MaverickNY | Pharma Strategy Blog

Peregrine Reports Promising Interim Survival Data From Phase II Cotara Brain Cancer Study

By MaverickNY on October 18, 2010

Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), a clinical-stage biopharmaceutical company developing first-in-class monoclonal antibodies for the treatment of cancer and viral infections, today reported interim data from an ongoing Phase II clinical trial of its novel brain cancer therapy Cotara(R). Interim median overall survival was 86 weeks for a cohort of 14 patients with glioblastoma multiforme (GBM) treated at first relapse with a single infusion of Cotara. Cotara is a targeted monoclonal antibody linked to a radioisotope that is administered directly into the tumor, destroying the tumor from the inside out, with minimal exposure to healthy tissue.

via ir.peregrineinc.com

I thought this was an interesting announcement this morning from Peregrine. Glioblastoma multiforme (GBM) is a particularly nasty malignant cancer, with a tendency to aggressiveness and is generally difficult to treat.

Cotara is a novel experimental antibody based on tumour necrosis therapy (TNT). Although these are only early phase II results based on a portion of the full 40 patients expected in the trial, they look encouraging so far.

I suspect the reason for the press release is that the data is being presented at a neurosurgery meeting that's ongoing at the moment in San Francisco.

Definitely a development worth watching, but ultimately, a larger scale phase III trial will be needed before we can be sure whether or not it will be a valuable addition to the armamentarium.

Upcoming cancer conferences – will you be there?

By MaverickNY on October 15, 2010

The last quarter of the year is always a busy one on the conference circuit in oncology, particularly in December with the annual ASH and the SABCS meetings back to back. We almost always need the Holidays after that just to recover!

Here's my schedule for the next few weeks:

Oct 20th: Xconomy, 'War on Cancer', Boston hosted by Millennium

Oct 27-30th: AACR colorectal cancer biology and therapy symposium, Philadelphia

Nov 8-13th: Greenspan Chemotherapy Foundation Symposium, Marriott Marquis Times Square, NY

All three meetings look particularly interesting this year, with a big focus on biology and new product development.

While Pharma is facing some big patent cliffs over the next two years, there are a lot of interesting new compounds coming along in the pipeline in phase I/II right now. Hopefully, some of these will make it through to regulatory filing in a few years time.

If you are around at these meetings, do stop and say hello – it's always good to meet readers in person, however briefly. If you haven't put any of these in your diary, do check them out!

Talkers vs. Doers « in over your head

By MaverickNY on October 15, 2010

Doers make things happen. Talkers get the credit.

There are always people in the background of any huge project or enterprise. They worked hard, read a lot, and experimented so things could get done. They let achievements speak for themselves, and sometimes, that works for them. More often than not, though, they don’t get enough credit for the work they did. They don’t draw attention to it, they just do it.

Talkers do the opposite. They are so good at rallying people together, at inspiring them or just getting themselves noticed that, often, they realize that’s all they need to do. People who pay attention to talkers think “why would he lie?” or “he really believes in himself,” so they believe what the talker says even though there may not be evidence of it.

The result is that doers work harder to get their stuff noticed, whereas talkers just talk more. Both sides work (kind of). But what we really need people in between.

via inoveryourhead.net

I loved this post from @julien this morning and realised how true it is of many corporations, especially Pharma in the US.

Over time, I have learned to reflect carefully and be wary of the talkers and the salesy people who make a lot of noise, and ask myself the key question – what do they actually achieve other than toadying to the bosses?

Often, it is the quiet people in the background that really make things happen on key projects. They're the real glue that keep teams functioning well and the people you should look after and keep happy.

Who does that in your organisation?

#ESMO 2010 round-up #3

By MaverickNY on October 14, 2010

Back from Milan and ESMO 2010, I thought it would be a good idea to quick a final quick overview of some of the early data from phase II trials that look interesting and might be worth watching as the research evolves (in no particular order).

1. Addition of cetuximab to cisplatin increased survival in triple negative breast cancer

Jose Baselga presented the results of a multi-centre randomised trial (from Spain, Belgium, Austria, Portugal, the UK and Israel) that compared the combination of cetuximab (Erbitux) with cisplatin versus cisplatin alone in 173 women with triple negative breast cancer (TNBC).

Although the overall response rate (ORR) trended in favour of the combination (20.0 vs 10.3%), the result did not meet the pre-specified assumptions. Interestingly though, the progression-free survival (PFS) showed a significant improvement with the addition of cetuximab (3.7 vs 1.5 months, P<0.03). Two months doesn't seem much, but in an advanced, highly aggressive disease, it may represent a disproportionally large improvement.

I'm not sure why cisplatin was chosen as a comparator, especially as TNBC is a particularly hard subset to treat, but the trial is ongoing to determine overall survival and a phase III study will likely evolve to determine if the results are repeatable in a larger population.

2. GSK2118436 in advanced melanoma with brain mets looks promising in a phase I/II study

By promising, I mean this was a very small cohort of patients who saw some early and unexpected evidence of tumour shrinkage in brain mets that had evolved from primary melanoma. The scans shown by the presenter, Georgina Long, from the Melanoma Institute Australia and Westmead Hospital in Sydney actually gave me goosebumps and it wasn't the chill in the room. You just don't expect to see such noticeable shrinkage with a single agent in this setting because this is a horrid, aggressive disease that has a nasty tendency to metastasize easily.

What was interesting about this study is that GSK2118436 is a BRAF inhibitor that also specifically targets V600E, similarly to Plexxikon/Roche's PLX4032. In both cases, they bind to the protein and shut down signaling activity. Although the trial is very early, since it looked at 3 different cohorts, the small subset with brain mets (n=10) were what caught everyone in the audience's attention, although good responses were also seen in the advanced melanoma group without brain mets.

To put the results in context, all 10 patients experienced some control of their brain mets, with 9 of the 10 patients having reductions in the overall size of their tumours. The overall reductions ranged from 20-100% of brain metastases that were 3mm or larger in diameter before treatment.

That just doesn't happen with advanced melanoma with brain mets… at least, I've never seen such dramatic responses before.

The big questions for me are how long will the responses be durable before resistance sets in and how soon is a larger scale trial going to get up and running? This is a very promising and most unexpected development that is worth following.

Dr Long summed it up very nicely:

“The ability to inhibit oncogenic BRAF is the most important development in the history of drug treatment of melanoma.”

3. ARQ-197 continues to show positive results in NSCLC

In this presentation, the final results of the phase II trial in non-small cell lung cancer (NSCLC) were discussed. We've covered this promising agent, ARQ-197 (ArQule/Daiichi Sankyo), a small molecule c-MET inhibitor, before on this blog.

A final analysis looked at the complete results in more depth. Patients treated with ARQ 197 plus erlotinib (Tarceva) developed new metastases in a median time of 7.3 months compared with 3.6 months for patients treated with erlotinib plus placebo.

What I found interesting in this study was that this effect was more pronounced among patients with non-squamous (NS) histology, since the median time to develop new metastases was 11.0 months in the ARQ 197 plus erlotinib arm compared to 3.6 months for those treated with the control arm (erlotinib plus placebo). I'm not sure why the NS over squamous histology should matter, but they clearly benefitted more.

The sponsors, ArQule and Daiichi Sankyo, have announced that they plan to pursue a phase III trial in this setting. It would, however, be nice to see an analysis of any lung biopsies collected to see if there are any relevant biomarkers that would explain the differences in histology and responders, otherwise many physicians may see this as an incremental improvement, if confirmed in a larger trial. Were thre any differences in people who were EGFR mutation or MET positive, for example?

There was certainly some energetic discussion in the Q&A, with tough questions asked of the speaker regarding why go ahead with a phase III study given a small benefit and why use OS when PFS is small and complicated by crossover, all very fair questions. Like many, I'd really like to see more granular analysis of who is responding to this agent and why before rushing into a phase III trial that may see a disappearing of any positive signal when investigator bias is eliminated in a larger randomised trial.

4. METMAB showed promising results in a subset of lung cancer patients

In the same session, David Spiegel presented the data from a phase II study with a different c-MET inhibitor. Here, patients with advanced NSCLC (n=128) were randomly assigned to receive either erlotinib plus METMAb (Roche/Genentech), a monoclonal antibody that binds specifically to the MET receptor on cancer cells or a control arm (erlotinib plus placebo).

The reason for the interest in c-MET inhibitors is that MET activation has been implicated in the resistance of lung cancers to EGFR inhibitors such as erlotinib. The big question is therefore whether a combination of the two would overcome resistance or not, thereby prolonging life.

In this study, participants were tested for mutations in the EGFR gene and also for expression of MET in tumour samples.

The results were interesting – 51% of patients whose tumours expressed MET and those who received METMAb plus erlotinib had better OS and longer PFS than those who received erlotinib plus placebo.

Furthermore, in the subset of MET+ patients, adding METMAb to erlotinib nearly halved the risk of disease progression or death during the study compared to those treated with erlotinib plus placebo. In addition, patients whose tumours did not express MET protein appeared to do worse when treated with the METMAb/erlotinib combination, suggesting that the biomarker may be able to determine who is more likely to respond to therapy.

This is good news if it is repeatable in a phase III trial and show durable efficacy with good tolerability, because then potentially, oncologists would be able to screen and preselect patients for treatment with METMab rather than expose all patients to the systemic side effects without hope of it working.

Last but not least, there was some updated information on the novel trastuzumab-DM1 (T-DM1) combination therapy (Roche/Genentech).

4. T-DM1 continues to show solid results in metastatic breast cancer

Edith Perez presented the results of a phase II study looking at first line treatment with a new combination agent, trastuzumab-DM1 or T-DM1, in metastatic breast cancer.

As far as I know, T-DM1 is the first of a new type of cancer therapy known as an antibody-drug conjugate. Basically, it binds together two existing cancer drugs with the aim of delivering both drugs specifically to cancer cells, ie trastuzumab (Herceptin), an approved monoclonal antibody that targets the protein HER2 and DM1, a chemotherapy agent that targets microtubules. The goal of the new combination is too see if cardiotoxicity, a common problem associated with standard anthracycline therapy, is reduced and if efficacy is subsequently improved.

Women with breast cancer were randomised to treatment with either trastuzumab plus the chemotherapy drug docetaxel, or T-DM1. All 137 participants had HER2-positive metastatic cancer, with no prior chemotherapy for their metastatic disease.

The good news is that the early results demonstrated that T-DM1 has good anti-tumour activity as well as much lower toxicity when evaluated side by side to standard therapy.

After a median of approx 6 months of follow up, the overall response rate of in women who received T-DM1 was 48% compared with 41% in the control arm (trastuzumab plus docetaxel). The rates of clinically relevant adverse events were also significantly lower in the T-DM1 arm (37%) compared to the rate in women given traztuzumab plus docetaxel (75%).

Overall, I think the slight improvement in ORR was more than compensated by the dramatic improvement in side effects, which ultimately affect a patient's quality of life when undergoing cancer treatment. According to my chicken scratch notes from the session, cardiotoxicity and myelosuppression were both much improved in the T-DM1 arm over standard therapy.

Perez noted that the final analysis of the PFS data is expected in 2Q 2011, which I'm sure will be eagerly awaited based on the encouraging early data, although feeling better is one thing, but ultimately the sine qua non is will the women live longer?

All in all, I'm glad I trekked all the way to Milan for ESMO. There was more positive and promising early data than expected and aside from the repetitive blister walks, it was an enjoyable event. It was also nice to catch up with some friends in person and meet several readers of this blog who kindly came up and introduced themselves – I hope you all enjoyed the conference as much as I did!

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#ESMO 2010 round-up #2

By MaverickNY on October 12, 2010

"Do or do not. There is no try."

Master Yoda

2010 looks to be a good year for prostate cancer after a six year wait since the last therapy (docetaxel) was approved for what was then known as hormone refractory (now called castrate resistant) prostate cancer, or CRPC, for short.

This year has already seen two new approvals for the disease, namely:

Sipuleucel-T (Provenge) from Dendreon in asymptomatic or mildly symptomatic CRPC prior to chemotherapy.
Cabazitaxel (Jevtana) from sanofi-aventis in docetaxel failure CRPC.

In addition to these, we have also seen new data for two other novel hormonal therapies, namely abiraterone (Cougar/J&J) and MDV3100 (Medivation/Astellas) in the CRPC setting.

MDV3100 is now entering phase III trials in the 2nd line and asymptomatic setting, while the phase III data was presented on abiraterone here at ESMO yesterday in the Presidential Symposium.

Abiraterone was originally developed by the Institute of Cancer Research (ICR) in the UK and is a CYP17 steroid inhibitor that prevents the biochemical conversion of cholesterol to testosterone. Testosterone is secreted by the testes, adrenal gland and prostate tumour to ensure it's growth and survival via androgen receptor (AR) signalling. The simple idea here is that biochemically inhibiting the key pathways with both abiraterone and a steroid such as prednisone or dexamethasone, will lead to improve outcomes for men with prostate cancer.

The proof of the pudding lies in a randomised phase III trial to determine whether the combination is both safe and effective.

The results were interesting, to say the least.

The overall survival (OS) was as follows:

Abiraterone + prednisone: 14.8 months
Placebo + prednisone: 10.8 months

The PSA response also favoured the treatment arm:

Abiraterone + prednisone: 38.0%
Placebo + prednisone: 10.1%

Adverse events with abiraterone treatment were obviously higher than for placebo, but in general it appeared well tolerated and an important common side effect was fluid retention (30.5% of patients, with 2.4% of them being severe ie grade 3/4 in severity).

No data on the circulating tumour cells was given at this meeting, but the analysis is underway and will be published in 2011.

The big questions that spring to my mind are how do these results stack up against what we have and is the control arm ideal?

Cabazitaxel was approved earlier this year in combination with prednisone versus mitoxantrone plus prednisone, with an OS benefit of 2.8 months. Previously, mitoxantrone was approved in 1996 with a survival benefit over prednisone. Other therapies were not so lucky – GPC's satraplatin showed no benefit at all over prednisone.

If we look in the absolutes, the 3.9 month benefit for abiraterone sounds great until we look at the relative vales and comparators in more detail:

2nd line metastatic setting:

Satraplatin vs prednisone: 14.3 vs 14.3 months
Cabazitaxel + pred vs mitox + pred: 15.1 vs 12.3
Abiraterone + pred vs prednisone: 14.8 vs 10.9

Mitoxantrone generally offers some benefit over prednisone, based on the original head to head trial, leading it to become the first chemotherapy to be approved for advanced prostate cancer by the FDA. I've no idea why mitoxantrone plus prednisone was not used as the control group instead of prednisone alone, but we can only evaluate what we have.

You have to say, based on this top line overview, GPC were really unlucky to have a placebo group do uncommonly well! An OS of 10-12 months for prednisone might well be a most logical expectation, but that's how clinical research goes sometimes.

It's odd, but had the abiraterone control group done as well as satraplatin's control, the outcome difference would likely be minimal and not significant. Such is the crapshoot we call R&D! Overall, my sense is that mitoxantrone plus prednisone does better in terms of OS than prednisone alone, so we would expect abiraterone's control group to be lower than cabazitaxel's, making the relative difference higher, and that is indeed the case based on the data so far.

Still, we also have to think about this from the patient perspective. Many men are like my own Father was – they would much rather pop a pill or have an injection than go through chemotherapy and risk feeling sick and have their hair fall out. Indeed, I suspect he was typically of many 70 year olds who declined chemotherapy, but might have considered abiraterone or sipuleucel had they had been available ten years ago.

If you're wondering what will happen next, well according to the press releases, J&J will be submitting the filing to the regulatory authorities by the end of the year, which means we should know some time in 2011 whether we will have a 3rd active drug approved for this cancer.

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#ESMO 2010 round-up #1

By MaverickNY on October 11, 2010

It's been an interesting weekend in Milan at the European Society of Medical Oncology (ESMO) meeting and rather than cover the same news as everyone else based on the press briefings, I'm going to take a slightly different slant in my roundup today and tomorrow.

In the past, the ESMO meeting has sadly been used as a dumping ground for negative data as it is less likely to draw as much attention as say, making the same announcement at it's big sister, ASCO. This year was different though, with quite a few companies announcing positive data, which was nice to hear.

I thought this was a good sign until I noticed in the small print that they were mainly small phase II trials. Many of us know that it's very hard to extrapolate 30-100 patients to a broader universe, as we have seen with the very high attrition rate in phase III cancer trials over the last 18 months, often despite promising earlier data. A single arm, single agent study in a small sample also tends to have some element of bias compared with a randomised, blinded and well controlled trial in a 1,000 plus patients.

What this means is that what was once a positive efficacy signal has all but disappeared over time with larger patient cohorts free of investigator bias. It would therefore be fairer, and more accurate, to say that these studies are "early, but promising" or something similar.

Instead, we get bombarded with screaming headlines.

Ok, I understand CEO's want to maintain their share of voice and keep the positive data coming to drive the share price, but really, part of me wants to wince or cringe and say that perhaps a little circumspection goes a long way. It may be more realistic to say under promising and over delivering is always better than the other way round. These trials are very early.

To paraphrase Jerry McGuire: "Show me the phase III data!"

Then I'll start getting excited and enthusiastic if the results hold up without any excessively nasty toxicities that would make me think twice about taking something.

What's hot in molecular diagnostics and biomarkers? #aacrMD #2

By MaverickNY on October 8, 2010

At the AACR meeting on Molecular Diagnostics and Cancer Therapeutics meeting in Denver, there was quite a bit of interesting scientific data coming out on cancer biology and biomarkers, so here is a quick synopsis of what appealed to me:

1. IGF-1R is over expressed in a subset of triple negative breast cancers (TNBC)

This presentation, from Witkiewicz et al., was interesting because they showed that IGF-1R might be a useful prognostic biomarker in TNBC. Usually, TNBC, which occurs in 15-20% of all breast cancers and is associated with a poorer prognosis, so finding a subgroup that might actually do better could be useful. Gene amplification was seen in 23% of the cases investigated. Caution must be exercised here, however, just because something is over expressed or amplified, does not mean that it is mutated, and therefore a potential druggable target with a therapeutic as we saw with the negative phase III results with figitumumab, an IGF-1R inhibitor in lung cancer.

What I would like to know though, is how many women with TNBC also have the BRCA1 or 2 mutation and have amplified IGF-1R? We know that targeting a cancer with one drug at one or two mutations in solid tumours has modest effects. But what if we target several things with a combination therapy, for a specific subset, then that might possibly yield different results altogether.

2. Molecular biomarker analysis using circulating tumour cells (CTCs)

Siminder Atwal, a Genentech scientist, presented her work on CTCs, with the idea of determining whether they could be used as a predictive biomarker by correlating CTCs with HER2 status in archival tumour samples. CTC's in theory should match tumour biopsies since they are cells that have shed from the primary tumour. The Genentech scientists found that they were indeed correlated, with a high concordance (95%) using the CellSearch system. Of course, EpCAM expression can vary in some tumour types, complicating analysis and interpretation, but it looks like they saw some early hints that molecular biomarker status in CTCs are indeed reflecive of the biomarker status in patient tumours.

Predictive biomarkers allow us test whether a patient is likely to benefit from a given treatment, so the obvious and leading question is whether this work could be extended to look at eg CTC's in colorectal, lung or breast cancers to determine whether a patient is more likely to respond to bevacizumab (Avastin) or not. It would probably be easier in breast (lots of biopsy samples) and colorectal (lots of surgery providing samples).

At the moment, there is no way of telling who is most likely to respond to Avastin, so a predictive biomarker test would be really useful for clinicians before deciding on treatment, rather than having to expose thousands of patients to the systemic side effects. Given that the FDA have to make a decision by the year end on the full approval of Avastin in breast cancer, it is a shame that they likely won't have this sort of data to help guide a decision.

3. BRCA1 mutations in prostate cancer

Gerhardt Attard gave an enlightening talk entitled, "Circulating tumor cells: Potential uses, pitfalls and challenges in their use as pharmacodynamic markers" but what struck me was not so much the fascinating information about CTCs as his mention that a subset of prostate cancer patients have the BRCA1 mutation. They tested the impact of olaparib, a small molecule PARP inhibitor from AstraZeneca, and found that all three responded.

A study open for men with prostate cancer and either BRCA1 or 2 mutations is currently recruiting patients. Given the interest with PARP inhibitors in breast and ovarian cancers, I'll be following this development with great interest.

Greetings from ESMO in Milan

By MaverickNY on October 8, 2010

Oh my, I can't believe I slept for 9 hours solid last night and woke up with no jetlag and access to the New Twitter interface, finally! It must have been the long walk I took around the Duomo and Brera districts or perhaps the Negroni apperitivo, but hard to believe that is a logical anti-jetlag solution!

Today is Super Friday at ESMO, in other words, the corporate symposia. There are a lot of interesting presentations that I'm looking forward to, but they are rightly embargoed and I can't talk about them yet. Thus we have a whole day of corporately sponsored 'educational sessions'. I may not tweet these events, except perhaps two; one from Roche at 3pm on angiogenesis and another from J&J at 4.30pm discussing advanced ovarian and prostate cancer.

Sadly, I'm not as big a fan of Super Fridays as I used to be. Why? Because they used to be educational events, now many seem more biased and shilling a company's drug without fair balance or context. Am hoping that's not the case here, but in the last couple of years, the focus has definitely drifted too far at some meetings.

For me, I'm much more of a purist and a fan of sessions that address pros and cons, controversial issues and with fair balance, then let the audience vote and decide before and after the presentations as that often keeps the presenters on their toes.

Ah well, times change, like Mrs Thatcher famously said, this lady's not for changing on the issue for now ;)

ESMO, Milano 2010

By MaverickNY on October 7, 2010

I’ve arrived at ESMO a little weary from the red eye to Milan from New York and looking forward to an interesting meeting.

Several blog readers have already come up to say hello so if you’re here, don’t be shy – do introduce yourselves!

The industry symposia are tomorrow (Friday) but I’m particularly looking forward to the prostate cancer session on Monday. We should get to see what the Cougar/JNJ abiraterone data looks like in taxane refractory castration resistant prostate cancer. It’s not often when we hear of 3 major improvements in overall survival in one tumour in a year, making 2010 a very interesting area for this disease with the earlier approvals of Provenge and Jevtana.

It’s going to a fun meeting. Watch this space over the weekend for highlights.

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ecancer.tv an open access cancer resource

By MaverickNY on October 6, 2010

I'm a bit crunched for time today with last minute preparations before dashing off to ESMO on the red eye but I would like to share a cool online cancer resource with you.

At the recent EHA meeting in Barcelona, one new resource that came to my attention was ecancer.tv run by the folks from Brandcast Health. This is what the site looks like:

This European site has a lot of interesting videos of experts talking about news, new data and current affairs relating to cancer. At EHA, I attended the press briefing they hosted, which was also filmed. It discussed the treatment of elderly cancer patients and was very well done. A number of critical issues were discussed by academics and patients on the panel, including Jan Geissler, a great guy who represents the European Cancer Patient Coalition and is a CML patient himself.

The mission of ecancer medical science, the companion open access medical journal is an interesting one:

"European cancer research is of a very high quality but is fragmented, un-coordinated and slow in translating benefits to patients. Cancer care delivery is also excellent in some European countries but by no means all. If state of the art treatment was available to all cancer patients, the World Health Organisation has estimated that over 20,000 lives would be saved annually.

ecancermedicalscience aims to improve communications between sub-specialised cancer scientists and clinicians by working interactively and faster – offering authors a rapid peer review process. Submit your paper and you'll hear if it will be published within three weeks.

ecancermedicalscience actively encourages the communities of sub-specialised scientists and cancer carers to exchange ideas and research, speeding up the time it takes from discovery, to patient benefit."

Obviously more interviews will be posted after ESMO this weekend, but take a few minutes and check them out.