Over the last few months, I've been having some interesting conversations with various people involved with cancer research and have been impressed with how many are going about looking at the clinical trial conundrum with a new and fresher lens. Sometimes doing the same thing repeatedly isn't always in the best interests of everyone, the researchers, doctors, patients, manufacturers, regulatory authorities.
The good news is that there are some new initiatives being discussed that break the mould from just looking at either first-line metastatic or relapsed, refractory disease as the first port of call in a isolationist nihilistic approach. This is good news and I'm hoping that more people taking on a broader, more holistic perspective will change the kaleidoscope of collective thinking.
Think about it.
What happens when patients stop adhering to therapy? How does that affect outcomes? What education is needed to help address this? Who should provide the education? Giving out pills boxes and chips in lids isn't going to change much without a link to why it matters.
At the recent EHA meeting, Jan Geissler gave an excellent overview of the broader factors affecting patients in two different sessions from the patient perspective. I hope it opened many physicians eyes to some of the underlying issues. This issue is nowhere near as simple as many may think. In a different session, David Mahon gave a fascinating talk on the impact of patient adherence on outcomes in CML based on some serious research. As one might expect, they were affected negatively, but the shocking piece of information was how many physicians encouraged dose holidays or skipping a dose, saying it wouldn't matter. This creates the wrong impression to start with.
More recently, the news that compliance with chronic tamoxifen therapy for treatment of hormone sensitive breast cancer is often poor, is not a surprise given the tolerability issues associated with the drug, but what is surprising is how little take-up this made in the medical news (HT Jody Schoger). How many women had a poorer outcome from their hormone treatment as a result of less than 90% compliance? What can be done about it? Very little comment or analysis in the medical press or advocacy world ensued.
In the end, we need more creative leaders working on this problem, a greater synergy between translational and biology research with clinical practice, cross functional working groups that involve multiple stakeholders, including patient advocacy, working towards a common goal for the greater good.
It is only when all of these factors come together in multi-functional teams that faster and better progress in cancer outcomes, in terms of both survival and quality of life, will ultimately be made. Where's that Cowbell when you need it?
Interesting news in Pharmaland today as we hear that Pfizer has decided to voluntarily withdraw gemtuzumab ozogamicin (Mylotarg) from the market and the FDA declined to grant Ziopharm an SPA for their phase III trial with palifosphamide (palifosfamide for those reading in American English) in soft tissue sarcoma.
The first is unexpected, the second interesting.
Mylotarg
In 2000, Wyeth (now part of Pfizer) were granted accelerated (fast track) approval in AML for Mylotarg, an anti-CD33 monoclonal antibody, on the basis of response rates, with the intent that survival data would provide evidence for full approval. Unfortunately, like Iressa's situation in lung cancer, that did not happen so polite withdrawal is the only option in this situation. Perhaps the only surprise is that it took a decade for it to happen.
It's not a big loss for elderly AML patients, given the drug never showed any major efficacy benefit and the side effect profile of fevers, chills, nausea and vomiting severely impacted quality of life for many frail people. Many AML patients are over 60 and in much less robust health compared to younger, fitter patients who might be candidates for high dose chemotherapy and a transplant. This is where Mylotarg was supposed to offer hope, given the limited options. In this setting, the ideal drug would be a targeted therapy without too many debilitating adverse events. Early toxicities with Mylotarg, however, were not pleasant:
"... among all patients evaluable for early toxicity the
fatal induction toxicity rate was significantly higher in
subjects given the combination of standard induction chemotherapy
and Mylotarg than in those treated with chemotherapy alone."
I always look at sales as a good indicator of whether physicians like a drug or not. At around $35M annually, Mylotarg clearly wasn't a popular option. Sometimes we need to focus on what matters - response rates per se (around 10-13% complete responses) don't mean much in isolation, but extending lives does, hopefully without too much collateral damage. In this situation, Pfizer made a good call.
Palifosfamide
Ziopharm's management team have been very bullish and brimming with confidence lately, however, such sentiments can sometimes turn out to be irrational exuberance. The phase II PICASSO trial with palifosfamide and doxorubicin versus doxorubicin alone has completed enrollment with initial promising interim results in metastatic or unresectable soft tissue sarcoma and the company were clearly hoping to negotiate an SPA with the FDA for the phase III trials, but it seems negotiations have broken down on that front, with concomitant fall in the share price.
The trial design is interesting for several reasons.
Firstly, the current standard of care for treatment of soft tissue sarcoma is ifosfamide plus doxorubicin but there's no comparator arm with ifosfamide, an old chemotherapy now available generically.
"Palifosfamide (ZIO-201) is a proprietary stabilized metabolite of ifosfamide."
Meaning it's a second generation version of the generic, but is it any better than ifosfamide? We won't know with the proposed design. Of course, the current reimbursement structure means that oncologists will make more revenue from a branded drug (6% of $1000 is more than 6% of $100), whereas in the old scheme, there was more usage of generics because the spread was greater than for newer, more expensive therapies.
Secondly, the big sticking point for the FDA was the proposed primary endpoint, ie PFS rather than overall survival (OS). One does not always follow the other, but seriously, accepting OS as the goal may well have been an easy win-win for Ziopharm. It seems a little odd that they chose not to go there in the initial discussions with the FDA:
"In a recent communication, FDA has indicated that the Company could conduct the pivotal trial as designed without SPA and that approvability would be determined by the data, balanced with risks and benefits. FDA presently considers the endpoints as designated for the proposed pivotal trial as not supportive of SPA in this disease setting, although they would grant SPA with modified endpoints."
If changing the endpoint from PFS to OS is all that is needed for garnering an SPA, I think I would grab it and go. It's much easier to gain approval if you meet the criteria for a pre-negotiated SPA, as Roche/Genentech have shown with Tarceva several times, even with marginal, yet significant improvements, based on well powered studies. Going it alone without agreement with FDA is a recipe for disaster down the road, as many small biotechs have discovered to their dismay over the last 18 months.
Yesterday brought two new approvals in a day from the FDA in completely different cancer types.
In the morning, sanofi-aventis' cabazitaxel (Jevtana) was approved in castrate-resistant prostate cancer after failure of docetaxel (Taxotere) several months ahead of schedule. This approval comes hot on the heels of Dendreon'ssipuleucel-T (Provenge) in asymtomatic metastatic prostate cancer last month.
What this means is that once androgen ablation therapies stop working, there are three new treatment options for men with prostate cancer, none of which compete with each other, with the possible exception of the chemotherapies, since docetaxel is often given in second-line in men who previously responded well and have had a treatment break. It will be interesting to see if this approach continues or if oncologists will prefer cabazitaxel in those with a good performance status.
The real impact of cabazitaxel though, is on other agents in development. Currently, abiraterone (Cougar Biotech/J&J) and MDV3100 (Medivation/Astellas) were being tested in docetaxel refractory prostate cancer, but now there is a new standard of care, whereas previously there was none. Clearly, common sense suggests that their role might be more impactful earlier in the disease, either after hormonal therapies fail, instead of or in combination with them, especially given that they are oral therapies, making them attractive to urologists.
Classic drug development usually means starting in the relapsed or refractory metastatic setting. The next few years will be thus be interesting to watch, especially if the agents in clinical trials prove successful. For now, Dendreon have a couple of years breathing space until the market potentially starts to get more crowded.
The other Priority approval yesterday was for Novartis' nilotinib (Tasigna) in newly diagnosed chronic myeloid leukemia (CML) on the basis of higher and earlier response rates versus the current standard of care, imatinib (Gleeevc). Full approval follows later once the survival data is more mature, but the early 12 month data looks interesting with a significant advantage to nilotinib over imatinib. It's still early though, survival curves can do strange things over time and can cross over.
Still, it's a promising start and a good result, especially since the bar was raised very high by imatinib. Prior to imatinib, ten year survival in CML was 10 to 20% at best with high dose interferon, but imatinib raised that dramatically to 90%. The second generation TKIs such as nilotinib and dasatinib (BMS) will thus potentially represent incremental survival improvements to 93 or 94%, to put them in context.
Of course, nilotinib's approval will possibly impact dasatinib (Sprycel) since they have just filed for the same indication, making Priority review more unlikely. The last time that happened to two drugs in the same cancer type was for Erbitux (ImClone) and Avastin (Genentech), who filed a few weeks apart, but in two different indications (newly diagnosed and 3rd line).
If dasatinib does get a Priority review after nilotinib it will set a new precedent, but if it doesn't get Priority review, I wonder if an ODAC will occur given that's usually what happens with standard 12 month review?
What's fascinating about the dasatinib data is that it also demonstrated earlier and deeper responses than imatinib, but the front-line data presented by Drs Kantarjian and Baccarani at ASCO and EHA respectively, did not appear to show any earlier survival benefit at 12 months for dasatinib vs imatinib, unlike nilotinib. I say 'appear' because the curves were very close together and no P value was given, so my assumption is that they weren't significantly different at this stage. That may change over time, but for now, the DASISION data presented by Dr Kantarjian showed a 12 month OS of 97.2% to dasatinib and 98.8% to imatinib, presumably not a significant difference. Deaths in the two arms were 10 and 6 respectively, again favouring imatinib, but not significantly.
Obviously, comparing these curves at 5 years would be a much fairer comparison for overall survival, but for now, the 12 month data is all we have to go on and there are early differences between nilotinib and dasatinib.
It was also interesting to watch the often hyped and inelegant reporting of the data by the media at the Congresses proclaiming superiority. We know that in solid tumours, shrinkage or tumour response does not always lead to an improved survival benefit for the patient. Similarly, in leukemia, we also measure response rates - in this case - complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR), as initial surrogate markers for initial approval, but survival is also critically important for full approval in the US. Interestingly, the early log 4 reduction (CMR) rates seemed to slightly favour nilotinib over imatinib (but not significantly), however none were presented at ASCO or EHA for dasatinib over nilotinib (unless I missed the slides).
Ultimately, ASH will herald the 2-year and 18-month data for nilotinib and dasatinib respectively, which will hopefully be an important milestone on the way to seeing how the mature five year survival data will evolve.
Disclosure: I'm a former Novartis employee and marketing director for Gleevec, so naturally I'm slightly biased towards imatinib :). Many thanks to @erohealth for proofreading suggestions.
After the success of the American Society of Clinical Oncology (ASCO) Twitter aggregation, with over 250 readers over the course of the weekend, I thought it would be fun to repeat the experiment for the European Hematology Association (EHA) meeting in Barcelona this weekend. The tweet volume is likely to be significantly less tough, with fewer people tweeting from the event.
Most of the topics I'm interested in will be on leukemias, lymphomas and myeloma, so if you are interested in these cancers, you can follow the feed below. I've aggregated two hashtags, #EHA10 and #EHA2010.
Additionally, Dr Anas Younes from MD Anderson Cancer Center will also be attending and following his tweet stream may also be instructive, especially if you are interested in his specialty, lymphomas.
Do feel free to join in remotely in the back channel and add links, comments or ask questions if you feel so inclined. The more the merrier!
I'm particularly looking forward to the Patient Advocacy symposium chaired by Jan Geissler, an awesome guy who just happens to have CML. While the science and clinical data are important, it's also critical to hear and learn from the advocacy viewpoint.
On the healthcare (#hcsmeu) front, I'm also hoping to meet fellow Twitter buddies, Miguel and Angel for an impromptu tweetup of #hcsmeuES. If you're on Twitter and interested in healthcare, check them all out, all three are great gentlemen I would highly recommend!
As many readers here on PSB know, I've not been a big fan of genome-wide molecular profiling, preferring an oncogene addiction approach to drug development and targeted cancer therapies. However, every once in a while something comes along that stops you in your tracks and makes you think differently.
This morning I was reading the latest copy of the New England Journal of Medicine over coffee and was fascinated by a review article by Drs Lenz and Staudt at the NCI on the molecular genetics of diffuse large-B-cell lymphomas (DLBCL), which account for 30-40% of newly diagnosed lymphomas.
As the review article points out, it is well know that different subsets of diffuse large-b-cell lymphomas are associated with different overall survival rates after initial anthracycline based therapy. For example, it is more favourable in people with PMBL and the GCB subytype but less favourable in those with the ABC subtype. R-CHOP therapy has improved survival in people with ABC, but the cure rates are still lower than those with the GCB subtype. Gene expression signatures can help identify the subtypes and predict survival rates:
Current therapeutic treatment with chemotherapy has made headway in improved survival, but in order to make further headway, new approaches are very much needed. Targeted therapies have now begun to expand clinical trial options.
The article talks about numerous pathways, but I particularly liked this one, which details the Nuclear Factor kB (NFkB) signalling pathways in normal and malignant lymphocytes:
Essentially, signalling is initiated when a SRC family kinase ( SFK) phosphorylates tyrosines in the immunoreceptor tyrosine-based activation motifs (ITAMs) on B-cell subunits. SYK is then recruited to the ITAMs through the SH2 domains and becomes active. Many of you will remember SYK inhibition from previous posts on Rigel's fostamatinib, a SYK inhibitor. I think Celgene also mentioned a SYK inhibitor in early development at their recent R&D Day, although the Rigel-AZ is further ahead but more erratic in it's results, at least in immune disorders. A more recent paper in Blood looked promising in NHL and CLL, though. Companies are clearly starting to look at specific inhibitors in the downstream pathway for lymphomas and chronic lymphocytic leukemia.
What's interesting about the cartoon above is that you can also see that phosphatidylinositol-3-kinase (PI3-kinase) is activated in parallel, activating the mTOR pathway. These two targets are getting a lot of attention from Pharma in the clinic, especially in leukemias and lymphomas, and we may well see more of their latest development at AACR next week and ASCO in June. Exelixis and their partner, sanofi-aventis (a client), for example, have already announced 12 abstracts at ASCO, including 6 on their PI3K and mTOR inhibitors, but they are focusing on lung cancer, a much more difficult carcinoma, rather than NHL, where there is a strong rationale.
It's good see new treatment modalities being tested in leukemias and lymphomas and not just solid tumours, where most companies inevitably focus due to the larger population sizes. That said, the challenge in lymphoma is going to be identifying rational combinations that kill lymphoma cells synergistically. As we learn more about the underlying biology of the disease, targets and biomarkers, so more effective and less toxic solutions may evolve.
Lenz, G., & Staudt, L. (2010). Aggressive Lymphomas New England Journal of Medicine, 362 (15), 1417-1429 DOI: 10.1056/NEJMra0807082
Friedberg, J., Sharman, J., Sweetenham, J., Johnston, P., Vose, J., LaCasce, A., Schaefer-Cutillo, J., De Vos, S., Sinha, R., Leonard, J., Cripe, L., Gregory, S., Sterba, M., Lowe, A., Levy, R., & Shipp, M. (2009). Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia Blood, 115 (13), 2578-2585 DOI: 10.1182/blood-2009-08-236471
Yesterday afternoon, the FDA and ODAC met for a second time in the day to review the application for omacetaxine from ChemGenix. The drug was tested in limited trials in people with chronic myeloid leukemia (CML) for whom tyrosine kinase (TKI) therapy with drugs such as imatinib, dasatinib or nilotinib had failed or who had the T315i mutation.
My previous analysis from last month is here. Unlike the concerns in the morning with safety and efficacy associated with pixantrone in NHL, this time the FDA were clearly concerned about the validity of commercially available assays to detect the T315i mutation.
I did a search to see what was out there for testing T315i and found two:
Interestingly, the DxS one clearly states that it is for research purposes only, not for diagnosis. I'm not sure if the Quest test has been approved commercially, but it would seem odd of the FDA to make a song and dance about a widely available test if there is one available, so it is possible that both are only available for research purposes so far and as such, not approved for commercial use. Or it may be that the Quest one is approved but has not yet been validated with omacetaxine. It isn't overly clear from the information we have so far.
Either way, Kerri Wachter was on the scene at the meeting and tweeted the vote succinctly:
This isn't really surprising: if you are claiming to target a particular marker or target, then you need a validated companion diagnostic test to be commercially available once the drug is approved. I think what the FDA is saying to ChemGenex is that they need to do a small study comparing and validating the data between commercial assays and the ones used more commonly in hospital Path labs for research purposes and clinical trials. It's not a big deal, but it does need to be done.
After yesterday's post about the I-SPY trials in neoadjuvant therapy for breast cancer and how they may speed up the process of bringing new innovative cancer drugs to the clinic faster, I was reflecting on my own experiences with imatinib (Gleevec).
The Philadelphia Chromosome was first identified in 1960 by Nowell and Hungerford. Gleevec was finally approved by the FDA in May 2001, 41 years later.
Between 1999, when I arrived in the US and working in New Product Development at Novartis until 2001 when Gleevec was launched, I attended scientific meetings including AACR, ASH and ASCO. Often, Dr Judah Folkman, a scientific researcher from Harvard, would talk about angiogenesis and hypothesised that was the principal mechanism by which tumours grew. I listened to his ideas many times because I was curious and found the concept both fascinating and intuitive. There was a long line of drugs that failed to work though, and every meeting seemed to bring yet more negative results.
Now, Folkman first advanced the angiogenesis theory in 1971 in the New England Journal of Medicine, but it wasn't until 2002, when bevacizumab (Avastin), a VEGF inhibitor that prevented angiogenesis from happening, was finally approved for the treatment of colon cancer. At that point you go, 'oh wow' and realise that Folkman's theory was indeed proven correct.
Thus a tale of two incredible cancer drugs that both took a relatively long time to evolve from scientific idea to effective treatment in people with cancer. Or perhaps they were actually relatively 'quick' compared to others, but why it takes this long is something we can surely do better at.
Last night I was researching ideas for drug development and innovation since the concept of bench to bedside fascinates me and came across this enlightening video from a lunchtime talk that Dr Susan Desmond-Hellmann gave last year at UCSF. Oddly, she seems to have trodden similar thought processes and asked why and how can we speed things up as well.
The short lecture is well worth listening to for those interested in drug development - the good doctor explains the bench to bedside concept far better than I:
Sources for scholars and clinical scientists:
The NEJM doesn't appear to go back beyond 1993 online, but the original reference to Folkman's article is at:
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186.
A more recent one from 1995, which provides an update is available online at: NEJM
This morning the newswires (HT Mike Huckman) are full of the BioSante (formerly Cell Genesys) news on their leukemia vaccine, GVAX, which is being tested to see whether it is a viable approach for eradication of minimal residual disease. Accordingly, BioSante announced:
"Positive results of a human clinical study that show that its GVAX Leukemia vaccine may be able to reduce or eliminate the last remaining cancer cells in some chronic myeloid leukemia (CML) patients taking the drug Gleevec (imatinib mesylate). All patients enrolled in the trial used Gleevec for at least one year and still had cancer cells present. The study was conducted by researchers at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, led by Hyam Levitsky, M.D., professor of oncology, medicine and urology at the Cancer Center. The research was funded by the National Institutes of Health."
Currently standard of care for CML is daily treatment with an oral tyrosine kinase inhibitor (TKI), imatinib (Gleevec), with the option of two second generation TKI's nilotinib (Tasigna) and dasatinib (Sprycel) being available if the imatinib fails. All three of these drugs are effective at inhibiting the enzyme associated with the gene BCR-ABL, which occurs in every CML patient and essentially shut off production of the excess white blood cells so that the cells stop growing and eventually die.
There are various degrees of response with TKIs and at the American Society of Hematology meeting in December, Tim Hughes from Adelaide presented the concept of a safe haven as you can see from the chart below:
Source: Dr Tim Hughes, Adelaide, Australia
Obviously, the deeper the response, the more likely a patient would attain a major molecular response (MMR) and provide a safe haven from treatment relapse.
The important question then becomes one of how low should one go in order to
Optimise treatment response and
Provide enough protection without increasing side effects?
Going back to the quote at the top of the post about GVAX, we can see that the researchers goal was to eliminate minimal residual disease (MRD) and kill all detectable cancer cells below what is currently possible with TKI therapy.
In the article published in Cancer Clinical Research (free PDF download courtesy of AACR), it seems that according to the researchers
"Thirteen patients had a progressive decline in disease burden, 8 of whom had increasing disease burden before vaccination. Twelve patients achieved their lowest tumor burden measurements to date following vaccine, including seven subjects who became PCR-undetectable."
Now while this is very good news to hear that it can be accomplished, the numbers are very small and we don't have any data whatsoever yet to prove that achieving the nirvana of MMR is actually necessary for the majority of CML patients. None, nada, zilch. We also do not have any idea from the article how durable the vaccine results will be yet as there may be an attenuation of response over time.
We do know from the IRIS updates that newly diagnosed people with CML now have a much longer life expectancy of around 7+ years on average when treated with imatinib. Stem cell transplants are curative in some patients, but that decision is fraught with a risk-benefit trade-off of 20% procedure related mortality and the risk of graft-versus-host disease and other long term complications afterwards.
In conclusion:
It will be interesting to see what impact this vaccine will have in the long term in terms of improved survival for people living with CML and whether future research will demonstrate a clear need to eliminate minimal residual disease below what is currently possible. These are promising results and I look forward to seeing more data over the next few years as the answers evolve. The ultimate goal is always to find a cure but whether this approach will help achieve that remains to be seen.
Smith, B., Kasamon, Y., Kowalski, J., Gocke, C., Murphy, K., Miller, C., Garrett-Mayer, E., Tsai, H., Qin, L., Chia, C., Biedrzycki, B., Harding, T., Tu, G., Jones, R., Hege, K., & Levitsky, H. (2010). K562/GM-CSF Immunotherapy Reduces Tumor Burden in Chronic Myeloid Leukemia Patients with Residual Disease on Imatinib Mesylate Clinical Cancer Research, 16 (1), 338-347 DOI: 10.1158/1078-0432.CCR-09-2046
Last night and this morning brought some topical news on the leukemia front.
Just before 5pm EST yesterday, the FDA announced they had approved Roche/Genentech'srituximab (Rituxan) in chronic lymphocytic leukemia (CLL). Rituxan is already approved for non-Hodgkins Lymphoma (NHL) and rapidly the standard of care when combined with CHOP chemotherapy in this disease. CLL is the most common adult leukemia and tends to affect older patients.
According to the Roche press release this morning, the FDA approval was for:
"Rituximab plus fludarabine and cyclophosphamide (FC) chemotherapy for people with either previously untreated (first-line) or previously treated (relapsed or refractory) CD20-positive chronic lymphocytic leukemia (CLL)."
The CLL data was presented last year at ASH, showing that FCR led to improved survival compared to FC alone. FDA's press release highlighted the results:
"The safety and effectiveness of Rituxan was evaluated in two studies that measured progression-free survival, defined as the time a patient in the study lived without the cancer progressing.
In one study of 817 patients who had not received any prior chemotherapy, progression-free survival was eight months longer for those receiving Rituxan plus chemotherapy than for those who received chemotherapy alone. In another study of 522 persons whose cancer had progressed following other chemotherapy drugs, progression-free survival was five months longer for those who received Rituxan plus chemotherapy.
The FDA analyzed the data on patients 70 years of age and older who had received Rituxan and found no evidence that adding the drug to chemotherapy benefitted elderly patients compared to receiving chemotherapy alone. However, there was also no evidence that Rituxan was harmful to elderly patients."
This approval affects several companies in the CLL space.
Late last year, GSK received approval for their CD20 antibody, ofatumumab (Arzerra) in CLL in the refractory setting but are likely to be impacted by rituximab's approval in both first and second line CLL. My guess would be that physicians will be very comfortable and experienced using the Roche/Genentech monoclonal antibody and therefore using it in CLL as well as NHL will not be a difficult stretch.
Bendamustine (Treanda), from Cephalon, is an old drug that has been making a comeback in NHL and after the success of the bendamustine-rituximab (BR) combination in NHL that was presented at ASH, it may well become the new standard of care there instead of R-CHOP. Trials are ongoing with BR in CLL and if positive, I can see that becoming a solid option in CLL in the not too distant future. For now, FCR looks like being the most efficacious first-line option in CLL, replacing FC. It may not be long before BR offers similar or better efficacy than FCR with fewer side effects. We will have to wait and see.
The other news that was interesting in my inbox is that Novartis (a client), announced that nilotinib (Tasigna) received FDA priority review for newly diagnosed patients with early-stage chronic myeloid leukemia (CML):
"FDA priority review status is granted to therapies that offer major advances in treatment or provide a treatment where no adequate therapy exists. This status accelerates the standard review time from 10 to six months. Tasigna demonstrated that significantly fewer patients progressed to more advanced stages of the disease than the standard of care Glivec® (imatinib)* at 12 months. Tasigna also showed a statistically significant improvement over Glivec in every other measure of efficacy in the trial, including major molecular response (MMR) and complete cytogenetic response (CCyR) at 12 months."
Novartis and BMS were in a race to file for the front-line indication for their second generation tyrosine kinase inhibitors (TKIs) with comparative trials versus the standard of care, imatinib (Gleevec/Glivec). Novartis presented the initial Tasigna results at ASH in December in a late breaking abstract that pointed to earlier and deeper responses with nilotinib compared with imatinib.
BMS didn't presented any data from their randomised registration trial at the meeting, but recently announced at the JP Morgan Healthcare conference last month, that they expected data to be available at ASCO. I'm not sure whether they submitted a regular abstract or a late breaker, but it will be interesting to see what the data looks like and the big question now is when will they be filing Sprycel with the FDA for the front-line indication?
It going to be an interesting few months ahead in leukemia, that's for sure!
That sure was a hot alert sitting in my inbox this morning.
In looking carefully at the AstraZeneca ($AZN) press release, it seems that the details are as follows:
Much of the focus in the news is on the RA indication, although AstraZeneca do not have a franchise in this area. All of their inflammation products on the market have been in the respiratory, not immunology, area as far as I can remember, making them an odd choice for a partner. Still, AZ have had a few flops recently (Iressa being a spectacular one in oncology) and with a weak pipeline, they are desperate for some near term success to drive revenues sooner rather than later. The recent announcement that 8,000 jobs will be cut is indicative of much cost cutting is going on.
Previously, we have discussed the Rigel RA data when the initial phase IIb data was disappointing and failed to meet at least one primary endpoint according to Rigel's press release last July. This raised alarm bells in many Pharma licensing departments and significantly raised the risk for fostamatinib in RA.
That said, the data for fostamatinib in chronic lymphocytic leukemia (CLL), are much more promising as discussed post ASCO last year. The agent is a SYK inhibitor and updated results presented by Dr Friedberg et al., at ASH in December confirmed that the data is still holding up.
All of the analyst news seems to be rehashes of the joint press release focusing on RA, which of course, is a much bigger, but higher risk, indication than CLL. In looking at the Rigel pipeline, fostamatinib was the last product seeking a partner:
My assumption is that AstraZeneca will also be taking up the options on all of the indications for R788, including the oncology ones and not just RA from Rigel.
It may well be that in the final analysis, the CLL data will turn out to be more solid than the RA data if the phase II trials are anything to go by, but time will tell. The good thing is that AZ have an oncology franchise, albeit not in hematologic malignancies.
This week, (10th February) the FDA's Oncologic Drugs Advisory Committee will be meeting to review the filings from Cell Therapeutics ($CTIC) and ChemGenix ($CXSPY) for pixantrone and omacetaxine, in relapsed refractory NHL and CML, respectively.
I've just taken a few minutes to read the briefing documents and here are my initial thoughts.
Cell Therapeutics, a Seattle based biotech company, are going to have a very tough morning on Wednesday in DC for the following reasons:
The pivotal study had a very poor accrual with only 140 out of 320 patients enrolled.
Substantial cardiac and hematologic toxicities.
Risk:benefit trade-offs are always going to be a question for debate in the third-line setting, but CTI may well have shot themselves in the foot by closing enrollment early. This led the FDA to raise an important questionabout the study and whether there was sufficient information:
"the level of evidence necessary to draw conclusions from this Phase 3 study and the reliability of these conclusions."
Ouch.
After recent trials and tribulations over studies in elderly patients with AML had problems with a placebo comparator, it was good to see that in PIX301, patients were randomized 1:1 to single agent pixantrone or the following choice of comparators:
Oxaliplatin
Ifosfamide
Vinorelbine
Etoposide (PO/IV)
Mitoxantrone
Gemcitabine (only at U.S. sites)
Rituximab (only at U.S. sites)
Patients were treated for up to 6 cycles.
However, perhaps the most damning part of the FDA briefing document is the impact of halting enrollment early:
"The pivotal trial, PIX301, was discussed at an End of Phase 2 meeting on October 8, 2003. At this meeting, FDA stated, “Accelerated approval could be based on an interim analysis of a surrogate endpoint with completion of the trial demonstrating an improvement on a clinical benefit endpoint (survival or symptom benefit).”
FDA recommended that the trial assess complete response and the duration of complete response. Subsequently, agreement was reached concerning a Special Protocol Assessment for PIX301.
On March 28, 2008, CTI notified the FDA of an early halt to enrollment for PIX301. The study was not stopped at a planned interim analysis and early study stopping invalidated the applicant’s Special Protocol Assessment."
Based on this history, I think CTI will have a tough time arguing for approval on the basis of a shortened 140 patient study. It is clear in the FDA's analysis that they do not believe statistical significance was reached for the key efficacy measures.
Meanwhile, ChemGenex, a biotech company based in Australia with an office in San Francisco, are applying for approval of omacetaxine (Omapro) as treatment of adults with chronic myeloid leukemia (CML) who have failed prior therapy with imatinib and have the Bcr-Abl T315I mutation.
Interestingly, the FDA had completely different concerns with this filing.
The main issue with omacetaxine was that a commercially available assay does not exist for the T315i mutation and the company apparently didn't submit any information on how they were going to address this going forward. It's one thing to have central labs and academic labs do testing for trials, but given the majority of CML patients are seen by community oncologists in the US, a commercial assay is crucial for enabling decisions to be made on when to start therapy if the T315i mutation appears.
I would be surprised if a such a test hasn't been considered, but we will see what happens at ODAC on Wednesday. Approval may possibly be delayed until one is made available.
This is my second to last report on the interesting new data coming out from the American Society of Hematology (ASH) meeting in New Orleans, LA earlier this month. They've taken a little long than I expected to get through due to our current workload and client reports, so sincere apologies for the backlog.
The final update will be a comprehensive one on chronic myeloid leukemia (CML), but today I wanted to focus on myelodysplastic syndromes or MDS for short. Let's start with a basic question: what are they?
According to the NCI:
"The myelodysplastic syndromes (MDS) are a group of disorders characterized by one or more peripheral blood cytopenias secondary to bone marrow dysfunction. MDS are diagnosed in slightly more than 10,000 people in the United States yearly for an annual age-adjusted incidence of 3.4/100,000 people."
MDS can arise naturally or as a result of chemotherapy given to treat acute myeloid leukemia (AML). Unfortunately, secondary MDS has a much poorer prognosis than de novo.
lenalidomide for patients with deletions of chromosome 5q31.
A few years ago I remember sitting in a packed plenary session and getting goosebumps hearing about the lenalidomide data in patients with 5q31 deletions, or maybe it was the freezing hangar where the presentations were being held, but the science behind the concept was fascinating.
The question is, what was hot this year at ASH in MDS? Here's a roundup of some of the interesting data I thought was interesting and relevant to this disease:
Bortezomib (Velcade): This study suggested that Millennium's drug, currently approved for the treatment of myeloma and mantle cell lymphoma, may be effective in MDS. The study included 10 MDS patients with a median age of 64 years. Bortezomib was given at a dose of 1.3 mg/m² on days 1, 4, 8 and 11 every 28 days for a maximum of eight cycles. 6 patients completed all eight cycles. Of the 6 evaluable patients, 3 patients (50%) achieved a minor red blood cell response, and three patients (50%) achieved stable disease. 7 out of 10 patients survived to the median follow-up of 24 months.Four patients experienced severe neutropenia (low white blood cell count), and six patients experienced severe thrombocytopenia (low platelet count). 7 patients experienced other non-blood cell-related side effects including diarrhea, fever, skin rash, and pneumonia. It was concluded that single agent bortezomib has some initial efficacy in achieving hematological improvement in MDS patients but a larger sample of MDS patients is needed to confirm these results.
Lenalidomide(Revlimid): Some German researchers looked at gene expression profiles to try and predict responses to therapy in MDS. They found that single sample prediction could discriminate 3 out of 8 patients as possible responders to lenalidomide, but this was not correlated with the clinical course of those patients while on treatment with the drug. In addition, it appeared that none of the MDS-patients receiving lenalidomide showed significant clinical response as defined by reduction of transfusion requirement by 50% or transfusion independence. The researchers concluded that prediction of response to treatment with lenalidomide in patients with Non-Del 5q myelodysplastic syndrome by gene expression profiling remains difficult.
A phase III trial looked at the optimal dosing for lenalidomide in 205 patients wo were randomised to receive either 5mg or 10mg of lenalidomide versus placebo. Previous phase II trials have shown that lenalidomide resulted in transfusion-dependence (RBC-TI) in 67% of patients and complete cytogenetic response (CyR) in 45% of patients with RBC transfusion-dependent low or intermediate risk MDS with del5q.
The researchers concluded that both doses of lenalidomide were generally well tolerated and achieved significant transfusion dependence and CyR. Lenalidomide 10 mg was associated with better RBC-TI and CyR than 5 mg, while maintaining a comparable safety profile. The data supported the use of 10 mg as a starting dose, with dose reductions or discontinuations, if needed.
Arsenic trioxide (Trisenox): A phase II study investigated the combination of ATO and ascorbic acid is tolerable. The drug was administrated intravenously over 1 hour at the loading dose of 0.30mg/kg/day for 5 consecutive days, followed by 0.25mg/kg/day twice weekly for 15 weeks. Ascorbic acid 1000mg was given by IV within 30 minutes after each arsenic trioxide infusion.44 patients were enrolled in the study and 10 obtained a response (23%), including 1 complete remission. In 8 out of 10 responders, the response was evident within the first 8 weeks of treatment. 52% patients discontinued treatment because of various factors including disease progression (11%), severe adverse events (32%), drug unrelated adverse events (5%) and withdrawal of consent (5%). Severe neutropenia and thrombocytopenia were observed respectively in 45% and 23% patients.
Overall, the researchers concluded that the combination of ATO and ascorbic acid was tolerable and active in about 25% of MDS patients. The addition of ascorbic acid to ATO does not increase neither the toxicity nor the response rate to ATO. The tolerability of this regimen is reduced in elderly and high risk patients.
Vorinostat (Zolinza): Merck's HDAC was initially approved for CTCL, a rare form of NHL, but we have seen little dramatic data from other clinical trials since. There is, however, significant logic in testing epigenetic therapy in MDS. This phase I study looked at the combination of vorinostat with decitabine in the treatment of newly diagnosed AML or MDS using 6 different dosing schedules including concurrent and sequential therapy. 72 patients were entered into the study with a median age of 68 years and 58% were male. To date, 69 patients have discontinued. Of the 70 patients evaluable for safety, 69 experienced AEs, the majority of which were relatively mild ie grade 1/2 in severity and included nausea, diarrhea, fatigue, constipation, and vomiting. In MDS patients receiving concurrent therapy, complete remission (CR) was achieved in 2 out of 5 patients, stable disease (SD) in 1 patient, partial remission (PR) in 1 patient, and hematologic improvement in 1 patient; all 6 of the patients who received sequential treatment experienced SD.Overall, although preliminary, the data is promising and indicates that the combination of vorinostat and decitabine, either concurrently or sequentially, is possible without significant toxicity.
In all, while MDS is a particular difficult to treat disease, the initial results suggest that further investigation of drugs such as bortezomib, lenalidomide, arsenic trioxide and vorinostat is warranted and if further studies show more durable and repeatable responses, we may potentially see some new treatment options for MDS in the near future.
At the American Society of Clinical Oncology (ASCO) meeting earlier this year, we learned that rituximab added to standard fludarabine plus cyclophosphamide improved overall survival in patients with chronic lymphocytic leukemia (CLL), even in elderly patients of 70 years old.
Six months later, one of the highlights of the American Society of Hematology
(ASH) meeting held in a rather cold, wet and windy New Orleans, was updated data presented by
the same German CLL Study Group (GCLLSG) confirming the combination of
fludarabine, cyclophosphamide and rituximab (FCR) as the current front-line
standard of care in chronic lymphocytic leukemia (CLL).
Michael Hallek of the University of Cologne reviewed updated results from the GCLLSG CLL8 study, in which FCR was compared against the combination of fludarabine and cyclophosphamide (FC). At ASH in 2008, data was presented showing FCR to be superior to FC in terms of response rate and progression free survival (PFS). This year at ASH, Hallek presented updated data showing that patients in the FCR study arm still had a statistically significant higher overall survival (OS) compared to those receiving FC.
The published abstract shows the OS rate at 37.7 mo was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01). At the conference, Hallek presented data showing an 87.2% OS in the FCR arm versus 82.5% in the FC arm (P=0.012) at three years for those who achieve a complete response. There is a clear survival benefit from treatment with FCR as compared to FC, particularly in those patients who have Binet A or B stage disease.
The data for this combination suggested that it appears to be safe and effective. Response rates for BR were similar to those obtained with FCR. However, there were significantly less neutropenias with BR than would be expected with FCR. This has led the GCLLSG to initiate a protocol (CLL10) comparing FCR against BR in front-line CLL. The results from this study will show whether the new standard of care in front-line CLL should become bendamustine in combination with rituximab in the future.
In the poster sessions, a number of interesting ones jumped out at me that may be worth looking at in the clinic for the future.
Lenalidomide (Revlimid) has shown early promise in CLL in the CLL5 AGMT study. This was a phase I/II study that looked at combining fludarabine with rituximab with escalating doses of lenalidomide. Although only a small number of evaluable patients (n=6) were available, all 6 patients responded and 3 achieved a complete response. 40% of the patients were dose limited due to skin and vascular toxicities so the protocol was amended to include thrombo-prophylaxis and delayed start of prophylaxis against pneumocystis. It is too early to tell whether this regimen will reach the prime time but the risk-benefit trade-off may turn out to an issue.
An interesting compound that I have been following for a little while is Trubion's TRU-016, which is a small modular immunopharmaceutical protein (SMIP) being tested in relapsed and rferactory CLL. It targetes CD37, expressed predominantly on B-cells. In a phase I study, interim results were presented from CLL patients (n=33), demonstrating a manageable safety profile despite grade 3/4 myelosuppression. The DLT and MTD had not yet been reached. Reductions in peripheral lymphocytosis were observed, together with some objective responses in the higher dose cohorts. hopefully, further data will be available on this novel agent at ASCO in the summer.
Overall, with new monoclonal antibodies in development and the recent approval of ofatumumuab in refractory CLL, it is likely there will be interesting new data and further changes to the standard of care over the next two or three years. Biomarkers are also slowly emerging in CLL research, and while it is early days yet, it is good to see some attention finally being given some importance in this disease both from a predictive and a prognostic standpoint.
We can expect some compelling new data in the treatment of CLL, hopefully by ASCO in June 2010.
Acute myeloid leukemia (AML) is a truly nasty disease and one I hope never to have the misfortune to be diagnosed with.
Last month, at the Chemotherapy Foundation in New York, Dr Norman Wolmark gave an entertaining lecture on what he called the "Decade of Discontent" in colorectal cancer, a bleak period where no new therapies or stunning ideas emerged and the researchers bogged themselves in answering minutiae rather than focusing on the bigger picture.
He could well have been describing AML.
Why?
Take a look at this slide that was shown at the AML Super Friday educational symposium (the reference is from Dohner et al., (2009), published in Blood and how complex the disease has become with a myriad of phenotypes being described:
But this approach begs a most important question:
Which of these mutations or phenotypes are actually relevant and what is driving the cancer's survival and ability to outwit treatment?
No one really knows and thus it illustrates the frustration inherent in making a nasty disease ever more complex. Just because a mutation exists or a pathway is overexpressed does not mean that it is critical to the survival of the leukemia cells! Sometimes the mutations occur as artifacts, a function of a generally increasing leukemic burden over time as the disease gets more established.
Undoubtedly, the 14% of AML patients who have no additional mutation beyond the t(9,11) translocation that defines the disease, probably do best and at least attain a complete response (CR). The issue of how to keep them there, thus preventing relapse from occurring is an entirely different matter. We need more smart young researchers like Dr Gail Roboz in New York who asked the Chemotherapy Foundation audience what can be done to keep more AML patients in remission?
In ALL, which is more common in children than adults, there are well accepted maintenance therapy strategies for maintaining remission. In AML, post transplant or chemotherapy, there are none. Why it is not clear, but certainly something that can be easily tested with the plethora of targeted agents we have available on the market or in the clinic.
At the American Society of Hematology meeting in New Orleans this week, we attended a number of education and oral sessions discussing AML and read many posters on the topic too. What was startling was how little real progress has been made over the last five years... there were numerous versions of induction and conditioning regimens associated with stem cell transplantation, a general agreement that using the current targeted agents in late stage relapsed or refractory disease is doomed to failure because the leukemic burden is too high...
Dr Wolmark's 'decade of discontent' comment rang loudly in my ears while walking around a huge cold hangar on Monday reading poster after poster with little positive news to inspire or encourage. Skipping to the CML, CLL or NHL poster sections brought cheer and hope by comparison.
Part of the problem with AML is that many of the patients are diagnosed in the elderly, thereby limiting options either because the regimens are highly toxic and less well tolerated, transplant is not an option (survival decreases in the over 55 yo) or they have co-morbidities and multiple mutations, reducing the effectiveness of therapy.
There is, therefore, a clear need for alternative approaches in this population as well as better therapies for the very young who at least have a chance of cure by preventing relapse.
At ASH, some abstracts did catch my eye. Genzyme's clofarabine (Clolar) is one such interesting drug, currently approved for acute lymphocytic leukemia (ALL) and being tested in elderly AML patients. FDA's ODAC recently declined to approve clofarabine in elderly AML patients in the relapsed/refractory setting because the trial was compared to placebo. The same thing happened with Vion's laromustine (Onrigin) in the elderly AML setting. We will probably have to wait until the comparative trial data is available for clofarabine in 2010 before any major decision can be made as to the drug's safety and efficacy in the elderly population. There were no new abstracts on laromustine at this ASH meeting.
Meanwhile, some other interesting companies with early phase I/II data in AML included Sunesis and Cyclacel, both of which have seen their stock price rise since ASH on publication of the data.
Sunesis are developing voreloxin, a chemotherapy given as an infusion and used either alone or in conbination with cytarabine (araC) in heavily pre-treated AML. In the combination study (#645), the researchers found that:
"Among evaluable first relapse (n=36) and primary refractory patients (n=28), preliminary median overall survival is 7.8 months and the remission rate is 31% (complete remission [CR] 27%, complete remission without full platelet recovery [CRp] 2% and complete remission with incomplete recovery [CRi] 2%).
Historical median overall survival data in primary refractory and first relapse patients on currently available chemotherapies range from Voreloxin in combination with either bolus or continuous infusion cytarabine was generally well-tolerated. Infection-related toxicities were the most common Grade 3 or higher non-hematologic adverse events. In addition, Grade 3 or higher oral mucositis was observed."
A poster (#1037) was also presented on voreloxin in elderly AML, and while the data looks interesting initially, I would have major concerns about the registerability of the data given that it is a single arm study of the sort that the FDA and ODAC has repeatedly baulked at:
"Median survival was 8.7 months in Schedule A; 5.8 months in Schedule B; and 7.3 months (preliminary) in Schedule C (72 mg/m2 on days one and four).
Median duration of remission was 10.7 months and one year survival was 38% for Schedule A. For the other schedules, median duration of remission has not been reached and one year survival is too early to evaluate.
Patients age 75 or older (N=49) with at least 1 additional risk factor at diagnosis, a population identified by the National Comprehensive Cancer Network (2010) AML Guidelines as having poor outcome to standard treatment,experienced a CR rate of 30% and a 30-day all-cause mortality of 5%.
Survival in these patients was too early to evaluate.
Based on trial results, Schedule C has been determined to be the recommended pivotal dose regimen. For Schedule C, response rates (CR and CRp) are 38%; 30- and 60-day all-cause mortality are 7% and 17% with improved tolerability over Schedule A."
Cyclacel is a NJ biotech developing an oral prodrug for AML, MDS and CTCL called sapacitabine, a nucleoside agent that targets DNA synthesis and cell cycle arrest. Several phase II studies were presented at ASH, including interesting data on long term follow up in elderly AML patients from an MD Anderson study (#1061) and another in MDS (#1758).
It should be noted that while the one-year follow up data looks promising in AML, the study design suffers from the same issue as tipifarnib, clofarabine, laromustine, and voreloxin in that there is no comparator arm from which to compare and determine if the investigational agent is actually significantly prolonging life in AML.
Overall, it was a disappointing meeting in AML and I sincerely hope that some mre enlightening data emerges in 2010 rather than face the dreaded precipice that Wolmark so pithily described.
At the American Society of Hematology meeting last weekend, I had the pleasure of listening to an enlightening education session on CML from Drs Brian Druker, John Goldman, Moshe Talpaz and Tim Hughes, all leading lights in the field.
Prof Goldman's talk was particularly riveting because he always uses examples from history to illustrate the challenges of today, then offers a fair and thoughtful strategic road map for the future. One such example was to remind us that way back in 1996 before the clinical trials with tyrosine kinases even began, a paper appeared in Cancer Research describing the synthesis of a new compound:
These sort of articles appear in science and cancer journals every day as a new compound is born and the big question is whether is will end up a drug star or wither and be terminated in the Pharma pipeline scrapheap. However, what was touching about the article was the rather European statement in the abstract noting the following:
May have?
Wow, I love a droll understatement... CGP 57148 went on to become renamed imatinib (Gleevec) and became a cancer blockbuster, changing the lives of many patients with CML, GIST and some rare myeloproliferative diseases driven by PDGF or KIT.
Later today I will post an update on what's hot in chronic myeloid leukemia from ASH and how the new second generation TKI's nilotinib and dasatinib may offer yet more hope for patients with CML in the near future, as well as other agents in development for the rare T315i mutation that none of the approved TKI's currrently inhibit.
For now, it is sometimes good to reflect on history and feel a sense of awe and wonder that a small molecule chemical compound could eventually lead to 60-70% of CML patients attaining a complete cytogenetic response. I'll guarantee those results turned out to be far more stunning than the authors of the paper ever imagined.
{Disclosure: I'm a former Novartis marketing director who was involved in the new product development and subsequent launch of imatinib in CML and GIST, so my bias and enthusiasm for both the drug and the many wonderful and brave CML and GIST patients who participated in the clinical trials is apparent.}
Buchdunger E, Zimmermann J, Mett H, Meyer T, Müller M, Druker BJ, & Lydon NB (1996). Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer research, 56 (1), 100-4 PMID: 8548747
This blog is published by: Sally Church, PhD of Icarus Consultants, Inc. The contents of this blog are the intellectual property of the author and all rights are reserved. No commercial use, copying or distribution is permitted without the author's express permission.
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