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Posts from the ‘Conferences’ category

Follow the conversation from 2011 San Antonio Breast Cancer Symposium

By on December 6, 2011

Greetings from the frigid cold of Texas Hill Country! It’s 38F and a little nippy here at the San Antonio Breast Cancer Symposium (SABCS), brrrr! Later this morning, I will be recording my premeeting video but the outdoor Riverwalk filming has been sadly cancelled due to the inclement weather. However, I will post a synopsis of my hot topics and main highlights that I plan to be covering at this event.

In the meantime, for those of you following remotely, you can follow the conversations and join in the discussion around progress in breast cancer on Twitter using the hashtag #SABCS. To make it easy to read all the tweets, you can use the widget below to see what’s going on – tweets will start in earnest this afternoon with the main sessions.

Gone to dog drug heaven…

By on November 29, 2011

That was the quaint phrase used by one of the presenters at the recent AACR-EORTC-NCI Molecular Targets meeting in San Francisco.

Apparently, some drug or two was considered, too toxic (fair enough) or lacking in efficacy, hence the requisite binning of a multi-million dollar program to the scrapheap.

Yesterday’s post, however, reminded me that maybe sometimes, it’s not that the efficacy was lacking but the clinical trial design or tumor type or even line of therapy was the best one.  Let’s consider a couple of recent ideas here:

  1. The aurora kinase inhibitor PHA-739358 didn’t show any efficacy in adenoncarcinoma of the prostate, but the target, aurora kinase A may be a key one in some neuroendocrine tumours of the prostate.  These are very different subsets requiring a different approach to patient selection criteria and screening, which might potentially lead to a higher response rate in a small subset.
  2. At the above AACR meeting, I was discussing mTOR inhibitors in breast cancer with a few people.  Everyone noted how interesting it was that Wyeth’s temsirolimus failed to show any efficacy in a large phase III trial in women with ER/PR+ newly diagnosed breast cancer when given an aromatase inhibitor and the mTOR.  In contrast, Novartis took a different approach and used the AI and mTOR combination in second line therapy using everolimus and exemestane and saw dramatic responses. Why the difference?  Well, mTOR is known to cause resistance to AI over time, so it would make more sense to add it in later, rather than upfront.

There are many many other examples like this.  Sometimes, the key is in better understanding of the underlying processes from basic research.

For me then, dog drug heaven might not always be due to a poor molecule, but a failure to figure out where and how the drug might have worked effectively.  Dr Len Saltz (MSKCC) summed this up nicely at the NY Chemotherapy Symposium earlier this month:

Now, while Dr Saltz was specifically discussing the potential role (or lack of) for PI3K inhibitors in colorectal cancer, I do think his maxims hold very true for any targeted agent being evaluated in the clinic and something that cannot be emphasized enough.

The first point is obvious, but many sadly seem to miss it!  More preclinical and translational research is key to determining what the targets are and which ones matter in which tumor types.  Without that rational approach, you might as well throw mud at a wall and see what happens.  The second point speaks to the therapeutic index of the drug and whether we are shutting down the pathway enough to stop aberrant activity.  The final point is absolutely crucial – is the target a driver or a passenger?  If it’s the latter, the first two will not matter a jot no matter what we throw at it, in fact all that happens there is more toxicities are introduced and that’s not a good thing for the patient on the receiving end.

These issues become even more pertinent when we consider how regimens and increasingly, clinical trials, are moving more towards double and perhaps even triple combination therapies in an effort to shut down a pathway more completely.

In the meantime, the dog drug heaven days will likely continue.

 

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Update from AACR Molecular Targets 2011 #2 – Angiogenesis

By on November 22, 2011

Angiogenesis inhibitors have seen a long and rather chequered history since Judah Folkman first propounded the concept that tumours grow by adding new blood vessels. Many of these inhibitors have ended up in the dog heaven scrap heap, so to speak, while others (some monoclonals, some small molecule inhibitors) have made it to market in some indications, but failed miserably in others.  All in all, it’s been a bit of a crapshoot at best for manufacturers trying to crack this particularly difficult nut.

Perhaps the most famous (some would say infamous) drug is bevacizumab (Avastin), a monoclonal antibody to VEGF-A, which has been approved for colon, lung, glioblastoma, renal cancers but just had its approval revoked in advanced breast cancer by the FDA due to a poor risk-benefit and efficacy profile.

Although Vascular Endothelial Growth Factor (VEGF) has been the target most associated with angiogenesis, there are quite a few other pathways involved in the process, including Platelet Derived Growth Factor (PDGF), Placental Growth Factor (PIGF), Fibroblast Growth Factor, Notch, angiopoeitins (eg Ang1-3 and Tie2) and many others.

Recently, at the European Multidisciplinary Cancer Conference (formerly ECCO and ESMO) in September, new data emerged on two new angiogenesis compounds in colorectal cancer, namely aflibercept (VEGF-Trap) from Regeneron and BIBF1120 (Vargatef) from Boehringer. Both drugs showed promising efficacy and tolerability data in a phase III (VELOUR) and a phase II trial, respectively.

I’m not going to go into details of those trials here, but to expand on the idea of angiogenesis further, because it makes logical scientific sense to target several aspects of the process to see if improved outcomes result. Closely related to this is lymphangiogenesis, which is the formation of new lymphatic vessels from pre-existing lymphatic vessels, in a similar way to blood vessel development or angiogenesis.

According to Tobler and Detmar (2006), a simplified angiogenic and lymphangiogenic mechanism is thought to look something like this:

angiogenesis

It was therefore with great interest that I came across Regeneron’s latest poster at the AACR-EORTC-NCI Molecular Targets meeting last week. They looked at the idea of combining aflibercept (VEGF) and (Ang2) to determine whether there was a synergistic effect. The angiogenesis process is described below (courtesy of Regeneron):

VEGFAng2

The answer, in short, was yes.

They found that combined blockade of both VEGF (aflibercept) and Ang2 (REGN910) promoted noticeable tumour necrosis and growth inhibition in colorectal cancer xenografts over either agent alone.

Of course, we don’t know which biomarkers will be useful predictors of response, but that’s a discussion in itself for another post.

Now, while these results are encouraging, it does not mean they will automatically translate to patients in the clinic, but I do think it looks like a promising dual targeting approach that is well worth exploring further.  In the research there appeared to be no obvious signs of additional toxicities with the combination.  This is one specific multi-targeted approach that we may see more of in the clinic going forward. What this space for progress!

References:

ResearchBlogging.orgTobler, N. (2006). Tumor and lymph node lymphangiogenesis–impact on cancer metastasis Journal of Leukocyte Biology, 80 (4), 691-696 DOI: 10.1189/jlb.1105653

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AACR Molecular Targets Meeting

By on November 12, 2011

For those of you interested in this year’s AACR-EORTC-NCI meeting on Molecular Targets being held in San Francisco this year, you can follow the tweets from the hashtag #aacr in the widget below.

This is one of my favourite meetings of the year. I’m not expecting the same volume of tweets as the annual AACR meeting, mainly because a lot of the data being presented tends to be of an unpublished nature so people tweet those less – I certainly do!

If anyone has any questions, you can tweet me @maverickny. AACR also have an official Twitter and are very helpful.

The elusive mystery of KRAS and EGFR inhibitors in colorectal cancer

By on October 20, 2011

The other week during a conversation with Dr Gordon Mills (MDACC) at the European Multidisciplinary Meeting (EMCC) in Stockholm, he mentioned the conundrum of variable responses to EGFR inhibitors in colorectal cancers and the impact of RAS.  Originally, it was thought that patients who had wild type, but not mutated, KRAS were more likely to respond (see Allegra et al., 2009 in the references below).

The reality, however, is that variable responses to therapy have actually been reported by several groups with cetuximab and panitumumab. De Roock et al., (2010) reported better outcomes with cetuximab in patients with p.G13D-mutated tumours than with other KRAS-mutated tumours, contrary to the US and EU Guidelines, so the situation is clearly more complex than first thought.

Dr Mills speculated that part of the issue may lie in the sensitivity of the assays used at different institutions, since Sanger sequencing requires that 20% of the DNA must have RAS present, whereas the next generation sequencing techniques used at MD Anderson will pick up 1% of the DNA. We don’t know whether that difference will matter or not yet, but it’s an intriquing element that may well be highly relevant going forward.

Meanwhile, at the EMCC meeting there was an update on panitumumab, a monoclonal anti-EGFR in the PICCOLO trial in EGFR mutated colorectal trial that may shed some new light on the matter. This trial, like many UK studies, was highly complex. While the primary endpoint of overall survival was not met, the biomarker analysis revealed some interesting subtleties.1

The trial involved patients (n=1198) randomised to receive either panitumumab or cyclosporin with single-agent irinotecan in advanced colorectal cancer. According to the authors:

“It opened as a 3-arm study in 2007; but from June 08 prospective KRAS testing was introduced and KRAS-wt patients were randomised to Irinotecan / Irinotecan + Panitumumab, KRAS-mut patients to Irinotecan / Irinotecan + Cyclosporin.”

 

What do the latest findings show?

Firstly, the PICCOLO results confirmed some previous findings in that improvement in PFS and response rate were seen in patients with KRAS/BRAF wild-type tumours who received panitumumab, but no benefit from panitumumab in patients with KRAS or BRAF mutated tumours.

Secondly, the biomarker subset analysis revealed some subtle hints of where we can look in further trials. In explaining the lack of overall survival benefit, the subset analysis showed that almost a third (29%) of the wild-type patients were also found to have other mutations, thereby conferring resistance to the drug. The question then is why and what was the cause?  In digging deeper, some interesting nuggets emerged…

Thirdly, it seems that the patients who tended to see a good response had a broad wild type profile for KRAS, NRAS, BRAF and PI3K, whereas those who had a mutation for any of the above kinases did not have as good a response. This suggests that the biomarker testing may need to be extended beyond wild-type and mutant KRAS to avoid resistance to EGFR therapy developing. The results also provide a clear direction in where the adaptive resistance pathways are and thereby where different/new combination strategies may need to evaluated in the clinic.

The future for advanced colorectal cancer is very bright as we learn more about the biology of the disease and how to treat it, but it is also becoming highly complex!

References:

ResearchBlogging.orgAllegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, McAllister PK, Morton RF, & Schilsky RL (2009). American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 (12), 2091-6 PMID: 19188670

De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, Van Cutsem E, O’Callaghan CJ, Khambata-Ford S, Zalcberg JR, Simes J, Karapetis CS, Bardelli A, & Tejpar S (2010). Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA : the journal of the American Medical Association, 304 (16), 1812-20 PMID: 20978259

  1. M.T. Seymour, S.R. Brown, S. Richman, G.W. Middleton, T.S. Maughan, N. Maisey, M. Hill, C. Olivier, V. Napp, P. Quirke Panitumumab in Combination With Irinotecan for Chemoresistant Advanced Colorectal Cancer – Results of PICCOLO, a Large Randomised Trial With Prospective Molecular Stratification. ECCO, Stockholm 2011: Abstract #6007  ↩

Upcoming Fall cancer meetings

By on October 11, 2011

November always brings two of my favourite smaller meetings on the oncology calendar, so here’s a quick snapshot of what’s coming soon.

First up is the NY Chemotherapy Foundation Symposium Foundation, also known by many as the Greenspan Meeting, in honour of the late Ezra Greenspan who founded the event. This year, it will be at the Marriott Marquis in Manhattan from November 8-12th. For those interested, here is the 2011 program.

NY Chemotherapy Foundation SymposiumThe annual Greenspan Memorial lecture is usually held at lunchtime on the Thursday of the event and the talks are usually both informative and entertaining. The last two presenters have included experts such as Norman Wolmark on colorectal cancer and Larry Norton on cancer cell seeding.

This year, it is Martine Piccart’s turn and she will be discussing:

“CURE OF HER2 POSITIVE BREAST CANCER WITH NO OR MINIMAL CHEMOTHERAPY AT THE DOOR STEP?”

That should prove to be an provocative talk!

The Greenspan meeting is always useful for practising community oncologists in the Tri-State region because it largely focuses on clinical data (with some new developments in R&D highlights) and where the practice of cancer treatment is changing.

The second meeting I’m attending (they’re virtually back to back) is the AACR Molecular Targets and Cancer Therapeutics conference, also euphemistically known in Pharmaland as the EORTC meeting, although it is co-sponsored by the AACR, EORTC and NCI and alternates between the US and Europe.

AACR Molecular Targets and Cancer Diagnostics 2011This year, it’s in San Francisco and you can view the program here. I’m particularly looking forward to the personalised medicine plenary session, which features luminaries such as:

  • Jose Baselga (MGH)
  • Levi Garraway (DFCI)
  • William Pao (Vanderbilt)

Other interesting talks include:

  • Tona Gilmer (GSK) BRAF and MEK inhibition in melanoma
  • Scott Ebbinghaus (Merck) Dual inhibition of mTOR and IGFR pathways
  • Jean-Pierre Issa (MDACC) Novel agents for epigenetic therapy
  • Christine Eischen (Vanderbilt) Mdm2 regulates DNA repair and chromosome stability
  • Johann de Bono (Marsden) Androgens, biomarkers, and abiraterone

And many many more.

The great thing about this meeting is that there aren’t too many concurrent sessions – I really hate missing interesting presentations because they clash with something else!

If you’re attending either meeting and would like to meet up or say hello, do let me know.

Making a Difference: an interview with Dr Gordon Mills

Earlier this year, I announced that there were two people I was hoping to interview next as part of the ongoing Making a Difference series, where thought leaders share their ideas and vision on emerging and important topics in cancer research. Previous discussants have included the following:

Today, I am delighted to announce that one of those identified thought leaders, Gordon Mills (MD Anderson), kindly agreed to be filmed while at last week’s ECCO (European Multidisciplinary Cancer Conference). Dr Mills is Chairman of the Department of Systems Biology, Chief of the Section of Molecular Therapeutics, Professor of Medicine and Immunology, and Anne Rife Cox Chair in Gynecology. He is also one of the best strategic thinkers I’ve come across in cancer research who not only understands the big picture, but also the detailed subtleties.

Originally, we collected audio-visual to ensure an accurate recording for the usual transcript that gets posted here on the blog, but it came out well and the subject was so compelling that we deemed it well worth watching as the first thought leader video interview here on Pharma Strategy Blog.

Dr Mills gave one of the three keynotes in the first Presidential Symposium at the Stockholm meeting, along with Drs José Baselga (MGH) and Tak Mak (U. Toronto) in a fascinating session on Personalized Medicine. This session covered the whole gamut from therapeutics, biomarkers, assays and to metabolism. I took the liberty to include a couple of Dr Mill’s slides to illustrate the points we were discussing in the video below.

We’ve come a long way over the last decade in terms of progress, but hopefully, as technology and our knowledge improve further, the best is yet to come.

This is the fifth interview in the series with thought leaders in the Making a Difference series – it covers a wide range of critical topics including BRAF, mTOR, PI3K, EGFR and RAS – please do check it out:

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Update on MEK and AKT inhibition in RAS driven cancers

By on October 3, 2011

A couple of interesting developments have emerged over the last week with AKT and MEK inhibitors, specifically Merck’s MK-2206 and AstraZeneca/Array’s AZD6244, that are well worth discussing.

  1. At the ECCO/EMCC meeting in Stockholm last Tuesday, Johann De Bono discussed the combination data for MK-2206 and AZD6244 in KRAS driven colorectal cancer.
  2. Later the same week, Array Biopharma announced the initial results from a randomized phase II placebo-controlled study that compared the efficacy of selumetinib (AZD6244/ARRY-886) in combination with docetaxel compared to docetaxel alone in the second-line treatment of patients (n=87) with KRAS-mutant, locally advanced or metastatic non-small cell lung cancer (NSCLC).

Now, to be clear, I like the concept of AKT and MEK inhibitors, especially in select combinations, but the key thing here is the right combinations in the right context.

Let’s take a look at the lung cancer KRAS data first. One of the challenges I have with this approach, is that we’ve know for a while that BRAF and KRAS driven cancers behave rather differently according to Wee et al., (2009):

“Previous studies have found that whereas BRAF mutant cancers are highly sensitive to MEK inhibition, RAS mutant cancers exhibit a more variable response.”

Variable response is not an encouraging phrase when planning clinical trials!

Let’s take a look at the pathway itself:

We can immediately see that MEK is downstream of RAS, meaning that even if we target MEK, unfortunately RAS and KRAS is still largely untouched upstream. This is important to remember when considering the actual results later.

The other key factor to consider is what are the adaptive resistance pathways that might evolve as a result of treatment with a MEK inhibitor? In an ideal world, logical combinations would be tested that target both the primary driving mutation or aberration, as well as the adaptive resistance, to try and shut down the pathway more completely than targeting either alone. Another key question that needs to be addressed is what is driving the KRAS aberrant activity in the first place?

We’ve discussed MEK numerous times here on PSB, but the Wee et al., (2009) MEK paper stands out in particular. They identified a critical resistance pathway to MEK inhibition, namely PI3K. Although we discussed this originally in the context of BRAF driven tumours such as melanoma, it is well worth discussing again here in regards to KRAS driven tumours given a MEK inhibitor is being tested.

They observed that:

“Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance.”

It isn’t clear from the Array press release whether any of the patients with NSCLC exhibited PIK3CA mutations or loss of PTEN, but they definiely do occur in this disease. It will be interesting to see of more meta data is available at the forthcoming AACR Molecular Targets meeting next month.

I’m not a big fan of chemotherapy plus a single targeted agent, because as you can see from the evidence above, the pathway is not being shut down by one targeted agent and resistance is not being addressed at all. The chances of such a combination working (by that I mean increasing overall survival), I think would be fairly low.

According to the press release, the study did not see a significant improvement in overall survival (OS) but did show an encouraging response in the form of progression free survival (PFS):

“The key secondary endpoints of progression-free survival, objective response rate, and alive and progression-free at 6 months were all demonstrated with statistical significance, showing improvement in favor of selumetinib in combination with docetaxel versus docetaxel alone.”

Indeed, at the recent AACR and ASCO meetings, there was also some encouraging early signs from Genentech’s PI3K inhibitor, GDC-0941, as a single targeted agent with chemotherapy in NSCLC (a very small early trial), albeit not KRAS specific, but defined more broadly by squamous and non-squamous histology. Thus, all is not lost with the MEK agent yet – if we combined MEK and PI3K inhibitors in NSCLC patients previously treated with chemotherapy, we might have a better chance of succeeding and shutting down the pathway, based on evidence offered from Wee et al’s preclinical research:

“At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death.”

As a result, they went onto to suggest a logical treatment approach:

“Our study provides molecular insights that help explain the heterogeneous response of KRAS mutant cancers to MEK pathway inhibition and presents a strong rationale for the clinical testing of combination MEK and PI3K targeted therapies.”

Of course, clinical trials like this always progress incrementally, such that we test a MEK or a PI3K inhibitor alone to determine safety and efficacy activity, then perhaps in combination, which requires another phase I dose finding study to determine the ideal dosages and whether they are too toxic or not combined.

So while either single agent targeted therapy with chemotherapy in and of itself is not a win, there are signs that combining the two may be more appropriate. I would still want to know what is driving the KRAS activity though, given MEK and PI3K are downstream of it. It is entirely possible that a third agent would be needed to shut down the pathway more completely in that patient subset.

At ECCO, De Bono (Royal Marsden) discussed the combination of AstraZeneca’s MEK inhibitor (AZD6244) and Merck’s AKT inhibitor (MK-2206) in RAS mutant colorectal (CRC) and lung (NSCLC) cancers. The results here were not a big win in the former, with 8/15 patients showing no antitumour activity to date.

There are several things we can conclude from the initial data:

  • If we have the right combination for the right target in the right patient subset, then the therapeutic index of the agents is lacking and we need better drugs
  • Are the targets (AKT and MEK) critical?
  • Is something else driving the KRAS activity (see below)*?
  • Are we shutting down the adaptive resistance pathways (escape routes?)
  • Which patient subsets are most likely to respond and how do we best characterise them (ie need more biomarker data)?

And so on… there are always more questions than answers sometimes.

    * Note: This situation could well be similar to BRAF in malignant melanoma, where it is the V600E mutation that is driving the BRAF activity, thus specifically targeting ithe mutation rather than the kinase will have a greater clinical effect than targeting BRAF broadly. In this case, if we really believe KRAS is critical to the lung or colorectal tumour’s survival, then we need to figure out what is driving it before progress is made. Frank McCormick’s elegantly simple wac-a-mole concept for pathway inhibition is very apt here!

No doubt we will see more detailed data and an update soon, perhaps even at the forthcoming AACR Molecular Targets meeting next month.

References:

ResearchBlogging.orgWee, S., Jagani, Z., Xiang, K., Loo, A., Dorsch, M., Yao, Y., Sellers, W., Lengauer, C., & Stegmeier, F. (2009). PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers Cancer Research, 69 (10), 4286-4293 DOI: 10.1158/0008-5472.CAN-08-4765

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An in-depth review of the Phase II T-DM1 data in first-line metastatic breast cancer

By on September 30, 2011

The other day I highighted the phase II data from the T-DM1 (trastuzumab emtansine) trial as one of my top four abstracts at the ECCO European Multidisciplinary Cancer Conference (#emcc2011) in Stockholm.

For those of you interested in ADC technology, I wrote about the fascinating concept previously, if you want to check it out.

I think T-DM1 is a really exciting development for several reasons, so let’s take a look at the study in more detail.

  1. T-DM1 is an antibody drug conjugate (ADC), which combines the trastuzumab monoclonal antibody with a cytotoxic agent, maytansine, via a linker. This new molecule is stable and allows the structure to hold together until it reaches the cancer cells, wherein the chemotherapy is released in a much more targeted fashion than giving chemotherapy and Herceptin as separate drugs by infusion. With the traditional approach, it means that the chemotherapy will target normal cells as well as cancer cells, leading to significant side effects, including cardiotoxicity.
  2. ADC technology is designed to allow the combination to be delievered more specifically to the tumour, while also potentially reducing the side effects for patients.
  3. In this study (TDM4450g), T-DM1 was compared with the standard of care, trastuzumab (Herceptin) plus docetaxel in women with HER2+ metastatic breast cancer who had been previously untreated ie first-line therapy.
  4. It should be noted that maytansine is a very powerful cytotoxic that was originally seen as too toxic when given by traditional infusion. Combining it as an ADC therapy, however, reduces some of the associated adverse events since it can now given in a more localised fashion where it is most needed, ie in the tumour itself.

One of the challenges with the T-DM1 trial, though, as Martine Piccard, the Discussant correctly pointed out, is the open label design. One must be careful in interpreting data from them, as Kaufman et al., (2007) observed:

“Placebo controlled, double-blind trials can reduce bias when efficacy is studied. Open label designs can falsely suggest efficacy and fail to uncover harmful effects. Placebo controlled trials are considered ethical when there is no standard treatment better than placebo, and when participants are informed about the use of a placebo.”1

Unless a trial is blinded, we can never completely be sure the patients weren’t selected to either arm without bias, even if unconscious. Now, I’m not saying that was the case here, merely that one must be aware of both the limits and potential possibilities.

That said, my least favourite studies are open label single arm trials, but that wasn’t the case here, since half the women were randomised to receive the standard of care, ie trastuzumab plus docetaxel, making it a good comparison to see if any improvement can be attained. However, a double blind placebo controlled (in place of docetaxel) randomized trial is always a more reassuring design than an open label one.

That said, unlike pills, it is much harder to give chemotherapy blinded because the dosing is calculated as per kilogram of body weight, a dead giveaway. Thus, T-DM1 is given as 3.6 mg/kg, while the trastuzumab dose is given per 6 mg/kg, whereas docetaxel (75 or 100 mg/m2) versus placebo can clearly be be more easily blinded.

We must also remember that this is an exploratory phase II trial designed to see whether there is an efficacy signal or not. The study endpoint was PFS. Phase III trial designs are often much more robust.

What do the results show?

The proof of the pudding is ultimately in the analysis, not the theory, though.

The good news is that Dr Sara Hurvitz (UCLA) presented data that was actually much better than I expected, which is very heartening to see. Usually, in metastatic disease, where there is a very high disease burden, we sadly see increments of ~2 months or less in many investigational agents, so anything more than that is a real standout.

In the TDM4450g trial, the efficacy and tolerability results were impressive:

  1. Patients lived a median of five months longer without their disease worsening ie the median progression free survival (PFS) was 14.2 months vs. 9.2 months (HR=0.59, P=0.035) in favour of T-DM1 over the standard of care.
  2. Note: any HR under 0.60 is scarily good news – that means a huge 41% reduction in the risk of the disease worsening or death was seen.
  3. Overall survival had not yet been reached at the time of the presentation in the T-DM1 arm, another good sign that the data are likely to be durable.
  4. Women in the T-DM1 arm generally experienced fewer adverse events compared to those who received Herceptin plus chemotherapy: the rate of Grade 3 or higher adverse events was reduced by nearly half (46.4% vs. 89.4%).
  5. In addition, more women on Herceptin plus docetaxel discontinued therapy due to side effects compared to T-DM1 (28.8% v. 7.2%).

Here’s a snapshot of the PFS curves – you can decide for yourself what you think:

PFS in Phase II T-DM1 trial versus trastuzumab plus docetaxel

So far, so good.

However, in the interests of fair balance, there were some side effects that appeared more in the T-DM1 arm, namely:

  • Thrombocytopenia (30.4% v. 6.1%)
  • Increased liver enzymes such as aspartate transaminase (AST) (39.1% v. 6.1%)

The most significant adverse event for me though, was cardiotoxicity, which is a well known side effect of standard Herceptin plus docetaxel therapy. Here’s how that data looked at the time of the analysis:

Cardiac toxicity in Phase II T-DM1 HER2+ metastatic breast cancer study

As you can see, it was less in the T-DM1 arm than the standard of care, which is most encouraging.

Patient sentiments are important

I did a quick search to see what patients in the trial were saying and came across these two heartfelt posts I encourage you all to read – it will put your day into perspective. Participating in clinical trials is not a bed of roses by any stretch of the imagination and I salute these brave women in their fight:

In conclusion…

These data from the phase II T-DM1 versus trastuzumab plus docetaxel study are an excellent start, with promising efficacy and safety signals in favour of the ADC over standard of care.

The big unanswered questions are whether the overall survival (OS) will also be better (I really hope so) and whether the data is reproducible in a large scale phase III trial (ditto). We will have to wait a while to see the more extensive phase III trial results.

  1. Kaufman et al., (2007) Issues in SMA clinical trial design The International Coordinating Committee (ICC) for SMA Subcommittee on SMA Clinical Trial Design http://www.columbiasma.org/docs/news/Kaufmann%20Muntoni%20Trial%20Design.pdf ↩
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BOLERO2 data in breast cancer impresses at ECCO 2011

By on September 27, 2011

This year I decided to write some longer posts from the ECCO/EMCC meeting owing to the amount of potentially paradigm changing data coming out. These in depth op eds will roll out over the next few days.

Quite a few people have been asking what my picks of the conference are, so here goes, in order of Wow factor (purely from my perspective):

  1. Everolimus BOLERO-2 data in ER/PR+ HER2- breast cancer
  2. Alpharadin in advanced prostate cancer
  3. T-DM1 in HER2+ breast cancer
  4. Vismodegib phase III data in basal cell carcinoma

You can read more about the Alpharadin data on the companion Biotech Strategy Blog, but I will put up a post in the pros and cons of this therapeutic later in the week. It’s going to be very interesting indeed to see how this pans out.

Why did I pick the everolimus (Afinitor) data first over the others?

Well, regular readers here on PSB will know that I’m a great believer in

a) targeted therapies and
b) identifying mechanisms of resistance to determine logical combinations

We know that the PI3K-mTOR pathway is dysregulated in hormonal sensitive breast cancer leading to resistance, so a logical approach would be to treat women whose initial AI therapy has failed with another, but add in an mTOR or PI3K inhibitor. That’s exactly the case here.

The results? Simply stunning!

Jose Baselga presented the BOLERO-2 data to a packed audience. When he showed the slide for PFS, there were gasps in the audience around me – a shift in favour of the treatment arm (everolimus plus exemestane) over control (placebo + exemestane) not of the usual 1-2 months, but 6.5 months:

BOLERO-2 data at ECCO 2011

The side effect profile was consistent with what we know about mTOR and Aromatase inhibitors. One thing I would very much like to see is some subset analysis to see what factors separated the super responders from the average responders. This trial tested the combination in a general unselected population, but it would be nice to see if any factors can be derived from the data that suggests what might be predictive of response.

While these results are a major paradigm shift in women with hormonally sensitive breast cancer, the big question is can we do even better?

We also know from basic science that mTOR upregulates AKT, so eventually adaptive resistance will occur through that route too, but you can see where the next round of logical therapies might emerge in future. The current batch of AKT inhibitor have some challenging side effects when used in combination, but next generation of inhibitors might have a more tolerable and improved side effect profile.

All in all, I thought the BOLERO-2 data were my pick of the conference for major practice changing data and I hope to see this data submitted for approval to the Health Authorities very soon. This development is very good news indeed for women with ER/PR+ breast cancer.

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