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Posts from the ‘Pathways’ category

This week I have been in Orlando for the American Association for Cancer Research (AACR) Special Conference on prostate cancer chaired by Drs Arul Chinnaiyan (U. of Michigan) and Charles Sawyers (MSKCC).  It was a superb meeting, probably one of the best I’ve attended since the PI3K meeting that AACR hosted in February last year.  I wrote nearly half a Moleskine of notes that vaguely resemble chicken scratch – there were so many good talks that stimulated new ideas and explained a few scientific things I also didn’t know too well.  Learning is a continuous lifetime experience, after all.

During the meeting, I had a nice correspondence with one of our regular blog readers, the thoughtful Biomaven.  Peter mentioned some data on the androgen receptor (AR) as a potential target in breast cancer following Medivation’s recent conference call.  It’s an interesting topic and one well worth discussing.  Here’s a map of the AR pathway for reference:

Source: wikipedia

The AR is not something one naturally and immediately thinks of in women, since testosterone is usually considered a manly thing.  That said, it is present in women in both normal breast epithelial cells and ~70% to 90% of invasive breast cancers.

Until recently, the link, however between AR status and breast cancer survival is uncertain and perhaps a little controversial, but Hu et al., (2011) looked at the association between the AR status and breast cancer survival in the Nurses’ Health Study (NHS) – see references at the end for the link to the article.

What was the study about?

According to the authors:

“The NHS is a prospective cohort study established in 1976 when 121,700 female registered nurses from across the United States, aged 30 to 55 years, completed a mailed questionnaire on factors that influence women’s health.

Follow-up questionnaires have since been sent out every 2 years to the NHS participants to update exposure information and ascertain nonfatal incident diseases. Follow- up rate from 1976 to December 2007 is 98.9% in our study.”

Not to be confused with an population/epidemiology study from the NHS (National Health Service) in the UK!  The main goal of this study was to:

“… determine the association of AR status with survival outcomes adjusting for covariates.”

What did the research find?

Out of all the breast cancers followed (n=1467), 78.7% were AR+. Additionally, amongst the ER+ patients (n=1,164), 88% were AR+:

“AR positivity was associated with a significant reduction in breast cancer mortality (HR, 0.68; 95% CI, 0.47–0.99) and overall mortality (HR, 0.70; 95% CI, 0.53–0.91) after adjustment for covariates.”

The situation was very different in women who were ER- (n=303) though:

“42.9% were AR-. There was a nonsignificant association between AR status and breast cancer death (HR, 1.59; 95% CI, 0.94–2.68).”

In other words, AR+ confers a better prognosis in ER+ breast cancer.

Now, the relevance of all this research is potentially important when considering possible mechanisms of resistance to aromatase inhibitor (AI) therapy in ER+ breast cancer.  Recall that one mechanism of resistance to AI treatment is mTOR, which is why the BOLERO2 trial with an AI (exemestane) plus an mTOR (everolimus) in the relapsed setting did so well in ER+ women.  Not all of the women in the trial responded to the treatment though, suggesting that other factors may play a role in acquired or adaptive resistance.

What is the importance of AR to therapies for breast cancer?

Normally, knowing whether a particular situation has a better or worse outcome isn’t particularly helpful for patients, since it doesn’t predict which therapy might be more appropriate. However, there is some other AR and breast cancer research from Cochrane et al., (2011) which was presented to the Endocrine Society Peter referred to that tells us a bit more of the AR story:

“We postulate that ER+ breast cancers that fail to respond or become resistant to current endocrine therapies (tamoxifen or AI) may do so because they have switched from growth controlled by estradiol (E2) and ER to growth controlled by liganded AR.

We therefore sought to determine if blocking AR activity could serve as a therapeutic intervention for such tumors.”

What did they do?

Cochrane et al, (2011) stated that:

“We used breast cancer cells that express ER and AR such as MCF7 cells and a cell line that we recently isolated that contains more AR than ER.

Our data indicate that although DHT does slightly inhibit E2-mediated proliferation, DHT alone is proliferative in cells such as MCF7 with both ER and AR, and is even more proliferative than E2 when AR is more abundant than ER.”

What did the results show?

The results were a) interesting and b) a little surprising:

“We found that while both the anti-androgen bicalutamide and the triple acting, non-steroidal, AR antagonist MDV3100 block DHT and R1881-mediated proliferation of breast cancer cells, we made the novel observation that MDV3100, but not bicalutamide, inhibits E2-mediated proliferation of breast cancer cells.”

These results led the authors to conclude that:

“Anti-androgens, such as MDV3100, may be particularly useful to treat patients whose tumors fail to respond to traditional endocrine therapy despite being ER+, or who have ER-/AR+ tumors.”

Not surprisingly, Medivation announced on their recent conference call this month that they will be seeking to explore this phenomenon in clinical trials.  I think this is a logical and exciting development that is well worth a shot on goal.  We know that not all the women in the BOLERO2 trial responded to exemestane and everolimus, so other mechanisms must be at play here.  This is certainly worth exploring.

The question with the study design of me for me though, is patient selection.  How do we determine which women whose initial AI therapy leads to relapse should go onto an mTORor an AR antagonist?  I’m guessing that maybe biopsies will be part of the answer.

In conclusion…

On the positive side, it would be pretty cool if we could uncover two mechanisms of resistance to AI therapy in ER+ breast cancer and have some viable therapies to offer women once relapse or acquired resistance sets in.  It would start to offer a) hope and b) potentially prolong outcomes further as we determine ways to shut down the various escape routes and signaling pathways.  If the concept works, given that up to 30% of women with ER+ breast cancer may have AR+ signaling, then it would also be good news for Medivation and Astellas with MDV3100’s potential upside.

References:

ResearchBlogging.orgHu, R., Dawood, S., Holmes, M., Collins, L., Schnitt, S., Cole, K., Marotti, J., Hankinson, S., Colditz, G., & Tamimi, R. (2011). Androgen Receptor Expression and Breast Cancer Survival in Postmenopausal Women Clinical Cancer Research, 17 (7), 1867-1874 DOI: 10.1158/1078-0432.CCR-10-2021

4 Comments

Many readers will have noticed that the advanced prostate cancer market is rapidly becoming crowded with three new therapies (cabazitaxel, sipuleucel-T and abiraterone) already approved and several more in late stage development, including Alpharadin (radium-223) and MDV3100, both likely to file this year. In addition, others are focused on bone complications, such as denosumab, which is expected to have a tough ODAC meeting this month, and cabozantinib, a multikinase inhibitor currently in phase III trials.

Unlike breast cancer, where progression-free survival (PFS) is a used as a surrogate measure of survival, in advanced prostate cancer, overall survival (OS) has pretty much become the gold standard by which prostate cancer trials are reviewed. This makes it much easier to judge whether the drugs are having a positive effect on true efficacy, i.e. do patients live longer as a result of treatment.  PFS is particularly difficult to measure in prostate cancer, so it’s not surprising this approach has evolved as the standard measurement.

Interestingly though, Health Authority approval does not always mean reimbursement coverage, as NICE showed yesterday in declining to approve abiraterone in the UK on the grounds that it is too expensive. The BBC quoted a patient who had been on abiraterone for only three months, with a positive impact:

“I have my life back. I have a lot more energy and no pain. My quality of life is excellent. I wouldn’t even know I have cancer now, it’s that good.”

The BBC also quoted his wife, who had an excellent point:

“We know NICE has to take a lot of things into consideration, but when you have a terminal illness an extra four months is very precious.”

Source: BBC

Of course, it’s very much a case of balancing available resources with potential benefits and unfortunately, advanced stage patients will inevitably take the lion’s share in terms of budget for disease management. Post EMA approval, some local UK health providers permitted the drug to be used on an individual basis, raising the old contentious issue of the rather unfair post code lottery (zip code for Americans).

Going forward, no doubt there will be much political posturing and pressure, as you can see from Cancer Research UK, who helped fund the research, but hopefully a deal can still be struck between NICE and Janssen, the manufacturer, on price to enable British men broader access to the drug.

One of the things that has struck me lately, though, is how prostate cancer is attracting serious research focus, such that a heterogeneous disease is slowly being more segmented based on the underlying biology of the tumour. Examples include Arul Chinnaiyan’s superb work on the TMPRSS2-ERG fusion gene and Charles Sawyers’ work on the Androgen Receptor.

Thanks to Sawyers work we now know that the old terminolgy ‘androgen independent’ prostate cancer is an incorrect way of descibing advanced disease because as Clegg et al., (2012) described Scher et al’s original research findings in 2005:

“Despite administration of androgen-depleting therapies, continued androgen receptor (AR) signaling is a common feature of CRPC, attributed to AR gene-amplification, AR gene mutation, increased AR expression or increased androgen biosynthesis in prostate tumors.”

In other words, the AR is very much an oncogenic driver of the tumour’s survival.

This week, we saw promising data for MDV3100, an AR antagonist in the post chemotherapy setting but what of the pipeline beyond abiraterone and MDV3100?

Previously, we came across Aragon’s ARN-509 AR antagonist, which is much further behind in phase I/II clinical trials. Sawyers and Michael Jung, the co-inventors of MDV3100 while at UCLA also developed (along with several other scientists) additional AR compounds, the most promising of which became ARN-509. Aragon is a privately held company formed out of the UCLA discovery with the intent of developing and commercialising this compound.

The obvious question arises – is it a ‘me-too’ or potentially better than MDV3100?

Preclinical data has just been published in Cancer Research by Clegg et al., (2012) addressing this issue. They argued that, based on their findings:

“In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100.”

Of course, preclinical data doesn’t always translate to the clinical setting, but my first reaction was ‘Whoa!’

Let’s take a look at the agent in more detail.  ARN-509, like MDV3100, is a pure antagonist of the androgen receptor, unlike bicalutamide (Casodex), which has both agonist and antagonist properties.  The idea behind this is that there will be less resistance and greater therapeutic potential for more comprehensive binding with the receptor.

We know from work in Sawyers lab that MDV3100 targets splice variants, which have been shown to cause resistance in CRPC, but we don’t yet know how ARN-509 will fare on that front.

So why did Clegg et al., (2012) suggest that ARN-509 might be superior to MDV3100?

“Maximal therapeutic response in this model was achieved at 30 mg/kg/day of ARN-509, whereas the same response required 100 mg/kg/day of MDV3100 and higher steady-state plasma concentrations.

Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists.”

In other words, it’s much more potent and has a greater therapeutic index; these things are important clinically. It also has a longer half-life:

“ARN-509 exhibits low systemic clearance, high oral bioavailability and long plasma half-life in both mouse and dog, supporting once-daily oral dosing.”

Androgen deprivation therapies are more commonly used in castrate-sensitive disease, so this begs the question of whether there is anti-androgenic activity in the non-castrate setting:

“At higher doses of 30 mg/kg/day, robust tumor-regression (>50% reduction in starting tumor volume) was observed in 6/8 ARN-509-treated animals, similar to regressions observed in mice castrated on the day treatment initiated.”

The promising results led the researchers to conclude that:

“ARN-509 is a next generation anti-androgen selected for pre-clinical and clinical development based on its efficacy and pharmacodynamic profile in mouse xenograft models of CRPC.”

They also stated that:

“Unexpectedly, given a similar in vitro profile, ARN-509 is more efficacious per unit dose- and per unit steady-state plasma-level in mouse models of CRPC than MDV3100.”

In other words, ARN-509 is a next generation AR antagonist with a good efficacy and PK profile in mouse xenograft models of CRPC.  It’s clinical development, although further behind abiraterone and MDV3100, will be well worth watching over the next few years.

In summary…

While there has been a lot of activity in the advanced prostate cancer market lately with new approvals making a difference to the lives of men with prostate cancer, there are also several other promising near term agents in development, as well as some potentially more potent and effective treatments in early clinical development.  What we have seen to date is merely the beginning of new advances in R&D.

The early and advanced prostate cancer markets are likely to see some significant changes over the next 24 months, as new products based on rational drug design and an improved understanding of the biology of the disease make it to market.

More on prostate cancer coming soon!

All this new data is very timely, considering on Monday I’m off to the AACR Special Conference on Prostate Cancer, jointly chaired by Drs Chinnaiyan and Sawyers.  I’ll be interested to learn what new events are emerging as biological targets and what factors can help us predict response to treatment.  If you’re going to this meeting do stop and say hello, it’s always good to meet new people in the field.

References:

ResearchBlogging.orgClegg, N., Wongvipat, J., Tran, C., Ouk, S., Dilhas, A., Joseph, J., Chen, Y., Grillot, K., Bischoff, E., Cai, L., Aparicio, A., Dorow, S., Arora, V., Shao, G., Qian, J., Zhao, H., Yang, G., Cao, C., Sensintaffar, J., Wasielewska, T., Herbert, M., Bonnefous, C., Darimont, B., Scher, H., Smith-Jones, P., Klang, M., Smith, N., de Stanchina, E., Wu, N., Ouerfelli, O., Rix, P., Heyman, R., Jung, M., Sawyers, C., & Hager, J. (2012). ARN-509: a novel anti-androgen for prostate cancer treatment. Cancer Research DOI: 10.1158/0008-5472.CAN-11-3948

Scher, H. (2005). Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis Journal of Clinical Oncology, 23 (32), 8253-8261 DOI: 10.1200/JCO.2005.03.4777

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This weekend heralds the annual American Society of Clinical Oncology (ASCO) Genitourinary (GU) meeting in San Francisco, although ASCO held their press briefing today to provide an update on some of the key topics.

For those of you interested in Alpharadin (radium-225) in castrate-resistant prostate cancer (CRPC), check out the update of Dr Oliver Sartor’s presentation, which is covered on Biotech Strategy Blog.

The key topic that most interested me though, was Dr Howard Scher’s update on Medivation’s Androgen Receptor antagonist, MDV3100, in CRPC.  Previously, Medivation announced that the data showed an improvement in median overall survival (OS) of 4.8 months and this is still solid (Note: J&J’s abiraterone was approved by the FDA based on an OS of 3.9 months in the same population and must be taken with prednisone).

Three new things were important in this presentation though:

  1. There has been some previous concern about the risk of seizures, after they were reported in an earlier trial, but that was at much higher doses.  In this study, the now standard (and much lower) 160 mg dose of MDV3100, demonstrated low levels of seizures (0.6%), which is very reassuring and not something I think many will worry too much about.
  2. MDV3100 has a nice effect not only on OS, but also median time to confirmed PSA Progression, i.e. 8.3 months vs. 3.0 months for placebo (HR 0.248, P<0.0001). Yes, I had to do a double take at that HR – it’s quite phenomenal!
  3. Aside from PSA drops, patients often like to know if their tumour is shrinking or not as evidence of activity and progress. Dr Scher showed the soft tissue response by CT/MRI imaging. There was a 28.9% response rate with MDV3100 compared with 3.8% for placebo (P<0.0001).

From this data we can definitely say that patients lived longer, saw a positive impact on their PSA levels, and felt better compared to placebo. In terms of serious adverse events, there were fewer in the MDV3100 arm (28.4%) versus the placebo arm (33.6%). There were also slightly more discontinuations in the placebo (7.0%) than MDV3100 (3.8%) cohort.

Overall, I wasn’t at all surprised when the host, Dr Nicholas Vogelzang (Medical Director of the Developmental Therapeutics Committee of US Oncology) exuberantly said he had only one comment to Dr Scher’s presentation of the MDV3100 data,

“Wow, that’s very impressive! It’s unprecedented.”

For once, I thought that ‘impressive’ was actually an understatement to apply to a cancer drug.

I also talked to Dr David Hung, CEO of Medivation afterwards. Many readers will remember my interview with Dr Charles Sawyers, the co-inventor of MDV3100, last year about the science behind the development. It was nice to see Medivation’s side of the R&D story, which has gone pretty rapidly so far.

PSB: Are you going to be filing soon based on this data?

David Hung: We are having a pre-NDA meeting with the FDA. Once we have that meeting we will be able to give much more concrete guidance on when we will be filing.

PSB: Some of the pre-chemo trials have started, would they be due to report some data soon?

David Hung: We haven’t given any timelines on any of our other trials.

PSB: When I interviewed with Charles Sawyers previously, he said that many pharma companies were not interested in what is now MDV3100. What did you see in it when many others said “no”?

David Hung: Charles didn’t approach me. I found him! I had read, with great interest, his work on the AR. I was very familiar with his Nature Medicine publication in 2004 showing that overexpression of the AR is a significant molecular change in patients with castration resistant disease. While I think a lot of people thought that targeting the AR would create just another AR antagonist, like casodex, the data suggested to me there was more here.

Because, in Charles’ lab by being able to over-express the AR, we were able to much more carefully assay and screen compounds for their ability to block androgen receptor signaling very thoroughly. And we found in the process that a number of compounds in the series that we were testing had ability to not only block just AR binding by testosterone, which is something that Casodex does, but unlike Casodex these compounds were able to inhibit nuclear translocation as well as DNA binding and activation by the AR.

I am an oncologist by training and was pretty familiar with this area, so when I saw the compounds and saw the data in more detail, I didn’t agree that it would just be another casodex like molecule. I thought the mechanisms suggested that this drug could be special, so when I went ahead and licensed the drug back in 2005. We then took the program forward rapidly through development. We had to do all the standard pharmacokinetics, metabolism, tox, formulation work, then take it into a clinical trial as quickly as we could, led by Howard Scher. So, we were able to develop the molecule very quickly.

One of the differences with MDV3100 over weaker AR antagonists such as bicalutamide, is it’s ability to target splice variants. This was a surprising but important finding. I asked Dr Hung about them:

PSB: Does that potentially mean that the patients in the current trial data presented by Dr Scher, may actually do better over time or is the 4.8 months OS probably going to be the final number?

David Hung: Well, I won’t know the answer to that until I unblind the PREVAIL trial. What is very interesting from our phase 1 / 2 data is that the time to PSA progression in post-chemo patients in that data set is about 203 days. Yet, the time to PSA progression in the pre-chemo patients was 4x longer than that, 812 days, suggesting that the drug may have even more robust activity upstream than it does downstream. Downstream it already has robust activity. We will be greatly looking forward to seeing the PREVAIL data, because that is the pre-chemo population. If we can recapitulate our phase 1 / 2 results, that would be great news for patients.

PSB: At AUA last year, I heard from Charles Sawyers that if you inhibit the androgen receptor, you often activate the PI3-Kinase pathway. His colleague Neil Rosen had also noticed that if you inhibit PI3K, you activate androgen receptor in prostate models. So Charles was saying in their joint paper that the logical thing to do would be to combine an androgen receptor inhibitor and a PI3K-inhibitor to potentially reduce the resistance and hopefully improve outcomes. Is that the kind of combination you might consider in the future?

David Hung: We actually are. You point out exactly the kind of things that we think about. We look to see how our drug works and we look to see what mechanisms might possibly complement our drug. That is the way we think about potential combination studies that we might do.

All this is very exciting news for both Medivation (and commercial partner Astellas), as well as patients with advanced prostate cancer. I hope that the discussions with the FDA go well and we will see a filing, perhaps even with Accelerated or Priority Review in the near future. Based on the data so far, the data clearly shows that MD3100 can make a difference to the lives of men with advanced prostate cancer.

Next week, I’ll be at the American Association for Cancer Research (AACR) Special Conference on Prostate Cancer, jointly chaired by Charles Sawyers (MSKCC) and Arul Chinnaiyan (Michigan) to learn more about the biology of prostate cancer. It promises to be both a timely and exciting meeting!

References:

ResearchBlogging.orgChen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, & Sawyers CL (2004). Molecular determinants of resistance to antiandrogen therapy. Nature medicine, 10 (1), 33-9 PMID: 14702632

Carver, B., Chapinski, C., Wongvipat, J., Hieronymus, H., Chen, Y., Chandarlapaty, S., Arora, V., Le, C., Koutcher, J., Scher, H., Scardino, P., Rosen, N., & Sawyers, C. (2011). Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer Cancer Cell, 19 (5), 575-586 DOI: 10.1016/j.ccr.2011.04.008

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Pancreatic cancer as many readers know, is one of those cancers that is generally diagnosed later than most in stage IV and as a result, has a poor prognosis, often only a year or so from diagnosis.

It has been known for a decade that constitutive Kras and NF-kB activation is one of the signature changes in the disease in the majority (80-95% ) of patients. Kras is a particularly important gene because it is often involved with on-off signaling of other genes. In addition, mutational inactivation of a key tumour suppressor gene (Ink4a/Arf) also occurs in over half (50-75%) of pancreatic adenocarcinomas. What is not known, however, is what are the key signaling pathways downstream of Kras and how they relate to pancreatic cancer.

Earlier this month though, Ling et al., (2012) published some new data in Cancer Cell advancing our knowledge in this area:

“Our findings reveal that KrasG12D-activated AP-1 induces IL-1a, which, in turn, activates NF-kB and its target genes IL-1a and p62, to initiate IL-1a/p62 feedforward loops for inducing and sustaining NF-kB activity.”

They also noted the impact of this process, namely:

“IL-1a overexpression correlates with Kras mutation, NF-kB activity, and poor survival in PDAC patients.”

In other words, dual feedforward loops of IL-1a (induced by AP-1) and p62 are responsible for the IKK2/b/NF-kB activation by KrasG12D.

The group also observed:

“Our results show that TSC1 and FOXO3a pathways are involved in Kras-induced PDAC.”

In other words, they promote tumorigenesis.

What does this data mean?

In practice, this research suggests that several approaches might be potentially useful:

  • Inhibiting mutated Kras (specifically KrasG12D) may be a viable therapeutic target in pancreatic cancer.
  • Since IL-1a overexpression correlates with poor survival in PDAC patients, pharmacologic targeting of IL-1a may also be a useful strategy to consider.

Kras mutations appear in a number of cancers, including pancreatic and colon cancers, where in the latter case, they have been shown to cause resistance to EGFR inhibitors.  To date, strategies to target Kras have been disappointing at best.  There are also a number of MEK and other inhibitors being evaluated in pancreatic and other cancers, but I’m not sure that targeting downstream of RAS will have any effect in these cases, if mutated RAS upstream is the main issue:

Source: ReactionBiology

MD Anderson summed up this data in pancreatic adenocarcinoma nicely in a succinct press release describing the feedforward loops as a ‘vicious circle’ i.e.:

“A self-perpetuating loop of molecular activity that fuels pancreatic cancer by promoting inflammation, development of new blood vessels and blocking programmed cell death.”

 

References:

ResearchBlogging.orgLing, J., Kang, Y., Zhao, R., Xia, Q., Lee, D., Chang, Z., Li, J., Peng, B., Fleming, J., Wang, H., Liu, J., Lemischka, I., Hung, M., & Chiao, P. (2012). KrasG12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma Cancer Cell, 21 (1), 105-120 DOI: 10.1016/j.ccr.2011.12.006

4 Comments

It’s been quite a roller coaster ride for Hedgehog inhibitors of late.

Infinity Pharmaceuticals Last week, brought negative data as Infinity announced that their phase II trial with saridegib (IPI-926) had been stopped for futility in pancreatic cancer.  This trial sought to determine the impact of the hedgehog in combination with gemcitabine over gemcitabine alone in advanced pancreatic cancer.  Unfortunately, the trial was stopped for futility, meaning the control arm was doing better than the treatment arm.

All is not lost for pancreatic patients though, as Roche/Genentech have a phase II trial currently recruiting patients with the triple combination of gemcitabine, nab-paclitaxel and vismodegib.  Previously, we have discussed the impact of Abraxane on removing the stromal layer in pancreatic cancer in animal models using nanotechnology to enable therapy to work and I think this may be a more promising approach in the long run.

In contrast, there was good news this morning as the FDA approved Roche/Genentech’s vismodegib, now known as Erivedge, in advanced basal cell carcinoma (BCC) who are not candidates for surgery or radiation and for patients with metastatic disease.

The original PDUFA date was scheduled for March 8th, so this is an early approval, but one that is not entirely unexpected given the promising results previously presented at medical conferences over the last 12-18 months.

The goal of the trial was to measure overall response rate (ORR).  In final analysis, the results showed that 30% of the metastatic patients experienced a partial response (PR), while 43% of patients with locally advanced disease experienced a complete (CR) or partial response.  These results represent a clear advance for patients with this disease and studies are also ongoing looking at new combinations to overcome resistance and hopefully, extend outcomes further.

For those of you interested in pricing, it looks as though Erivedge will be $7500/month so that would be estimated $75,000 for typical 10-month course of treatment (HT Ruth Coxeter, CNBC).

Links:

FDA Press Release

Genentech Press Release 

 

There’s been quite a flurry of commercial news on the Pharma front this morning, with Amgen buying Micromet (whose leading product is blinatumumab in ALL) and Celgene announcing their acquisition of Avila Therapeutics who have a Bruton Kinase Inhibitor (BTK) AVL-292 in phase IB development for lymphomas, which was all the rage at the recent American Society of Hematology (ASH) meeting last month.

The big news for me today, though, wasn’t the commercial acquisitions but a gem of a paper relating to science and its significance for future cancer treatment.

One of the unsolved scientific conundrums that arose in my interview with Dr Gordon Mills (MDACC) at the European Multidisciplinary Cancer Congress (EMCC) meeting in Stockholm last September centred around the RAS pathway, and the BRAFV600E mutation, in particular.

Dr Mills astutely noted that while vemurafenib (Zelboraf) has shown activity in patients with advanced melanoma with the BRAFV600E mutation, he raised the important question why did we not see similar activity in mutated colon cancer?  Of course, one obvious conclusion might be that the target isn’t critical to the tumour’s survival… or is it?  The challenge though, is that these patients do particularly poorly, and usually that is a sign that the mutation is actively driving aberrant activity. Therein lies the quandary, leaving many researchers such as Dr Mills puzzled at the discrepancy and asking why?

This week I’ve been doing a series on colorectal cancer and it is quite by coincidence that today we learn more about the science of colon cancer and BRAFV600E mutations since Pralahad et al., (2012) have just published a Letter in Nature explaining that their research actually suggests that resistance mechanisms might be one of the culprits:

“We performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition.”

This finding surprised me because melanoma typically has low levels of EGFR expression, unlike more epithelial cancers:

“We compared EGFR expression in a panel of BRAF(V600E) mutant melanoma, colon cancer and thyroid cancer cells. Melanoma cell lines indeed express low levels of EGFR.

So what actually happens in melanoma?

“Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition.”

Ah, our old friend, feedback loops!  These have an uncanny knack of popping up in advanced cancers, as the cancer attempts to ensure it’s survival and overcome the targeted therapy, causing adaptive resistance to treatment in their wake.

You may be wondering how common is this mutation in colon cancer then? Well, Pralahad et al., (2012) observed:

“Our data suggest that BRAF(V600E) mutant colon cancers (occur in) approximately 8–10% of all colon cancers.

Note: bracketed bold addition mine.

What does this data tell us?

In short, a combination of vemurafenib and an EGFR inhibitor, such as erlotinib, cetuximab or gefitinib, might be a useful clinical approach to try therapeutically in patients with colon cancer harbouring the BRAFV600E mutation.  Of course, Roche/Genentech have both vemurafenib and erlotinib (Tarceva) in their portfolio, so it would be interesting to see whether proof of clinical concept could be established quickly in a phase I clinical trial.  EGFR inhibitors tend to be rather quirky though, and it remains to be seen whether a small molecule (erlotinib, gefitinib, afatinib) or a monoclonal antibody (cetuximab, pantitumumab) would be the ideal partner for vemurafenib in this setting.

While there is much yet to be done in R&D to advance the scientific research, this important finding teaches us that there is hope for this subset with a generally poorer prognosis yet.

I look forward to following the future clinical progress to see if a viable new combination treatment emerges in BRAF V600E mutated colon cancer – watch this space!

References:

ResearchBlogging.orgPrahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R., Bardelli, A., & Bernards, R. (2012). Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR Nature DOI: 10.1038/nature10868

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During yesterday’s discussion with Dr Ray DuBois (MD Anderson Cancer Center) about inflammation and methylation, the topic of CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) came up as you can see from the brief audio clip below:

Steve Baylin’s paper sounded most interesting, so I tracked it down – see O’Hagan et al., (2011) in the References below for the direct link.

CIMP is interesting to look at because it can occur in some 30% of colorectal cancer cases and has been previously shown to be an independent predictor of survival with 5FU in early or adjuvant CRC (van Rijnsoever, 2003). It is, therefore, a potentially useful molecular marker in this disease.

In O’Hagan et al’s (2011) current research, they stated:

“We demonstrate that inducing cellular oxidative stress by hydrogen peroxide treatment recruits DNA methyltransferase 1 (DNMT1) to damaged chromatin.”

Essentially, a link between several proteins involved in transcriptional repression to the DNA damage response was observed. A key part of this damage response is reactive oxygen species (ROS), elevated levels of which were shown by Federico et al., (2007) to constitute a key risk state for increased cancer susceptibility. Raised levels of ROS tend to occur as a result of alterations in cellular metabolism and inflammatory responses.

The current research from O’Hagan et al., (2011) takes our understanding of this process further:

“One of the intriguing implications of our data is the potential role for increased levels of cellular ROS that accompany cancer risk states such as inflammation in the formation of cancer-specific aberrant patterns of DNA methylation and transcriptional silencing.”

What is useful from a practical standpoint, is that the current findings build on their existing model, which considers a promoter CpG island, double-strand break DNA damage concept:

“We hypothesize that such localization of the DNMT-PRC4 complex and increase in DNA methylation at low-expression promoter CpG island-containing genes might be more persistent over the course of chronic ROS damage during tumorigenesis, setting up a scenario for the expansion of DNA methylation in the CpG islands involved.”

In other words, Dr Baylin’s lab have shown that chronic inflammation over time may lead to DNA hypermethylation. If we then consider the work from Dr DuBois’s lab discussed yesterday (in Xia et al., 2012), the connection between inflammation, DNA methylation and early development of colorectal cancer starts to make a lot of sense.

Tomorrow, I’ll be looking at early colorectal cancer in more detail and discussing how the roles of BRAF, KRAS and PIK3CA mutations and CIMP may play a role in tumorigenesis in colorectal polyps. Do check back to follow the ongoing story.

 

References:

ResearchBlogging.orgO’Hagan, H., Wang, W., Sen, S., DeStefano Shields, C., Lee, S., Zhang, Y., Clements, E., Cai, Y., Van Neste, L., Easwaran, H., Casero, R., Sears, C., & Baylin, S. (2011). Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1, and Polycomb Members to Promoter CpG Islands Cancer Cell, 20 (5), 606-619 DOI: 10.1016/j.ccr.2011.09.012

Federico A, Morgillo F, Tuccillo C, Ciardiello F, & Loguercio C (2007). Chronic inflammation and oxidative stress in human carcinogenesis. International journal of cancer. Journal international du cancer, 121 (11), 2381-6 PMID: 17893868

Xia, D., Wang, D., Kim, S., Katoh, H., & DuBois, R. (2012). Prostaglandin E2 promotes intestinal tumor growth via DNA methylation Nature Medicine DOI: 10.1038/nm.2608

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Recently, epigenetics has been very much to the forefront with promising new human data in lung and breast cancers.

Nature Medicine

This morning I was therefore thrilled to see some exciting work just published in Nature Medicine Online First from Ray DuBois’s lab at MD Anderson Cancer Center, on the potential role of inflammation and silencing of tumour suppressor genes in early colorectal cancer. Previously, the group looked at the role of COX-2 in intestinal inflammation and colorectal cancer and observed that:

“A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet and lifestyle are the risk factors for CRC.”

Epigenetics is rapidly becoming a crucial and fascinating field of research. Dr DuBois kindly provided an easily understood explanation:

Epigenetics is defined as “the study of heritable changes in genome function that occur without a change in DNA sequence.”

One of the things that many people have trouble with is grasping the difference between mutations (genetic changes) and methylation (epigenetics). I loved Dr DuBois’s quote from Thomas Jenuwein, an epigenetics expert in Vienna:

“The difference between genetics and epigenetics can be compared to the difference between writing and reading a book.  Once a book is written the text (genes or DNA sequence) will be the same in all copies distributed to the audience.  However, each individual reader of a book may interpret the story slightly differently, with varying emotions and projections…

In a similar manner, epigenetics would allow different interpretations of a fixed template and result in different read-outs dependent on the variable conditions under which the template is interrogated.”

 

What did the current research show?

In a succinct article, Xia et al., (2012) clearly demonstrated that:

  1. PGE2 promotes intestinal adenoma growth by silencing certain tumor-suppressor and DNA-repair genes.
  2. This process took place through the induction of DNMT1 and DNMT3B specifically.

This research is, however, the first time the connection between inflammation and epigenetic changes has actually been demonstrated scientifically, as Dr DuBois noted:

“This is the first time I know of that there has been such a clear molecular connection between the two, with clear cut effects on the pathway and how it has an effect on the downstream. We never expected the effects on some of the tumor suppressors and mismatch repair genes. That was pretty exciting when we found that effect.”

What was particularly interesting, though, is that they also showed that it might be possible to tackle these issues using an anti-inflammatory drug (celecoxib) and/or a methylating agent (azacitadine). Both of these drugs reduced the size and number of tumours in mice with colorectal cancer in their experiments. In addition, the best responses occurred when both drugs were used together, suggesting a powerful additive effect coud be achieved.

What are the next potential steps from this research?

Obviously finding the link between inflammation and epigenetic changes is important, but there is much work that still needs to be done. Dr DuBois laid out some important next steps:

“Ultimately, what needs to be done is that we need to map out the whole epigenome now under a variety of situations where we apply an inflammatory stimulus or change the state of inflammation because I think it is really telling us something about the underlying mechanisms there.”

We already know from existing research that there is infiltration of immune cells into the tumour microenvironment, and in some situations, that can stimulate the cancer to progress faster:

“One of the ideas that is emerging is that the intestine, especially the large intestine, is in a special niche where it has to respond to this microflora. If there is any breach in the barrier, like adenomas or developing cancers, then that can bring inflammation directly to the tumor microenvironment because of all those bacterial products and other interactions between the microflora and epithelial cells.”

This research is just the beginning – ultimately, we need to think in terms of effective chemoprevention and treatment based on our understanding of the underlying biology:

“It was totally unexpected and I think it is going to lead to some things that will hopefully help, as we do more research, understand better how these interactions occur. Colorectal is a unique situation because it got all those bacteria in the lumen.

There have been some isolated reports about different types of bacteria causing problems, but this really could explain how the genetic somatic mutations interact with the local environment in the colon. We will have to think about ways to intervene to try to prevent or treat the disease more effectively.”

From a clinical standpoint, an obvious follow-on from this research would be to consider a clinical trial for patients who are at extremely high risk for developing colorectal cancer, such as those with a genetic predisposition, to see if combination treatment with these two classes agents (anti-inflammatory and methylating agent or HDAC) would decrease their subsequent risk of developing colorectal cancer.

All in all, some very exciting research to kick off this week and well worth reading.

References:

ResearchBlogging.orgWang, D., & DuBois, R. (2009). The role of COX-2 in intestinal inflammation and colorectal cancer Oncogene, 29 (6), 781-788 DOI: 10.1038/onc.2009.421

Xia, D., Wang, D., Kim, S., Katoh, H., & DuBois, R. (2012). Prostaglandin E2 promotes intestinal tumor growth via DNA methylation Nature Medicine DOI: 10.1038/nm.2608

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I’ve been busy with other things offline since the last blog update from the American Society of Hematology (ASH) meeting in San Diego, but will be catching up on my notes from the conference over the next few days.

In addition, my colleague Pieter Droppert has already posted his topline impressions of the meeting on the companion Biotech Strategy Blog, which readers may be interested in:

  1. Ponatinib in CML
  2. Update on new advances AML and FLT3
  3. Interesting posters – BTK and PI3K

Meanwhile, I thought it would be a good idea to look at the pipeline developments in non-Hodgkin’s lymphomas (NHL) that I particulalry liked at ASH:

PI3K inhibitors

Pieter’s choice of PI3K as a hot topic turned out to be rather prescient given that:

a) Intelikine announced last night that the company is being bought by Millennium-Takeda in a deal worth $190M upfront with $120M in additional milestone payments. This is a great transaction all around, enabling clinical development to now begin for Intellikine’s two remaining PI3K-mTOR and selective isoform inhibitors and since Takeda have research facilities locally in San Diego, this will enable work to continue with minimum fuss and relocation.

b) As of this morning, Exelixis announced they have licensed their PI3K-delta inhibitor in preclinical development to Merck. This deal features an upfront payment of $12 million, but the company will be eligible for potential development and regulatory milestone payments for multiple indications of up to $239 million in the future.

Another PI3K inhibitor in the news is Calistoga’s CAL-101 (now owned by Gilead), a delta selective isoform inhibitor being evaluated in indolent NHL. At this meeting, the phase I data was presented in a poster. The patients enrolled to date (n=37) included those with follicular lymphoma, small lymphocytic leukemia and marginal zone lymphomas, all of whom had received prior therapy for their disease. In this study, CAL-101/GS-1101 was given in combination with rituximab and/or bendamustine to determine the safety profile.

The big question is whether the combination with chemoimmunotherapies would lead to added or overlapping toxicities – the authors, de Vos et al., concluded that answer was no and a good efficacy signal was seen:

“GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy.”

On the basis of this study and a prior phase I trial that determined the dose (150mg/BID), further continuation of the program in this indication appears warranted:

“The data from this trial will be used to design Phase 3 combination studies of GS-1101 in patients with iNHL.”

 

Anti-CD20 monoclonal antibodies

Rituximab was the first targeted cancer drug following its approval back in 1997 and has shown how important targeting CD20 has been in lymphomas and more recently, chronic lymphocytic leukemia (CLL). At this meeting, we saw an interesting new development in lymphomas from Roche/Genentech in GA101 (obinutuzumab). This is essentially a follow-on biologic to rituximab. In a previous post prior to ASH, I looked at the key questions that need to be addressed in order to displace rituximab, namely more activity in rituximab refractory patients, more efficacy/better side effect profile up-front or broader activity across several diseases.

What are the key differences between rituximab and obinutuzumab you might ask and does this impart any clinical benefit?

Well, rituximab is a humanised type I monoclonal antibody, whereas obinutuzumab is a humanised type II glyco-engineered antibody, both target CD20. What’s the difference between Type I and II? Well, according to Robak, 2009:

“GA-101 binds with high affinity to the CD20 type II epitope, resulting in the induction of antibody-dependent cytotoxicity that is 5- to 100-fold greater than observed upon treatment with rituximab.”

The proof of the pudding is always in the clinical data, especially randomised head-to-head trials. There were over a dozen abstracts on GA101 at ASH, but the most important one in this context was a phase II GAUSS trial from Sehn et al., which randomised patients with indolent B-Cell NHL to receive either rituximab or obinutuzumab in the relapsed setting:

Gauss trial schematic courtesy of Roche

And the result? The authors concluded that:

“Treatment with GA101 in patientss with relapsed NHL resulted in higher response rates compared to rituximab as assessed by both investigators and the IRF at an early time point.

GA101 was well tolerated, although a higher rate of IRRs was noted, the majority were grade 1/2 in severity and did not result in significant differences in treatment discontinuation.”

Where IRR is infusion related reactions.

This data is promising for obinutuzumab, but still very early – we will still need to see what happens in a larger scale phase III trial with more patients before we can draw more definitive conclusions. That said, I found the GAUSS trial data very encouraging indeed.

Bruton’s Kinase Inhibitors

In the first update, I highlighted how Bruton’s Kinase inhibition (BTK) was one of the exciting new emrging pathways in chronic lymphocytic leukemia (CLL), but new data was also presented on the leading BTK inhibitor, PCI-32765 (Pharmacyclics/J&J), in lymphomas.

The preliminary phase II data in mantle cell lymphoma (MCL) presented by Wang et al., in 48 patients (29 bortezomib-naive, 19 bortezomib-exposed) with a median of two prior treatment regimens (range:1-5).

Initial efficacy data was reported:

“The objective response rate (ORR) is 67% (16/24); ORR is 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort.”

The side effect profile seen to date was also described:

“Serious AEs (SAEs) have occurred in 8/39 patients (21%); 2 SAEs (1 rash, 1 febrile neutropenia) were considered potentially related to PCI-32765.”

I thought these results were encouraging – with good tolerability and encouraging signs of efficacy – certainly worthy of exploring in a randomised phase III trial in this indication. This is an agent we are probably going to hear a lot more about in the near future.

And finally…

There were a lot of new developments emerging at this meeting, particularly in the poster sessions and also in both phase I and II trials. It was impossible to keep up with everything, so this post is just a flavour of some of the abstracts either of us did manage to take in.

The challenge, as always, with ASH is their insistence of holding all the critical oral sessions on biology and therapy in leukemias, lymphomas, myelomas and myeloproliferative diseases almost on a single day, making it absolutely impossible to see/hear all the new and exciting data. Monday is, therefore, always a manic day. It’s a strange contrast from the long lulls on the Sunday where some of the oral sessions could have been hosted, perhaps the biology sessions, thereby freeing up a more flexible schedule for the clinical data on Monday. There is some weirdness and also dismay in seeing a biology and clinical session for the same topic (eg CML, Multiple Myeloma, Lymphomas or FLT3 in AML) clashing. Not everyone is a specialist, certainly the community oncologists who attend are not. This is silly scheduling and means that people presenting in a biology session often miss the clinical update for a trial they were a PI in, while attendees like me are regretably forced to choose from one or the other.

Sadly, not everyone can stay until Tuesday morning when a few more key oral sessions that include new data are held, for a meeting that began on Friday. This is issue compounded by no virtual meeting facility, one of ASCO, AACR, ECCO and even the NY Chemotherapy Symposium’s great online service whereby you can catch up with sessions you missed later. For me, this is a critical and integral part of modern cancer meetings.

I hate missing out on great or important data and hope that ASH will seriously consider virtual meeting access for future meetings – it really does help attendees – otherwise if you didn’t catch the sessions they are gone forever!  Personally, I was still watching (and enjoying) presentations I missed at AACR and ASCO in July, long after both meetings finished, and really appreciated their excellent webcasts/virtual meetings.

One of the sad things for me was it turned out to be the first time in many years that I skipped the Plenary session as there were some odd choices this year that simply didn’t resonate with me. For example, making Mylotarg, a drug withdrawn by the FDA recently, one of the meeting highlights made little sense to me because:

a) it will have no immediate clinical or even scientific impact for the practising oncologist and
b) there were far more dramatic results that I thought were worthy of broader dissemination

Overall though, this was a good ASH meeting from the point of view of exciting new data in phase I and II trials; clearly the oncology pipelines are beginning to show some early promise, but it was disappointing not to see more of them prominently highlighted. There were quite a few other abstracts I liked, but this overview should give a good flavour of some of the novel agents emerging for the treatment of NHL.

For those wanting information on Hodgkins Lymphomas, I’ll cover those in a separate post as there was too much data to cover both in one post.

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This year’s American Society of Hematology (ASH) meeting heralded a wealth of new information on pipeline compounds in early development. Although a lot of people were excited about myelofibrosis and the battle between Incyte’s ruxolitinib and YM Bioscience’s CYT387 (more on these in a separate update), the area that intrigued me most was the Bruton’s Tyrosine Kinase (BTK) inhibitors in B-cell lymphomas.

Background on the science behind the BTK pathway:

I’ve been following these novel agents for a while and was fascinated by two abstracts from the ASCO and ASH meetings last year. It became clear that BTK is a valid target in B-cell lymphomas after Advani et al., (2010) demonstrated at ASCO the effect of BTK inhibitor PCI-32765 monotherapy on responses in patients with relapsed aggressive NHL.1

Later that year, Ponader et al., (2010) showed that PCI-32765 abrogates BCR- and nurselike cell-derived activation of CLL cells in vitro and in vivo.2

Between them, these two abstracts offered a solid rationale for investigating BTK inhibitors in B-cell lymphomas and CLL.

Where are we now with clinical development?

Fast forward to ASH this year, Dr Susan O’Brien presented the initial phase I/II data in chronic lymphocytic leukemia (CLL), which was well worth waiting for the last day of the conference to hear.  She took us through the concept of the how the BTK pathway fits into B-cell malignancies:

BTKSource: Dr Susan O’Brien ASH 2011 CLL oral session, reprinted with permission 3

Essentially BTK is a critical part of the BCL pathway that leads to proliferation, so targeting it leads to cell death or apoptosis:

“BTK is a Tec family kinase that is required for B-cell activation mediated by BCR signaling.  The essential role of BTK in normal B-cell development is evidenced by the clinical syndrome X-linked agammaglobulinemia, in which BCR signaling is abrogated by mutations in BTK.

Signaling from the BCR is also believed to be required for the maintenance of cell division and survival in B cell malignancies, presumably via downstream phosphorylation of PLC-gamma by BTK, ultimately leading to the activation of the anti-apoptotic transcription factor NF-kB and the kinase ERK.

Additionally, BTK may also play a role in the pathogenesis of B-cell malignancies by regulating integrin-mediated migration and adhesion, through regulation of malignant cell response to lymph node-derived chemotactic factors, such as CXCL12 and CXCL13.”

What does the latest data show?

Here’s a quick overview of the preclinical and clinical data I managed to see at ASH. There were over 2,000 posters over three days, plus a day and a half of simultaneous oral sessions, so it was quite hard to keep up with the sheer volume of it all!

In mantle cell lymphoma (MCL) the preclinical data looked encouraging:

Ponader et al., (2011) provided a nice overview of the initial PCI-32765 preclinical data in mantle cell lymphoma (MCL) in a poster presntation.4

They concluded that MCL cells express surface IgM and BTK, which is involved in BCR signalling. In this study, PCI-32765 successfully blocked BTK function and inhibited MCL proliferation, except in resistant cell lines. The former explains why there were responses in patients, while the presence of the latter suggests that additional BTK independent pathways exist and need to be elucidated.

I think that figuring the mechanisms of resistance out is important because it will help suggest possible rational combinations with BTKi therapy in advanced disease.

In CLL, the initial phase I/II clinical data is early, but promising:

Over the last 18 months, patients with CLL (n=117) have been enrolled into five trials, although the interim data was reported in the two relapsed/refractory arms (asterisked arms) at this conference, at two different dose cohorts of PCI-32765, given orally daily at either 420mg (n=27) or 840mg (n=34):

PCI

Source: Dr Susan O’Brien ASH 2011 CLL oral session, reprinted with permission5

The overall response rate (ORR) of 67-68% for both doses in the relapsed, refractory setting showed impressive activity and a clear sign that the BTK target is a valid one in this setting. Although the CR rate was low (<5%), the majority of patients saw PRs in this setting. Those with bulky disease (common in advanced disease) tended to do better.

There were also dramatic changes in the tumour burden, with the majority of patients seeing a greater than 50% change from baseline. Sustained improvements in blood counts were also reported. What particularly caught my attention was the activity in patients with known poor risk factors such as 11q and 17p deletions, who tend to have noticeably poorer outcomes. Obviously this is only a small phase I/II trial and we will have to see what happens in a larger scale randomised phase III study to see if the results are reproducible.

Typical side effects were diarrhea, cough and fatigue (any grade and grade 2+). The most common grade 3 adverse events were pyrexia, fatigue and diarrhea. Bearing in mind this was a heavily pre-treated population, many of whom had received prior immunotherapy, I thought the results were promising. The downside of immunotherapy is that while it has shown effectiveness, it does leave patients, especially the elderly, rather beaten up. The lack of grade 4 events in CLL was especially encouraging in this group.

What are the main BTK inhibitors in development?

Johnson and Johnson announced they were licensing Pharmacyclics PCI-32765 compound for nearly a $1B just prior to the meeting.6

Based on the data seen over the last two years, I thought they got a steal – this looks like it will be a very promising agent indeed. However, while they are clearly the leading BTK inhibitor, based on the sheer breadth and depth of their program, they aren’t the only one in this niche.

Avila Therapuetics also have a BTKi in early development, AVL-292, but they only have one phase I trial ongoing that I could find. The initial phase I data in B-cell malignancies was also presented in a poster at ASH.7

You can see why J&J licensed the Pharmacyclics agent – it’s much more advanced in the clinic than the others:

BTK
What does all this data mean?

Emerging data on BTK inhibitors has started to show that they produce consistently effective and well tolerated agents in B-cell malignancies such as NHL, MCL and CLL. I think this is a new class we are going to hear a lot more about over the next few years, either alone or in combination with other therapies.

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