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Palifosfamide – a predictable miss in soft tissue sarcoma?

By MaverickNY on March 26, 2013

Soft tissue sarcomas (STS) are relatively rare and represent about 1% of all solid tumours. There are more than 50 subtypes of STS, making it an extremely broad and diverse cancer type.

What are they?

Simply put, they are malignant tumours that arise in the soft tissues of the body, such as the muscle, fat, tendons, nerves, even the synovial tissues in joints are not exempted. As such, with the exception of those originating in muscle (leiomyosarcomas) and gastrointestinal tumours (GIST), they tend to be small and difficult to reach cancers. They differ from bone related sarcomas such as osteosarcoma and Ewings Sarcoma, which are usually considered separate categories.

The most common types of soft tissue sarcoma include malignant fibrous histiocytoma (MFH, more recently renamed by leading sarcoma pathologists as high grade undifferentiated pleomorphic sarcoma or HGUPS), liposarcoma and leiomyosarcoma.

The challenges of treating STS

As you can imagine, with such a diverse group of tumours, in many ways they each represent different cancers whose only commonality is the original site of origin. I actually struggle to think of a more heterogeneous group of tumours. Each one may have a different driver e.g. we know that GIST is largely KIT driven and is therefore responsive to KIT inhibitors such as imatinib (Gleevec), sunitinib (Sutent), pazopanib (Votrient) and regorafenib (Stivarga).

Some STS are known to be chemo-sensitive, at least for a few months, such as angiosarcoma, leiomysarcoma and synovial sarcoma, while many (most) are sadly highly chemo-resistant and do not respond well to cytotoxic therapy. Surgery is usually the standard of care for many of these subtypes as a result.

This means that while common cytotoxics such as ifosfamide and doxorubicin might be helpful in treating angiosarcoma, ifosfamide in synovial sarcoma and gemcitabine with or without docetaxel giving a benefit of 6.3 months vs 3 months in leiomysarcoma, many will see litle or no effect from therapy. In essence, a broad catch-all trial of STS needs to be carefully thought out viz inclusion criteria because if too many non-chemosensitive types are included then they may well negate any positive gains seen with chemo-sensitive subtypes.

It is likely that such allcomer trial designs didn’t help trabectedin (Yondelis), ridaforolimus (mTOR) in the SUCCEED trial or palifosfamide, which Ziopharm reported failed to meet the primary endpoint of PFS in the PICASSO 3 trial this morning. While there was no doubt that some patients did well on ridaforolimus with extended periods of stable disease (SD), others didn’t and without a biomarker from phase II trials to predict which patients would do well with mTOR therapy in the phase III registration study, the odds become little better than Russian roulette for registrability.

All of these results were most unfortunate for patients living with the disease, since there are so few options and effective new approaches would be most welcome.

What about palifosfamide?

Palifosfamide is essentially a different formulation of ifosfamide with a few extra excipients also added. This type of approach is usually something that makes me wary – new formulations might improve toxicities or drug delivery (in theory) but they rarely move the efficacy needle in a big way. By that, I mean one might reasonably expect small increments at very best, certainly not paradigm shifting change in the way we see from new approaches with targeted agents such as treating a very clearly defined subtype such as GIST with a KIT inhibitor.

Ultimately, the lack of a clear target means that chemotherapy should be given to chemo-sensitive subtypes of STS. An examination of the PICASSO 3 registration trial, however, highlighted that while a diagnosis of STS was the key inclusion critiera, only GIST and Ewings Sarcoma were excluded.

This is an extremely broad allcomers trial and probably doomed the study to predictable failure from the start – little was learned from the ridaforolimus experience, unfortunately. It’s well known that I’m not a fan of either chemotherapy or catch-all studies and this throw-it-at-wall-and-hope-it-sticks approach was no exception.

The chance of success would likely have increased by excluding known chemo-insenstive subtypes and including only known chemosensitive subtypes such as angiosarcomas, synovial sarcomas and leiomyosarcomas. Yes, recruitment would be much slower, but a smaller N number in a more sensitive population would be less risky and also less likely to have the treatment arm full of patients who were unlikely to respond.

Where do we go from here?

The development of $ZIOP’s palifosfamide is likely headed for dog drug heaven at this point, given the press release from Ziopharm this morning gave no concrete details about the PFS numbers, stating that the:

“Phase 3 trial of palifosfamide (ZIO–201) for the treatment of metastatic soft tissue sarcoma in the first-line setting (PICASSO 3) did not meet its primary endpoint of progression-free survival (PFS). The study’s independent data monitoring committee (IDMC) has recommended that patients be followed for overall survival (OS), the study’s secondary endpoint, however the Company does not expect to continue follow up for OS.”

Until we more clearly define the biology of the various subtypes of STS and develop targeted agents for each subgroup based on what’s actually driving the tumour, we aren’t likely to see much progress in the short term. Given the recent phase III failures from trabectedin, ridaforolimus and now palifosfamide, I find it hard to see how Threshold’s TH-302 will fare any better.

Why?

Well, I do think pharma and biotech companies need to stop treating STS as one disease and instead, focus on the different subtypes, much in the same way that imatinib revolutionalised the treatment of GIST and encouraged other companies to enter what previously was considered a tiny market – it can be done. Doing yet another all comer/catch-all trial in a heterogeneous population without a clearly defined mechanism of action specific to a well tested subgroup, accompanied by more overly broad inclusion and exclusion criteria is sadly doomed to fail.

Help make colonoscopies more affordable as an effective screening tool

By MaverickNY on March 20, 2013

Patient advocacy is something I care about and spend time actively supporting two worthwhile causes, including the lovely folks at Fight Colorectal Cancer, headed by the indefatigueable Carlea Bauman and Nancy Roach. As someone who has lost several family members to colon or rectal cancer, this is something dear to my heart. I got involved largely through being inspired by the incredible Kate Murphy, who sadly passed away last summer.

Today, Fight CRC is spearheading a campaign to improve access to colonoscopies, a valuable scrrening tool to pick up the disease early. By some odd Medicare quirk, as far as I’m aware, there’s no co-pay for colonoscopies unless a polyp is picked up and removed. Obviously, it’s more straightforward to remove the polyp then and there rather than go through the prep and procedure again, but that incurs a co-pay… which in turn provides a barrier to more people being screened. Removing the co-pay would make colonoscopies more affordable for millions of people. We all know that prevention is better than cure.

You can do a number of things to help and join the fight!

Follow the campaign efforts on Twitter using the hashtag #conc2013
Donate to the Fight Colorectal Cancer cause
Call the number below to be put through to your representative to urge them to co-sponsor HR 1070, which has a worthy aim:

“To amend title XVIII of the Social Security Act to waive coinsurance under Medicare for colorectal cancer screening tests, regardless of whether therapeutic intervention is required during the screening.”

The more co-sponsors on the bill… the greater the chance of its enactment, another barrier to screening is removed and more saving of lives from colorectal cancer.

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Bromodomain Inhibitors – an exciting new target in cancer research?

One of the interesting things about basic cancer research is that new targets emerge all the time, offering fresh opportunities for developing novel therapeutics in the quest for clinical improvement. While you see many companies chasing the same well established targets, often generating me-toos, sometimes serendipity favours the bold and the brave, as we recently saw with Pfizer’s development of crizotinib for ALK+ lung cancer.

So what’s new on the R&D front?

Bromodomain inhibition is a novel cancer target and one that I am looking forward to learning more about at forthcoming annual meeting of the American Association for Cancer Research (AACR) in Washington DC.

The plenary session on Monday April 8 on Epigenetic Targets in Cancer includes a presentation by James Bradner (Dana-Farber Cancer Institute) on Bromodomain Inhibition in Cancer.

What are BET bromodomains?

Although there are 47 bromodomain proteins, a subset of four proteins are associated specifically with the BET bromodomain, including a terminal (T) node:

BRD2
BRD3
BRD4
BRDT

These bromodomains are acetyl-lysine binding pockets that target bromodomain-containing proteins to histones and thereby affect chromatin structure and function. The binding of BET protein bromodomains to chromatin regulates gene expression. Whenever histones are involved, epigenetics are never far behind.

Thus in simple terms, it is now believed that targeting the binding of bromodomain and extra-terminal [BET] proteins to chromatin, it may be possible to regulate gene expression, and in particular, the transcription of key oncogenes such as MYC, which can lead to arresting of cell-cycle progression and apoptosis (programmed cell death). In plain English, this means that cancer cells are selectively killed.

Some of the groups original preclinical work in this area was published in Nature a couple of years ago – it was ground breaking work because generally protein-protein interactions such as MYC are considered very difficult targets to drug, unlike tyrosine protein kinases (TKIs), which are more accessible. More recent work by Lin et al., (2012) in Cell elaborated on the significance of low and high MYC levels.

Since then, the research has moved into the translational and clinical space. Small molecule inhibition of BET is a drug development target of Cambridge, MA based Constellation Pharmaceuticals, who announced last September that they partnered with The Leukemia & Lymphoma Society to develop their novel BET for the treatment of hematologic malignancies.

Highlighting the significance of this work is the announcement in January this year (see Fierce Biotech’s piece for more details) is a $95M deal with Genentech, which includes a buyout option. I thought this was a smart move at the time, given the importance and solidity of the basic research findings. The venture funds invested in privately-held Constellation Pharmaceuticals clearly have an exit strategy in mind.

I am hoping that Dr Bradner’s AACR plenary presentation will discuss Constellation’s drug development pipeline.

What makes BET bromodomain inhibitors of even more interest as a potential target is the possibility that there may be biomarkers that will identify those patients most likely to respond to therapy. For those of you interested in a basic understanding of biomarkers, you can read more on Biotech Strategy Blog for an overview.

Preclinical research published by the group in the March 2013 edition of Cancer Discovery highlights how a genetic biomarker could be used to identify those cancer patients likely to respond to a new class of cancer drugs, BET Bromodomain Inhibitors.

MYC is overexpressed in many cancers but until recently, has largely been ignored as an ‘undruggable target’. A rare malignant childhood cancer known as neuroblastoma, for example, is associated with the amplification of the MYCN gene and generally considered to be difficult to treat unless it is caught early and surgical resection is feasible. New work published in Cancer Discovery by Puissant et al., gives hope that therapeutic targeting with bromodain inhibitors might be a feasible strategy to pursue.

Recent research published in 2011 in the Proceedings of the National Academy of Science (PNAS) by Jennifer Mertz et al., at Constellation Pharmaceuticals showed that you could target MYC dependence in cancer by inhibiting BET bromodomains. They showed that:

“Small molecule inhibition of BET bromodomains leads to selective killing of tumor cells across a broad range of hematologic malignancies and in subsets of solid tumors.”

Fast forward to the work published in Cancer Discovery. Using high-throughput screening the researchers at Dana Farber found that amplification of the MYCN gene in neuroblastomas was sensitive to BET bromodomain inhibitors. Using cell lines with MYCN amplification and a mouse model of neuroblastoma, they showed that BET bromodomain inhibitors prolonged survival and had anti-tumor effects.

The Cancer Discovery abstract describes the significance of this work:

“Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new com- pound class with promising anticancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, show a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma.”

What does all this data mean?

It has long been known that MYC protein is likely oncogenic in some tumour types, including some hematologic cancers and paediatric neuroblastoma, but the challenge has finding ways to effectively target it at effective therapeutic levels. This new research has now moved forward the field sufficiently, such that not only have potential biomarkers of response been identified, but inhibitors are also in advanced preclinical development. This is an exciting new avenue of research that is well worth watching out for in the future.

References:

Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W., Fedorov, O., Morse, E., Keates, T., Hickman, T., Felletar, I., Philpott, M., Munro, S., McKeown, M., Wang, Y., Christie, A., West, N., Cameron, M., Schwartz, B., Heightman, T., La Thangue, N., French, C., Wiest, O., Kung, A., Knapp, S., & Bradner, J. (2010). Selective inhibition of BET bromodomains Nature, 468 (7327), 1067–1073 DOI: 10.1038/nature09504

Puissant, A., Frumm, S., Alexe, G., Bassil, C., Qi, J., Chanthery, Y., Nekritz, E., Zeid, R., Gustafson, W., Greninger, P., Garnett, M., McDermott, U., Benes, C., Kung, A., Weiss, W., Bradner, J., & Stegmaier, K. (2013). Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition Cancer Discovery, 3 (3), 308–323 DOI: 10.1158/2159–8290.CD–12–0418

Lin, C., Lovén, J., Rahl, P., Paranal, R., Burge, C., Bradner, J., Lee, T., & Young, R. (2012). Transcriptional Amplification in Tumor Cells with Elevated c-Myc Cell, 151 (1), 56–67 DOI: 10.1016/j.cell.2012.08.026

Mertz, J., Conery, A., Bryant, B., Sandy, P., Balasubramanian, S., Mele, D., Bergeron, L., & Sims, R. (2011). Targeting MYC dependence in cancer by inhibiting BET bromodomains Proceedings of the National Academy of Sciences, 108 (40), 16669–16674 DOI: 10.1073/pnas.1108190108

Schnepp, R., & Maris, J. (2013). Targeting MYCN: A Good BET for Improving Neuroblastoma Therapy? Cancer Discovery, 3 (3), 255–257 DOI: 10.1158/2159–8290.CD–13–0018

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ASH 2012 update on ARRY-520 in multiple myeloma

By MaverickNY on March 1, 2013

After highlighting the interesting biomarker program associated with AVEO’s tivozanib in renal cell and triple negative breast cancers in the last post, several people wrote in asking about other biomarker programs that have piqued my interest. Regular PSB readers will know that I’m not a fan of catch-all trials at all because the population being studied is too heterogeneous – use of biomarkers can help select which patients are more likely to respond to a particular drug and thus produce greater efficacy.

Another small biotech doing some interesting and compelling biomarker work is Array BioPharma, based in Boulder, Colorado.

What’s exciting about the ARRAY pipeline?

They have a nice pipeline of interesting targeted agents that are being developed with several big Pharma partners including AstraZeneca (selumetinib) and Novartis MEK162), both MEK inhibitors. Dennis Slamon’s lab has published some initial data on their work on predictive biomarkers with selumetinib for those interested (see References below).

MEK inhibitors are thought to target KRAS, which causes resistance in lung cancer and melanoma. Combining MEK with a PI3K inhibitor may reduce the adaptive resistance and prolong survival. I’m expecting to see more on these at the forthcoming AACR and ASCO meetings in April and May. The approach is most likely to be incremental rather than a home run, though.

The ARRAY biomarker program that has intrigued me was presented in multiple myeloma (MM) at ASH in December. They have a novel kinase that targets Kinesin Spindle Protein (KSP) codenamed ARRY-520, which has a novel mechanism of action. For those of you interested in learning more about the basic biology of the KSP concept, I highly recommend checking out the papers in the Reference section below as they explain the targeting of the microtubilin concept well and how KSP inhibition differs from what we know of the taxanes as well as some useful background on the compound itself.

Some of you will remember previous KSPs that failed in the clinic such as ispinesib, for example, but not all compounds are equal or destined to fail. Much of cancer research is iterative – tweaking molecules to improve the conformation (shape), reducing side effects or improving potency. Sometimes a whole program can be canned because the company selected the wrong tumour type or trial design – you don’t always get multiple shots on goal in small biotechs!

What’s interesting to me is the focus of Array in multiple myeloma, a particularly difficult and foxy disease to impact clinically. The basic rationale behind this approach is that KSP is a microtubule protein required for mitosis (cell division); inhibition leads to cell death (apoptosis).

Now, remember the bedrock of therapy in MM has been proteasome inhibitors (bortezomib and now carfilzomib have been approved) and Immune Mediated inflammatory Disease agents or IMiDs (thalidomide, lenalidomide and now pomalidomide are all approved). This means that new agents with a different mechanism of action attract a lot of attention, especially if they can potentially be combined with existing drug classes to prolong survival and push patients into minimal residual disease (MRD) where the myeloma clone is drastically suppressed, much as we see in CML with the BCR-ABL inhibitors.

Inevitably, new drugs in MM are tested in a highly refractive population, either as a single agent or in combination with dexamethasone (dex) to determine if they have any efficacy.

Recall that two new agents approved by the FDA in relapsed/refractory MM had relative low single digit response rates (RR) as single agents i.e. carfilzomib (22.9%) and pomalidomide (7.4%) with improved RR in combination with low dose dex i.e. carfilzomib (34%) and pomalidomide (29.2%)

The two ARRY-520 analyses at ASH looked promising

Dr Satin Shah, ASH 2012

The first part of the phase II study from Shah et al., (Abstract #449) looked at patients who were highly refractive to bortezomib and/or lenalidomide.

They observed that ARRY-520 had encouraging efficacy with and without dex. The first cohort (n=32) evaluated single agent therapy with ARRY-520 and saw 19% confirmed responses (CR) and 15% partial responses (PR); the subset who were both bortezomib and lenalidomide refractory had an ORR of 15%.

Meanwhile, the second cohort (n=18) looked at the combination with low-dose dex and demonstrated a PR or better of 22% in a heavily pre-treated population (more than 10 prior regimens). Adverse events included the usual myelosuppression (neutropenia, thrombocytopenia, anemia) seen in myeloma, but importantly, no treatment related neuropathy was observed.

The second element of the analysis looked at the same patients, but described the results from a biomarker, alpha-1-acidic glycoprotein (AAG). AAG is a serum protein that can have elevated levels in MM. As Dr Shah noted, AAG is not known to bind to standard of care agents in MM but is thought to bind to ARRY-520 with a negative impact by reducing the available amount of drug. In other words, they have a sub-therapeutic exposure to ARRY-520.

In the phase II study, they found that the hypothesis was supported: patients with high levels of AAG had poorer responses, while patients without elevated AAG levels had much better responses and the ORR increased to 33%, a dramatic improvement. The pre-dose AAG levels therefore correlated with response.

Obviously, the biomarker will need to be validated in larger, randomized controlled trials, but it would be very useful to be able to select patients upfront who could receive ARRY-520 either in combination with low dose dex or with a proteasome inhibitor or IMiD and see a more pronounced response. An initial trial with carfilzomib suggested an acceptable toxicity profile, while this is an encouraging start, we still need more data on the safety and efficacy of the combinations going forward.

Assuming the ongoing Phase Ib combination trials demonstrate good tolerability and efficacy, ARRY-520 could be potentially be combined with dexamethasone and either carfilzomib or pomalidomide in the relapsed/refractory setting for greater responses than the doublets alone.

Some additional thoughts…

I thought the Array KSP compound looked very encouraging indeed – multiple myeloma is crying out for:

New agents with a different mechanism of action from the existing standards of care that can be combined to give solid results from triple combinations.
More competition in the refractory setting to push out the MOS further and try to achieve minimal residue disease (MRD), which would impact the lives of patients with multiple myeloma significantly.

Beyond Kyprolis and Pomalyst, here are other agents in phase III studies being tested in refractory MM such as the HDACs e.g. panobinostat and vorinostat. The vorinostat data presented at ASH in 2011 was singularly disappointing, but hopefully we will hear about the phase III panobinostat results later this year.

In the meantime, Array have a nice compound in ARRY-520 and a potentially useful biomarker of response to help select patients upfront who are more likely to respond to treatment. As far as I know, they don’t yet have a partner for the program and may well need one for the large phase III trials that will be needed for FDA approval or they may well try to go it alone using the capital raised from the MEK partnerships. MM is certainly a promising avenue worth exploring for ARRY-520 and I look forward to hearing more about its development.

References:

Garon, E., Finn, R., Hosmer, W., Dering, J., Ginther, C., Adhami, S., Kamranpour, N., Pitts, S., Desai, A., Elashoff, D., French, T., Smith, P., & Slamon, D. (2010). Identification of Common Predictive Markers of In vitro Response to the Mek Inhibitor Selumetinib (AZD6244; ARRY-142886) in Human Breast Cancer and Non-Small Cell Lung Cancer Cell Lines Molecular Cancer Therapeutics, 9 (7), 1985-1994 DOI: 10.1158/1535-7163.MCT-10-0037

Sarli, V., & Giannis, A. (2008). Targeting the Kinesin Spindle Protein: Basic Principles and Clinical Implications Clinical Cancer Research, 14 (23), 7583-7587 DOI: 10.1158/1078-0432.CCR-08-0120

Tunquist, B., Woessner, R., & Walker, D. (2010). Mcl-1 Stability Determines Mitotic Cell Fate of Human Multiple Myeloma Tumor Cells Treated with the Kinesin Spindle Protein Inhibitor ARRY-520 Molecular Cancer Therapeutics, 9 (7), 2046-2056 DOI: 10.1158/1535-7163.MCT-10-0033

Will biomarkers revolutionalise treatment with tivozanib?

By MaverickNY on February 25, 2013

Following last weeks post on the phase III clinical data for tivozanib in advanced renal cell cancer (RCC), I thought it would be useful to provide an update on AVEO’s biomarker program.

I’m very excited about the work they are doing in this area and have been following them keenly since they first presented their initial work on myeloid cells in RCC at the AACR diagnostic conference back in 2010. Since then, other companies have also published work in this field, including Regeneron, who also noticed the presence of myeloid cells in their work with aflibercept in glioblastoma.

Biomarkers have been very much a bête noire in angiogenesis research – we know that some patients respond well to therapy, but others do poorly and may actually be worse off. The challenge has been finding a way to link biology with response in order to improve patient selection. Genentech/Roche have laudably spent millions in their quest for biomarkers with bevacizumab (Avastin), with researchers clearly very frustrated at the confounding data presented at the 2011 ECCO meeting in Stockholm. Clearly, we have a long way to go in this field.

Murray Robinson, Courtesy of AVEO

Last week I caught up with AVEO’s Murray Robinson (who is the Special Advisor to the CEO), to discuss the progress they are making on the biomarker front.

The recent ASCO GU meeting in Orlando highlighted very interesting data on a new biomarker they are researching, which involves a hypoxia gene signature in RCC (PDF download).

While this data is still preliminary at the moment, it is being tested prospectively in some ongoing trials in both renal and breast cancers. Readouts are expected by the end of this year and may reveal some interesting findings.

PSB: Does the hypoxia biomarker in your poster at ASCO GU connect with the myeloid biomarker you presented back in Denver at AACR, or is this completely different?

Murray Robinson: This is one is independent of that, completely different, although as you can imagine we are looking at the myeloid biology in this same dataset. To put that to rest, we ran into some technical details, technical challenges on that. Remember when you are doing these trials, you only get the material you get, and you don’t always get the quality, and can’t go back and recut it.

We are really looking forward for the marker in this paper as well as that that myeloid work, to an ongoing study of a 100 patients mostly in the US, RCC – BATON (Biomarker Assessment of Tivozanib ONcology) study and we will get to take another look at this hypoxia biomarker, the myeloid biomarker and a few others that we are looking at. That study will mature soon, we are expecting probably sometime later this year.

PSB: Are these two biomarkers going to be practical in the future for community oncologists to use or is it going to be something that is a research tool do you think?

All of us are now applying high resolution molecular analysis to all of the tumors, all the TCGA work, whole genome transcriptome on things. As the field has done that, we have all been amazed and enlightened by the complexity within what the field used to call a single genotype.

We are all recognizing there are many molecular subsets. This of course was first elucidated 10 years ago in breast cancer. In breast cancer we are very comfortable with these idea, it’s not breast cancer, it’s ER+, or HER2 amplified or triple negative. And of course treatment assignment can be based on that, and we are even further refining those subsets. We haven’t that kind of resolution until recently with many of the other tumor types.

Let’s turn to renal cell carcinoma, (RCC) which is the subject of this work. We in the field have long considered clear cell renal carcinoma, which is 85% of RCC, to be a tumor type. However, as the field has begun to sequence and do profiling on many of these tumors, we have begun to recognize that it is in fact more complex than that.

In our poster, we first cited some great pioneering work by Dr Kim Rathmell down at UNC Chapel Hill where she really was one of the first to take a look at these subtypes of clear cell, and has reported now, and we excerpted one of her figures from a recent paper of hers on our poster. And she sees three major subtypes of clear cell kidney cancer. Two of those subtypes she has talked about before, and we won’t spend much more time talking today. They don’t seem to differentiate for a number of key biological features. A third type she has identified, and we also independently identified, is the subject of this work.

What we, and others, have recognized is that there are new, previously underappreciated, subtypes of clear cell carcinoma. We focused on this one novel subtype, which Kim called Cluster 3, and we then applied some of our own bioinformatics platform to this, in which we have comprehensively charaterized tumors for key robust signatures.

We applied those key robust signatures that usually represent biology to this third tumor type. We saw that there were a number of key features in which these tumors varied, this is about 15% of clear cell RCC, so it is a relatively small subset. We noticed in particular that one of the dominant differentiating features of this tumor was the expression of its hypoxia responsive genes.

We recognize there’s a different tumor type here, and that the tumor type is now low for a large signature that we have had for hypoxia, and we of course are thinking translationally, and in terms of molecular diagnostics as well. We optimized to reduce that hypoxia gene signature to a nine gene signature and we optimized the ability to measure those genes often using single sections from clinical paraffin embedded material.

We are absolutely thinking about this biology and are looking toward to the development of a simple diagnostic test, if that were warranted.

We looked at that nine gene signature, quantified it then looked at its impact on response to tivozanib as well as sorafenib.

PSB: My understanding from looking at your poster in this particular subset with the hypoxic element is that some patients did better in response to tivozanib than others?

Murray Robinson: That is the observation that we made.

Our interest in looking at hypoxia in tivozanib is that hypoxia as we showed in one of our figures, that signature relates to the over-expresssion of key VEGF ligands, VEGFA, PLGF and VEGFC.

One hypothesis that we generated from these observations is that when the VEGF pathway is deregulated or overactive as it is in most of clear cell, then you are more likely to respond to a selective, potent VEGF pathway inhibitor like tivozanib. Conversely, then if you find a subtype that is not, the hypothesis is that it would not respond well.

We tested that in the study, and with the important caveat that we had 69 samples out of the total trial of 517 patients, then we looked at this subtype. Well, we predicted the subtype would represent about 15% of the total, so we went form 69 down to about 30 samples, then 15% of those I think we ended up with 4 of the low subtype in both [arms]. We all recognize those are pretty small numbers. We are really looking forward to the second study I mentioned to you.

PSB: You will still have to validate the results in a larger sample?

Murray Robinson: We think that would be prudent. We think it is difficult to make much out of 4 samples, however that is the amount that would be predicted. It is consistent with all the work that we have done previously. We are also certainly pleased that those 4 patients did not perform well on tivozanib, whereas in the remaining 85% of those patients, those patients did very well.

In fact median PFS of the high patients, representing 85% of the study population, was 18.3 months, which is very respectable progression free survival.

PSB: In other words you have a very good way upfront to potentially predict up front which patients might do well on tivozanib?

Murray Robinson: That was the hypothesis going into this, this was a prospectively designed hypothesis that we wrote up. It was not exploratory.

There is another point here that we’re pretty excited about. One thing we know about the field, that we didn’t 10 years ago, is that despite the original enthusiasm around the VEGF pathway as being a key angiogenesis inhibitor pathway, we all know the large amount of clinical data over the last 10 years with different VEGF pathway inhibitors has been disappointing.

I think there has been a lot of disappointment about the expectations about the VEGF inhibitors versus their performance. The VEGF pathway inhibitors are working, there are a number of indications there, but it certainly hasn’t been that universal broad-acting, cytotoxic agent that we all thought it was, would have been back in 1999.

The bigger question is can we use an understanding of the biology, an understanding of gene signatures, to better select patients in other indications? What we showed in this paper is that 85% of these patients have this VEGF deregulation signature and that is consistent with the fact that clear cell carcinoma actually exhibits robust single agent response to tivozanib and activity with other VEGF type agents.

We really are interested with the signature in expanding and using this as a biomarker outside of clear cell carcinoma, and we have now have done that. Those studies are in progress.

We did a survey of this hypoxia signature across multiple tumor types and made an observation that we are pretty excited about. That is, we found that the hypoxic signature is not as prevalent in those tumor types as it is in clear cell.

We did find that it was present in subsets of tumor types, and we particularly noted that in triple negative breast cancer (TNBC), the hypoxia gene signature is high in a high proportion of triple negative breast cancer.

That is interesting because there is some anecdotal or retrospective clinical data that suggests that VEGF pathway inhibitor agents may work a little bit better in triple negative breast cancer, a challenging tumor type with high unmet medical need.

That observation led to us starting a new phase 2 trial in breast cancer, the BATON-breast study that we started a few months ago. In that study, we will be looking at triple negative breast cancer and we are looking at a randomized phase 2, and we are looking at paclitaxel versus paclitaxel plus tivozanib. In that study we will be measuring the hypoxia biomarker signature.

We have started that and are planning on using a specific assay to look at those patients.

PSB: And finally, for the prospective renal trial with biomarkers when do you expect that to read out, is it anytime soon?

Murray Robinson: I would expect to look for that around the end of the year, recognizing that we don’t know when that’s going to mature, but second half of the year that is when we are expecting. We are looking forward to those results.

We think that there is a strong hypothesis for this and we are pleased in the TIV0-1 study that we saw data consistent with the hypothesis.

Some personal thoughts and additional insights…

Before anyone gets in too much of a tizzy, note that the data reported at ASCO GU are preliminary findings in a small sample size with only a few (n=4) hypoxia low patients, as Dr Robinson fairly pointed out. They need to be validated prospectively in a randomised controlled study to ensure that the initial findings are real and not a fluke. The good news, however, is that the consistent lack of response in these patients enabled the hypothesis to be tested further in new trials. It’s certainly a concept that worth testing.

We have known, or suspect, that VEGF inhibitors work in conditions of tumour hypoxia, but this is the first time I can recall anyone connecting the hypothesis to clinical response. Assuming that the findings can be validated in the prospective trials – and a commercial assay developed in the future – then the ability to select patients with RCC who are more likely to respond to a VEGF inhibitor such as tivozanib would be most welcome.

Would other VEGF inhibitors need to show the same effect or would a class effect be assumed? In my book, you can’t always assume that one biomarker for one drug will always translate to others without data. In this study a significant effect was seen for tivozanib but not sorafenib based on the hypoxia biomarker. We don’t know what the impact is with other VEGF inhibitors such as sunitinib, pazopanib, bevacizumab and axitinib. It will be most interesting to see what happens here, as the hypoxia biomarker made be a differentiating factor for tivozanib in the future.

The upside for a VEGF inhibitor in TNBC is potentially huge, much bigger than RCC. What would drive this element though is not only positive data but also a way to predict and select which patients are more likely to respond. Essentially, if the data is positive, it may well redefine a subset of the disease, much in the same way that CD117 (KIT) enabled GIST patients to be differentiated from other types of soft tissue sarcomas. When you can do that, it makes matching treatment to patients a whole lot easier for clinicians and pathologists.

ASCO GU update on tivozanib in advanced clear cell renal cancer

By MaverickNY on February 21, 2013

AVEO presented the phase 3 clinical trial data for tivozanib in renal cancer at the American Society of Clinical Oncology Genitourinary Cancer Symposium (ASCO GU) in Orlando last week.

The TIVO-1 data (PDF download), presented by Dr Robert Motzer (New York), showed a significant improvement in progression free survival (PFS) of 11.9 vs 9.1 months (P=0.042), but not median overall survival (MOS) i.e. 28.8 vs 29.3 months (P=0.105, HR 1.25). The lack of a significant MOS difference between the sorafenib and tivozanib treatment arms has received a lot of commentary recently, especially in light of the crossover clinical trial design.

Source: MSKCC

To put the clinical trial results in context, last week at ASCO GU, I interviewed Dr Motzer, (Attending Physician, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, and Professor of Medicine, Weill Medical College, Cornell University) for his perspective on the data.

PSB: I am very interested in the tivozanib data from AVEO/Astellas. What are your reactions to the results, bearing in mind that the overall survival was not significantly different from sorafenib?

Dr Motzer: The TIVO-1 study was a randomized trial of tivozanib versus sorafenib and the primary endpoint was progression free survival (PFS). Since the patients were all hoping to get tivozanib, we included in the trial design for those patients who were on the sorafenib arm, if they progressed, then we would be able to switch them over to the new promising anti-cancer drug tivozanib. What we found was that most of the patients that were progressing on sorafenib, were able to switch over and get tivozanib.

We feel that the survival being about the same on each of the two arms is maybe the result of the fact the patients on the sorafenib arm were able to receive tivozanib upon progression.

In fact, the survival was a little bit longer on the arm that got the sorafenib followed by the tivozanib, and the reason for that is that many of the patients were treated in Eastern Europe, in Russia, Ukraine, and the only access they had targeted therapies was through this study. So if they were on the sorafenib arm they were able to get both sorafenib and tivozanib, but if they were on the tivozanib arm most of them weren’t able to get any in second or third line therapy.

I think it’s important that patients get access to multiple lines of targeted therapies for kidney cancer, that is a very important thing.

PSB: Do you think, based on this data, that the drug is approvable by the FDA?

Dr Motzer: I think it should be. I think it is a very good drug, it’s effective, it has very little in the way of side effects. I think it should be an option. I think it should be approved and people should have it as an option.

Sorafenib is not one of commonly used first line agents in the United States, it has been sunitinib and now pazopanib may be the preferred agent. I would very much like to see a phase 3 trial that compares tivozanib to one of those two agents. I think that would probably provide the best information we have on how to make a choice for our patients.

PSB: What did you like about the side effect profile of this agent?

Dr Motzer: This drug is very selective for VEGF receptor, which we think is the most important target for kidney cancer response, and it has very little effects on other kinases. Many of the other drugs, they are all multi-targeted tyrosine kinases, but this one is more selective than the other ones.

Most of the side effects we see with the other drugs are from the drug hitting targets other than the VEGF receptor. So things like diarrhoea, skin sores, fatigue and so forth, that we see with the other drugs, we see very little with this one.

PSB: One of things that is noticeable in GU medicine over the last few years is the emergence of translational medicine and biomarkers, is there anything new going on in renal cancer that might help to better select patients, I think you have 8 or 9 different drugs available now, how do you choose going about which of these patients should get which of these therapies?

Dr Motzer: For the most part it is based on the evidence for efficacy and what setting the drug was studied on and it is also based on the safety profile. So if it looks like one drug is safer than another or better tolerated, then that’s often the choice to the patients.

What we don’t have is any kind of genetic profiling that can say this drug would be better for this patient and so forth. I think that is some of the work that needs to be done. There was actually one of the posters from AVEO, to try and develop some of this, like a signature for response to tivozanib. That was a poster shown here, done in a small number of patients, more kind of a pilot study. We need more of that in kidney cancer.

PSB: Do you think biomarkers will be more to the fore in renal cancer in the next couple of years?

Dr Motzer: Yes, I think the one thing is there are now a number of different medications that are similar class, they have the same mechanism of action, so I think it’s probably harder to find a biomarker to distinguish who will do better with one than another since they are related. I think the biomarkers would be important to see which patients does better with a VEGF targeted therapy like tivozanib, which one does better with an mTOR inhibitor like Torisel.

There are exciting new immunotherapies, the PD-1 antibody is very exciting in kidney cancer, for example. I think if we can identify drugs with different mechanism of action, then a biomarker might be of more use in terms of determining what is the best treatment, but when they are closely related it makes it more difficult.

The PD-1 antibody is being studied in a big global phase 3 trial by Bristol Myers Squibb compared to everolimus. There is a lot of excitement over that one. It is more of a targeted immunotherapy.

My perspective – some additional thoughts…

One of the things that got lost in the media hullabaloo when the final analysis was announced recently, was that the primary endpoint for the TIVO-1 trial was actually PFS, with median overall survival as the secondary endpoint, as Dr Motzer correctly noted.

Since tivozanib showed superior efficacy over sorafenib in the primary endpoint and a more tolerable side effect profile, then the chances of approval are higher than had both endpoints been not significant. OS is always nice, but in this disease competition is high and distinguishing between broadly equivalent agents a little harder.

In the poster, a subset analysis was presented of the North American/Western European data demonstrating MOS had not yet been reached in either arm, but 2-year survival rates were trending in tivozanib’s favour over sorafenib (75% vs. 60%). We will have to wait a little longer for the 50% point to be hit, but I thought this was encouraging. An update at ASCO in June may well be very timely.

The crossover trial design conundrum is one that other companies may well learn from – if the control arm has the potential to receive more therapy on progression that the test arm, then this will confound OS results in a global study. It’s not the first time it’s happened, but it does speak to addressing this issue more upfront in the study design. If PFS is the primary endpoint, then the issue is less of a problem but if companies need to demonstrate a clear differentiation in overall survival then a different approach might be necessary.

Several VEGF inhibitors are already approved by the FDA for the treatment of RCC (i.e. sorafenib, sunitinib, pazopanib, bevacizumab, axitinib) and in different lines of therapy, so the proof of concept for hitting the target in this disease is well established. Where they differ is that patients may well find some more tolerable than others or pricing/reimbursement may come into play as the competition heats up.

Presently, we have no valid biomarker for any of the VEGF inhibitors as a way of selecting a drug that a patient is most likely to respond to. Genentech/Roche have spent millions on biomarker research for Avastin with very little to show for it so far, proving how difficult this task really is.

Check back tomorrow for an update on tivozanib and biomarkers

Following the discussion with Dr Motzer, I followed up with Dr Murray Robinson, the Chief Scientific Officer at AVEO and will post our discussion on their fascinating research with biomarkers here on PSB. Although this research is unlikely to impact the registration trial data that is being reviewed by the FDA (the PDUFA deadline is July 28th for the TIVO-1 study), prospective inclusion of biomarkers in new studies may be very illuminating going forward.

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Tumor Lysis Syndrome – what is it and why is it important in cancer research?

By MaverickNY on February 18, 2013

After the hullabaloo on Friday regarding AbbVie’s suspension of the ABT-199 trials following not one, but two, unexpected deaths from tumor lysis syndrome (TLS), a few people asked what is this condition and what causes it?

In simple terms, lysis is a medical word used to describe the break up or breakdown of cells – whether through decomposition, destruction, or dissolving. Thus, we have hemolysis, which is the destruction of red blood cells with the release of hemoglobin.

Tumor lysis, however, is a medical emergency whereby the sudden production of massive amounts of potassium, phosphate, and nucleic acids into the systemic circulation overwhelms the body’s garbage disposal units, the liver and kidneys. Urgent hospital treatment is usually required, often diuretics can be helpful to flush out and dilute the excess potassium (too much can slow or stop the heart beating), but sometimes kidney dialysis is also needed to speedily remove the excess production of the potassium. Death can unfortunately (but not always) result.

TLS is most common in aggressive, fast growing (high grade) lymphomas and acute leukemias (e.g. ALL), but is less common in indolent disease such as chronic lymphocytic leukemia (CLL).

Given that AbbVie were testing their Bcl2 inhibitor in CLL, where TLS is rarer, some might think two deaths from TLS a surprise, especially given the positive results reported at the recent American Society of Hematology (ASH) meeting in December (more about the ABT-199 data).

This is not the first time TLS has been reported in leukemias though. Carl June (U Penn) presented the data on their chimeric antigen receptor therapy (CART), a collaboration with Novartis, in CLL and also childhood acute lymphoblastic leukemia (ALL) at ASH. Their lead therapy, CTL019 (formerly CART19), also leads to TLS in both ALL, where it is more common, and CLL patients, although he did state in the Ernest Beutler lecture that the patients received urgent renal dialysis and recovered.

Interestingly, Dr June described the TLS as occurring not immediately, but delayed until 20-50 days post infusion. Given what we know about autologous cellular immunotherapy, a delayed response is not a surprise, but in line with our scientific knowledge to date, since it takes a while post apheresis to activate the T-cells.

You can see from Dr June’s slide that the serum levels of creatinine and uric acid spiked around day 20, but the patient was hospitalized for TLS a few days later:

It is possible that the TLS occurs in CLL as a result of rapid efficacy and on target effects – in other words, the treatment is doing it’s job of killing the cancer cells, perhaps a little too well.

Final thoughts…

We will have to wait and see what happens with the larger randomized phase 3 trials for both ABT-199 and CTL019:

We don’t yet know whether the effect in ABT-199 is a dose-schedule issue or a compound structure issue (especially given the reformulation from the original navitoclax molecule).
If TLS is a persistent toxicity issue and efficacy is durable, then it may well limit both potential treatments to Academic centers with experience and resources to quickly monitor and treat such sudden events in future.
These are exciting molecules but care is clearly needed in managing the toxicities.

Contrast these approaches with ibrutinib, a tyrosine kinase inhibitor that targets Bruton Kinase, where the effects appear to be slow but steady inhibition of a key target driving CLL proliferation. TKI therapies are very Community oncology friendly in comparison, particularly for indolent diseases. Although the Bcl2 and CART therapies look very promising, they may need a more careful and judicious approach to reduce the risk of sudden deaths from TLS.

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Making a difference in Advanced Prostate Cancer – an interview with Bertrand Tombal

Since 2010, we have seen several technological advances in therapies for metastatic castration resistant prostate cancer (CRPC), leading Professor Bertrand Tombal (an Academic urologist in Brussels, Belgium) to describe 2011 as a Grand Cru year for CRPC at the European Society of Medical Oncology. One of the most promising therapies in this category was enzalutamide (Xtandi) from Medivation.

Enzalutamide is an anti-androgen receptor antagonist similar to bicalutamide, but differs in that it is a more potent inhibitor and has no agonist properties. Initially, it was approved by the FDA post chemotherapy but trials are currently ongoing in the pre-chemotherapy setting.

In patients with advanced prostate cancer with hormonally-sensitive disease, the treatment choices can be fairly stark – active surveillance (for low risk patients), surgery (for resectable disease), radiation (risk of long term side effects) and/or androgen deprivation therapy (ADT) for high risk patients with rising PSA. When ADT fails and PSA rises dramatically again, then men may receive an androgen receptor antagonist such as bicalutamide. An advantage of bicalutamide is that it avoids medical castration and has been shown to have a favourable safety profile compared to ADT.

ADT is useful for controlling PSA levels in high risk patients, but it is not without complications, as Prof Tombal discusses below and explains why there is a need for an alternative approach:

In US, however, ADT is more commonly used in high risk patients than bicalutamide.

The most obvious question though, is how might enzalutamide compare with bicalutamide in the advanced prostate cancer setting? To find out about progress here, I interviewed Prof Tombal about his poster being presented at the ASCO Genitourinary meeting yesterday.

PSB: How would you describe the rationale behind your study?

Prof Tombal: The first thing that is important is what is the philosophy of the clinical trial? There has been a lot of activity in medical treatment for prostate cancer with new drugs like abiraterone, Jevtana, new chemotherapies, a vaccine, but what they all have in common that they are used in patients who are failing hormonal treatment. Today, hormonal treatment worldwide is basically medical castration, meaning that you suppress the testosterone in the whole body to get an effect on the prostate and the metastases.

The idea was to test enzalutamide, not the way it is used and prescribed now in patients who fail androgen therapy, but in patients who have never received androgen deprivation therapy. There was always the hypothesis that it might not work for unknown reasons. So we took patients who needed hormone therapy, some of them were already quite advanced, and we gave enzalutamide alone.

PSB: What kind of results did you see?

We were extremely impressed by the amplitude of response of these men. If we look at the PSA decrease, when we did that hypothesis that if 80% of the men would have a good PSA response, we would potentially have a drug with some future in that setting. But it’s not 80%, it’s much more than that. Almost all the men responded extremely profoundly to the drug with a sharp decrease in PSA, and with a toxicity that apparently is less pronounced than with androgen deprivation therapy.

The hypothesis that we might have a drug that could eventually replace androgen deprivation therapy, we now we know that the idea seems to be working and we are now saying OK, now we might have a compound simply to replace androgen deprivation therapy in all these men who need it and suffer from side effects.

Now it is creating a new paradigm because now we have to think about how we are going to develop this in the next 4 to 5 years. What is striking with the result is that actually enzalutamide is the only drug you can use as an alternative. If you think, for instance, about Zytiga/abiraterone, it needs to be used with hormone therapy, it will never replace hormone therapy. Here it is a short series (of treatment) but you have to understand we went totally blind in that patient population.

What we can say about the results is that it is far beyond any expectations we made when we planned the trial.

PSB: How would these results compare with what you would expect with bicalutamide?

Prof Tombal: In Europe, bicalutamide is registered and we still use it. If I take for instance, my personal patients, I would say 10-15% of the patients are treated with bicalutamide monotherapy.

The problem with bicalutamide is that we know that the PSA drop is never what we see with LHRH agonists; we know it is a good drug, but the trial I have indicated, that it was a chemo-equivalent only for patient with minimal disease.

Although we have no direct comparison, but we have historical comparison in Europe because we use bicalutamide a lot. If we just look at the PSA drop for instance [with enzalutamide], it is apparently much more profound than [we normally see] with bicalutamide. That is clear.

From the patients in the trial, we have observed objective tumor shrinkage, and sometimes very impressive one, something we have not seen very well with bicalutamide. We have no direct comparison, but it is clear from my perspective that it compares well with bicalutamide in terms of side effect profile because there is no castration syndrome, there is a little bit of gynecomastia, little bit of fatigue, things that are extremely well tolerated by the patient in comparison to LHRH agonists.

But the tumor response, seems – and I do insist – much better than with bicalutamide.

PSB: So will you be planning any other head to head trials with bicalutamide or the LHRH agonists?

Prof Tombal: The problem of drug development is that actually the leading dancers are the regulatory authorities. If you go to EMA, European Medicines Agency, because bicalutamide is accepted we could easily plan a trial head to head bicalutamide versus enzalutamide. The problem is that FDA never registered bicalutamide, so we have to see how they are going to behave. There are plans to conduct a trial, but the exact design of the trial, and we can’t do nothing about this, will be decided by FDA. We don’t even know right know whether it is going to be one global trial, or trial made for Europe and the US.

Interestingly also, in contrast to all the agents that have been developed in castration resistant prostate cancer, nobody has ever gone to FDA with a modern plan saying these are the problems, these are the compounds. We don’t know how they will react.

Clearly if I had all the money and all the patients, the ideal trial would be a three arm trial comparing standard hormonal treatment to enzalutamide to bicalutamide. Because, if we do that then we could really have the answer both in term of survival and in term of quality of life.

I am a urologist by training, so most of the patients I see, I would say even 85%, they won’t die from the disease. Those who have aggressive disease are seen mostly by medical oncologists. The medical oncologist concern is primarily to increase overall survival. Where my concern as a urologist is to get a similar overall survival, to keep the good result we have right now, but lower the toxicity. If I want to answer both questions at the same time, the ideal would be a three arm trial to get all the information on the quality of life and overall survival.

PSB: I think the three arm trial would be most optimal and give the definitive answer

Prof Tombal: That would be the more elegant and would be the one that would be the most scientifically satisfying.

PSB: Are there any other combination trials with enzalutamide in that setting that have piqued your interest?

Prof Tombal: If you give me $1 million dollars and ask we what is the best combination, I would say it is enzalutamide and radium-223. Because, we know something in prostate cancer, it is that there is something magical that is happening when you combine radiation therapy and hormonal treatment. That is where androgen deprivation therapy has been shown to increase overall survival. All the trials done by SWOG, EORTC and early work back in the 70’s showing that if you hit the cell with some form of DNA breaking mechanism like radiotherapy plus hormone therapy you have got something magical.

To me, the association of a very effective anti-androgen and radiation therapy is something I want to see. One of the advantage on top of that is that these two drugs do not require corticoids and are extremely well tolerated. So this is really an association i don’t fear. Radium-223 is well tolerated. In all these men we identify now with oligo-metastatic disease, combining these two drugs, give me the drug, give me the money, I would be extremely interested.

PSB: Is that trial planned at all?

Prof Tombal: I think both Bayer and Medivation are speaking to each other, so I am quite sure it is going to be planned sometime.

Additional notes…

Although I spoke to Prof Tombal prior to the meeting, I was quite unprepared for the sheer impressiveness of the waterfall plot, which showed a PSA response (i.e. a reduction > 80%) at 25 weeks of 92.5% with a fairly narrow CI (86.2-98.8%).

In a previous interview, Charles Sawyers, the co-inventor of enzalutamide discussed its potential development, including the translational opportunities beyond CRPC in earlier disease.

It looks likely, with these latest results, that enzalutamide has clear activity in advanced (hormonally-sensitive) prostate cancer and a three arm trial, as suggested by Prof Tombal, would actually answer the key question of which therapy would be the optimal solution in this setting. Hopefully, we will see more advances in this area emerge over the next couple of years. If successful, this would be a large potential market opportunity for enzalutamide, potentially much bigger than the CRPC setting before or after chemotherapy.

Making a difference in pancreatic cancer – an interview with Dr Hedy Lee Kindler

Pancreatic cancer is one of those conditions I never hope to get. Why? Well, for starters, it’s one of the most difficult to treat tumour types, largely because so many patients are detected late, that is with stage IV metastatic disease. The annual incidence and prevalence are pretty much equal, suggesting that the for many with advanced disease, the lifespan is approximately one year or less. In fact, to put things even more succinctly, despite surgical resection, radiation and chemotherapy, more than 90% of people with pancreatic cancer do not survive beyond 5 years.

Over the last few decades we’ve seen a few incremental improvements from the original trials comparing 5FU (fluorouracil) and gemcitabine (GEM) to various gemcitabine based doublets and triplets such as oxaliplatin (GEM-Ox), docetaxel (GTX) and erlotinib. Things improved a little in 2010 though, with the landmark trial for FOLFIRINOX (5FU, leucovorin, irinotecan and oxaliplatin) being presented at ASCO, although the nasty toxicities involved tend to limit this regimen to fit patients with an excellent performance status being treated in Academia rather than the Community setting.

In between these two events, we saw multiple promising GEM-based doublets fail repeatedly after initial promising phase I/II data. It was a dismal period for pancreatic cancer researchers and clinicians.

With the advent of new data being presented at the recent ASCO Gastrointestinal meeting in San Francisco, I chatted with Dr Hedy Kindler (Associate Professor of Medicine, University of Chicago) who is well regarded as a pancreatic cancer expert and sees a large number of patients for this disease each year, about the advances in advanced pancreatic adenocarcinoma.

PSB: Very few of the doublets in combination with gemcitabine have succeeded, I think erlotinib was the only combination that got approved. So the first question to you is, what are you excited about now, what are the new things that are interesting in this disease?

Dr Kindler: The last time we spoke was in 2005 or 2006 – a lot has changed since then and Margaret Tempero summarized this very well today in her discussion about the changes over that period of time.

What did Dr Kindler like about the FOLFIRINOX data? Listen to the audio clip below to find out more:

Dr Kindler: Initially, the trial flew under the radar, many of us were not expecting that this was going to be such a positive trial. When we looked at the combination of these four drugs, it looked quite scarily toxic. For many of us, we chose our first few patients very gingerly. For me, my very first patient I used was a radiation oncology nurse in my center who I knew could be compliant, was performance status 0 and was incredibly healthy, and who I could monitor like a hawk.

Over time, I have learned that I can give this, not only to the perfect PS0 but to the PS1’s. I know that I can say with confidence to most patients, you can respond to this and we will gain disease control. We never had that with gemcitabine. You would expect after a few months that the disease would progress and they would feel minimally better. But now, we are seeing dramatic responses. We are extending this not only from metastatic, locally advanced, to many of those borderline resectable patients who are being transformed into resectable patients.

What is exciting with today’s meeting is that we are seeing that FOLFIRINOX Is not the only kid on the block and that the GEM/Abraxane data also shows activity. Certainly the Phase1/2 of GEM/Abraxane looked very exciting, but we’ve, all of us have learned that phase 2 results don’t always pan out to phase 3. It is very nice to see another regimen that shows activity. There is a caveat, 8.5 months is not 11.0 months. There is a difference between the two regimens, there is also a difference in the patient populations.

We can’t broadly say GEM/Abraxane is definitely inferior or definitely less toxic than FOLFIRINOX. As I look as how I am going to use the regimens, for the most part, the data today don’t change the fact that for most of my patients I am going to use FOLFIRNOX, because that is the regimen that has the higher response rate and that has the longer median survival, for most of my good performance status patients.

Will there be patients in whom I use GEM/Abraxane? I am eager to use it, l am eager to learn more about it, but I think it represents a new choice and not merely a new standard. Now I think what we are also going to learn over the future is that there will be certain patients who biologically it is better to use GEM/Abraxane, and as we get the SPARC data that may tell us. As we get other data on FOLFIRINOX we may determine that there are certain patients who should only get FOLFIRINOX. I think that is what we are going to learn over time.

There is still an unmet need of those patients who have a lesser performance status. Only 10% of the patients on the GEM/Abraxane study had a PS of 2, so I don’t feel comfortable extending utilizating that regimen in those patients yet, but there are a lot of PS2 patients who are under-served, who are going to still be getting only gemcitabine, in whom we now need to be looking at other palliative types of regimens and other approaches we can use to help those patients.

The fact that we have choices, that there are new regimens available and that it is not just one size fits all, I think is very exciting.

PSB: What about other gemcitabine based regimens such as GTX? Is that something that is in use commonly?

Dr Kindler: I certainly see GTX utilized in the Community, it is not a regimen of choice for me. I know it is a popular regimen in the Community. There have been many variations upon it, and it hasn’t been established in a phase 3. In fact, I saw a patient very recently treated in the community with GTX who had a PS of 0 and I was rather horrified that that PS0 patient had not received FOLFIRINOX, because I think she would actually have had less toxicity. That patient had a lot of toxicity but would have had a better outcome with FOLFIRINOX and that was based on phase 3 data.

I sense that there is still a lot of Community oncologists who are concerned about the toxicity of FOLFIRINOX, as I was initially, but as I have given it to more and more patients, and recognized – I see the patients on Day 1, first cycle 1 see them on Day 4, I see them on Day 8 – just that first cycle is challenging, so that the patient understands how they manage the diarrhea and other toxicities. Once I am comfortable that they are comfortable, then we just see them every other week.

As I am more comfortable giving this to more and more patients, I am really less intimidated by it, and so I am concerned there may be some people who are simply intimidated by it. You are comfortable with what you are comfortable with, you have a certain range of drugs, that you are used to giving and you are comfortable with it and it works well. Once you expand and try something else, you realize that’s not too bad. I hope people will feel more comfortable with regimens like that.

In terms of other GEM doublets, I think one thing the GEM/Abraxane data shows us is the validity of the meta analysis, which several years ago showed that patients with a good performance status do better with cytotoxic GEM doublets, whether it is GEM/CIS or whether it is GEM/OX or GEM/Cap there are subsets which do better with a GEM doublet, and we see that they have done better with this GEM doublet.

I hope that in the future we focus more on what is the biology, and not reflexively give gemcitabine +/- your drug here, as Jordan Berlin would say. Should you give GEM + this drug because it makes biologic sense, or should you give FOLFIRINOX + this drug or GEM/Abraxane + this drug, because it makes sense to do so from a biological stand point?

Are there subsets of patients, and maybe we should enrich? Your new wonderful targeted drug works only in patients with this wonderful target, so let’s enrich for this wonderful target and only offer that wonderful target to this subset of patients, and that happens to make sense to give with a FOLFOX based regimen so biologically we will give FOLFOX + or – your new wonderful target with said wonderful target.

I think we need to focus on that the way they are doing I-SPY in breast cancer and in other diseases.

PSB: Do you think that will happen in pancreatic cancer?

Dr Kindler: There have been many discussions about doing that. I think one problem in pancreas cancer is that it is not just a disease with one on/off switch. It is a very complex disease with much molecular heterogeneity. A very exciting, interesting presentation in the oral session today about the IL17A. That is a model, but if that is then brought out in patient systems, we may be able to target a subset of patients that way. There are many people who working on this and we hopefully will be able to. PANCAN has the goal of doubling the cure rate by 2020 and it may be achievable, but we’ll have to work pretty hard.

And finally…

The critical SPARC expression data for the phase III MPACT trial of Abraxane plus gemcitabine wasn’t available at this conference, but the presenter, Dr Daniel von Hoff assured me that it will be at ASCO in June. This analysis will potentially be critical in informing physicians whether those patients with high SPARC expression do better than those with low SPARC expression. The poster presented at this conference was based on an overall analysis of all patients, regardless of the biomarker.

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The inaugural report goes out later this month on advanced Pancreatic Adenocarcinoma, where I’ll be providing deeper insights and analysis relating to the market landscape and what the potential new developments with Abraxane, masitinib and S1 mean to both the Academic and Community settings:

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Will ASCO GI herald a new era for pancreatic cancer?

Today I’m heading off to attend the ASCO GI meeting in San Fransciso, and in particular, the pancreatic cancer sessions on Friday.

Source: ASCO

The event promises to be an interesting day with a keynote from Margaret Tempero (UCSF), as well as Daniel van Hoff (TGEN) presenting the much awaited nab-paclitaxel (Abraxane) data in advanced pancreatic ductal carcinoma and a poster on masitinib from the French researchers.

Many of you will recall the excitement expressed at ESMO in this data, although the topline data in the Celgene press release on the MPACT study this week suggests the overall responses were good rather than great.

For years, we’ve seen many doublets come along in combination with gemcitabine in clinical trials and largely fail. This is a very difficult disease to treat, with many patients sadly only lasting a year or less from diagnosis. Partly this can be traced back to the insidiously of the disease with it’s vague symptoms, and partly to the degree of oncogenic addiction to KRAS, which induces resistance and ensures the survival of the tumour.

The key with both the Abraxane and masitinib data will be in the details around potential biomarkers – and whether higher responses are seen in those subgroups or not. In Celgene’s case, it is hoped that patients with high SPARC expression will show better survival, while AB Science have annnounced the finding of a key biomarker of response with out offering any details until the presentation, we will see what each has to offer on Friday.

The other leading question is tolerability. Although gemcitabine is widely considered the standard of care for most patients and is well tolerated, younger patients are often given the FOLFIRINOX regimen upfront, which can lead to better responses at the cost of much higher toxicities, including hospitalisation.

If either Abraxane or masitinib demonstrate a similar survival advantage as FOLFIRINOX, a biomarker for selecting patients and an acceptable toxicity profile, then we may see a change in prescribing in this landscape in the not too distant future. For Celgene, the road ahead may be easier given the drug is already available for breast and lung cancers, whereas AB Science may need another trial with the biomarker first. Time will tell.

The ASCO GI meeting is at Moscone West, a huge black spot for wifi and AT&T reception at the last two cancer conferences I’ve attended there, so there’s unlikely to be much live tweeting.

I will, however, be producing a new report on the advanced pancreatic cancer landscape soon after the event, complete with insights and analysis, so if you would like to receive an early bird warning of this, please fill in the sign up form in the right hand margin.

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