a role, at least in BRCA mutated tumors. Beyond that it’s a matter of finding the right combination (one potential partner is Chk1 inhibitors)

  6. Hi Ohad, I first time read your article earlier this year “Biotechstocks to watch in 2012”, and i really liked it. I put 5-6 stocks ( ARRY, PCYC, CLDX, SGEN and INCY) out of all these PCYC is doing great, from your recent articles i understand that you do not have a long position in this stock, do you think this stock is over priced and is a “stay away” item? it moved from $19.80 to $32.20,

    i will appreciate your feedback.
    regards

  7. PCYC has a fantastic drug that is going to revolutionize hematology similarly to what Rituxan did in my opinion. Still, as the co is starting phase III studies there are not a lot of catalysts in the near future and expectations are quite high.

    Ohad

  8. Hello Ohad
    I have a question regarding the recent cdx-011 trial… it seems that TNBC is a target for CDX-011 – looking at the results and sub-groups CLDX’s trial identified patients with high expression of GPNMB and TNBC as two different sub-groups (out of a total 4) with the highest response rate. This to me is puzzling: it seems there is a gap in understanding of TNBC and why this kind of disease (whether expressing low or high GPNMB) is so responsive to cdx-011 (targeted to GPNMB expression).
    What do you think?
    Thanks
    Rick

  9. The term TNBC (triple negative breast cancer) characterizes tumors that lack estrogen, progesterone and her2 receptors. Looking at this group as a population for targeted therapy based onth sole criterion of not expressing the three receptors above is very tricky imo. This is why it is hard for me to give a lot of weight to this analysis.

    Ohad

  10. Hi Ohad,

    Re $SGEN – what do you make of the move towards treating cTCL. Surely if successful this has a big impact on potential ADCETRIS sales.

    Their Q1 call reported several incidences of off label use and there’s a ph3 just been initiated.

    Any thoughts?
    James

  11. Actually, CTCL is not concidered a huge opportunity as there are a lot of treatment lines for this relatively indolent disease. PTCL and DLBCL could be a different story.

    Ohad

  12. hey Ohad
    what do you think of the recent regulatory developments with the FDA and the use of other endpoint for accelerated approval of drugs (one of which is pathological complete response)?

    https://www.federalregister.gov/articles/2012/05/30/2012-12928/draft-guidance-for-industry-on-pathologic-complete-response-in-neoadjuvant-treatment-of-high-risk

    And what may this mean to the companies you follow that are involved in breast cancer drug development or oncology in general?
    Thanks!
    Thanks

  13. Ohad,

    Just checking in old friend.

    Hope all is well.

    Obviously w/ Bio/pharma plays in CLDX,EXEL,ALTH,GNBT,NVS,BMY,MRK,PFE,Dx(RGDX),SNTA and VICL, Im all ears on your reports.I suppose between PD-1 and ADCs you will be quite busy!

    CLDX w/ its ADC asset in 011 is front and center, and the glitch to properly apply for ASCO was a shame.That being said, they have released results and your SA piece covered the details well.I suspect Marrucci and Davis and Kelor are at ASCO for potential pharma meetings. If you come accross any such meetings or what appears to be meetings please inform us? Also they will present on GBM drug Rindo an abtract of the ReACT trial, probably more of an Attention getter looking for enrolees but if you come across it could you comment?

    Thanx in advance!

    Frank

  14. Ohad,

    One more thing, please.

    RGDX a Dx play is at ASCO again this year in the Cancer Dx space where Targeted Lung Assay is their niche play. Debbie Astow,PhD is the newly hired Science officer and I look forward to some feedback from their posters(attached below)if you have time?

    http://www.nasdaq.com/article/response-genetics-announces-presentation-of-lung-cancer-study-results-at-2012-american-society-of-clinical-oncology-annual-meeting-20120530-00459

    so 4 different ASCO presentations in very specific gene expressions, whats the significance?

    As you know both Pemetrexed and Crizotinib have carved out unique cancer niches and the test for them although NOT unique is RGDX provided by this small Dx company w/ sales revenues which I own and follow….

    Thanx in advance!

    Frank

  15. Ohad,

    Could you comment on ARRL’s results in HCC.

    Is it possible to compare EXEL’s drug to ARQL’s?

    Do you think CLDX should attempt a trial in neo-adjuvant breast cancer, given Pazdur’s recent article on TNBC in NEJM?

    Any buzz yet about the ARRY MEK inhibitors from either AZN or NVS at ASCO?

    Thanks.

    RB

  16. Richard,

    ARQL- I thought that given the circumstances the data is as good as it could be. The OS benefit in met+ was impressive and the curves look very good. The only caveat is the small sample size.
    I m meeting management later today.

    Hard to compare Cabo and tivozanib , too many differences between trials and pt population. I thought cabo’s data was interesting as well.

    CLDX- haven’t read that paper yet.

    ARRY- just got out of a meeting with kevin koch head of R&D. Data in kras lung expected tomorrow. They have so much going on and will have a busy ASH meeting. The p38 pain program also looks good.

    Ohad

  17. Ohad,

    An oncologist friend of mine says that ARRY’s 614 looks very good in MDS, a growing market due to aging population. On the last ARRY CC, the CEO said that Dr. Holden was brought on board specifically to deal with regulatory issues surrounding 614. (Going to pivotals from Phase I?) If all this is true, then ARRY has two proprietary molecules to go with all the great stuff partnered with AZN, NVS and AMGN. It seems greatly undervalued. (Of course, it was up 7% on Friday, when the Market was tanking, so maybe people are starting to pay attention. Around 75% institutional ownership. Your thoughts?

  18. Richard – I don’t know the indication enough to assess the drug but it sure sounds like they are excited with 614.
    They need a compound in p3 and I assume they will have 2 next year (614 and selumetinib).

    Mike – I follow them but so far didn’t observe anything spectacular with their ErbB3 antibody or the bispecific one. The next gen irinotecan doesn’t look that exciting either.
    It is importabnt to make the distinction between MACK which targets tumors directly and MITI which harnesses the immune system against cancer.

    Ohad
    Ohad

  19. What do you think of the ONXX data and what is your opinion of the vote on the 20th??

    Thanks

  20. I think data as single agent in double refractory patients is mediocre. I don’t think carfilzomib will be approved based on the single arm trial but eventually i believe it will be approved bassed on a p3 trial.

    Ohad

  21. Nice call on SNTA and ARRY before ASCO. Any opinion on the strength of the ARRY data released after the market close on Monday (6/4/2012)? Thanks for your insight.

  22. Hi Ohad.
    ARRY is down today despite of the good news. Do you think expectations were higher?
    Thanks Chris

  23. I attended both presentations for selumetinib in the lung cancer session and MEK162 in the melanoma session and thought the data was very good. Both drugs should move to p3 imo.

    Ohad

  24. Hi Ohad, thanks for all the ASCO update, good call on SNTA new 52w high

    Imgn was the biggest buzzzzzzz coming out from ASCO, all over the news, headlines everywhere. Do you still think PPS is too high?

    Did you see anything new worthy your list (i.e Are you going to update you virtual portfolio in coming weeks)

    thanks

  25. IMGN – I think the price fully represents T-DM1’s royalty stream in the metastatic setting. We need another clinical candidate with an efficacy signal to push the stock higher, that could happen next year.

    Will try to post an update soon.

    Ohad

  26. Dan,

    Yes I attended the Synta cocktail party, there were indeed quite a few folks from different groups. Didn’t see Adam Feuerstein, though.

    Ohad

  27. Mr. Hammer,

    Can you gives us you thoughts on the anti PD-1 data. Thank you.

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