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Medivation announce interim results of PREVAIL in pre-chemotherapy CRPC

By on October 22, 2013

This morning Medivation and Astellas announced the interim results of the PREVAIL trial in the pre-chemotherapy castrate resistant prostate cancer (CRPC) setting.

The independent data monitoring committee (IDMC) recommended stopping the trial early due to significant efficacy and unblinding the data.

Accordingly, the press release headline stated that:

“Study Will Be Stopped Early and Enzalutamide Will Be Offered to All Qualified Study Participants; 30% Reduction in the Risk of Death, Hazard Ratio=0.70 (p < 0.0001); 81% Reduction in the Risk of Radiographic Progression or Death, Hazard Ratio=0.19 (p < 0.0001.”

Now, I don’t know about you, but it’s quite a while since I saw a cancer trial with such an impressive hazard ratio (HR) for overall survival (OS) as well as being highly significant. Essentially, there is a 30% reduction in the risk of death compared with placebo even at this early point.

It was interesting though, that initial sentiments on Twitter suggested that some analysts were bothered by the absolute numbers when comparing the PREVAIL and AA-302 trials in the same setting. Enzalutamide achieved a 2.2 month improvement over placebo whereas abiraterone recorded a 5.2 month advantage, although in their case, the curve was only trending towards survival and did not cross the significance line.

Since the drugs were not compared in a head to head study, you can’t really compare apples with oranges even though the placebo arms were similar, at around 30 months each. The important point here is that one trial achieved statistical significance and the other did not. The clue is in the trial design and relative size of the respective studies.

Curious to see what urologist reactions were to the announcement, I checked out sentiments on Twitter, including Dr Benjamin Davies (Univ. of Pittsburgh) and Prof Bertrand Tombal (Leuven):

The other side of the coin, though, is some scepticism and nihilism from the analyst corner:

I’m kind of shocked that anyone would even think that, never mind say it. To be clear, those are not Adam’s words, but rather he’s summarising analyst chatter on the conference call (not verbatims), albeit in his own inimitable fashion. Obviously the point of new therapies is that you want patients to live longer, surely?! Their obvious disappointment, however, can be put into a context of sorts:

Sometimes I despair of people in the industry’s inability to understand basic statistics. What we have is snapshot, not the full data, that will come at a conference presentation when the full analysis is conducted post unblinding. Personally, I think these interim results, based on the HR and P value are encouraging, but what we really need to see are the survival curves because they tell a much more complete picture.

It should be noted that what many of the Wall Street analysts appear to have missed is that what we have is an early slice of the data – median overall survival (MOS) has obviously not yet been reached!  

It is also unfortunate that Medivation only used a small sample of at risk patients (n=59) at 30 months to estimate the survival since the rest were censored or dead as David Miller keenly observed:

 

This is a great way to create confusion unless you are expressly clear in the press release.

That said, if the trial is unblinded and placebo patients still alive are allowed to switch over, then we may only see the MOS for the enzalutamide arm in the future and not the comparator since the data will be confounded by switching.

Professor Bertrand TombalFor a different perspective, I also reached out to Prof Bertrand Tombal (Leuven), one of the lead European investigators in the trial, for his measured and considered thoughts on some of the key issues arising from this news:

1) What are your top line impressions of the PREVAIL data?

“I am a Urologist and every minutes patients are dying from prostate cancer, despite the last-years logarithmic infatuation in drugs. On top of that, recent data from Sweden that the proportion of patients dying from PCa without having received docetaxel is much larger than anticipated. So having more drug in the pre-docetaxel setting is critical, either to delay its use or treat patients that are and will remain unfit for it.”

“As a urologist, I am absolutely impressed by the delay in PFS and the unprecedented HR of 0.19 in radiographic progression-free survival. That speak to me….In addition, it does it without compromise and discussion on the impact on survival 0,70 and a 30% reduction in the risk of death..What more toxicity, especially when you know the limited toxicity of the drug.”

“It is funny to see how people have a different look of the 2 face of the co-primary endpoint coin…I look at PFS because it speaks to my patients.”

2) Many people in the US appear to be concerned that the absolute magnitude of the enzalutamide benefit is lower than that for abiraterone in the pre-chemotherapy setting (2.2 vs 5.2 months), what are your thoughts on this?

“I still have trouble understanding the meaning of a difference in median survival when the median are not reached ??? That’s computed median, arithmetic medicine if you wish. I want to see the curve…There is not mystery that regulators approve drugs based upon hazard ratios and not medians. They are much better representation of the benefit. In addition, due to the availability during the trial of approved drugs known to improve overall survival, placebo patients would be expected to have taken other drugs to increase survival.”

3) Not many countries in Europe have reimbursed abiraterone in the pre-chemo setting, is it likely that enzalutamide will be treated differently based on the fact it shows a significant OS?

“I don’t know, but in Europe most countries values Qualys and ICER, and for qualys you need to extent survival…It is more complex that a simple HR and we will need more results.”

4) Presuming enzalutamide is approved pre-chemo, which drug should urologists give first: abiraterone or enzalutamide?

“That a tricky one…Let’s say that the most popular drug so far is still bicalutamide 50 mg, and in absence of direct comparison between drug, convenience for the patient and the urologist is very often a very discriminating choice…”

5) The cumulative cost of prostate cancer care is increasing as new drugs are approved, is it going to be cost effective to treat for 32 months with an expensive new drug for only a 2 month survival benefit or do we need more effective treatment options?

“That is the real challenge, especially with the European Perspective. In Europe, where the access to treatment is mostly based on solidarity rather than private insurance, it means political choices, ethical choices and a lot of thinking on new model…based on performance, sure.”

Well said, sir!

Ultimately, we need to wait to see the full presentation and look at the survival curves before making a more informed decision. Hopefully, this data will be presented at the ASCO GU meeting in January, making a very interesting start to the 2014 cancer conference calendar.

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Update on iNHL and CLL – idelalisib, obinutuzumab and ibrutinib

Yesterday, Gilead announced on their 2Q Earnings Call that they plan to file their PI3K delta inhibitor, idelalisib (formerly CAL-101), with the FDA later this year in indolent non-Hodgkin’s Lymphoma (iNHL). Discussions with both FDA and EMA have already been initiated based on the phase II results in CLL and iNHL.

Many of you will recall the CLL data presented at ASCO by Dr O’Brien (MD Anderson) and Jennifer Brown (Dana Farber), followed by the iNHL data update presented in Lugano by Dr Salles (Lyon Sud).

The single arm NHL study 101-09 evaluated idelalisib (150 mg BID) in patients (n=125) who were refractory to rituximab and alkylating agents. In other words, there is a high unmet medical need for a new alternative therapy option.

As background, recall that previous trials with ofatumumab (4 prior regimens) and bendamustine (2 prior regimens) demonstrated an overall response rate (ORR) of 22% and 76% respectively, with a duration of response (DOR) of around 5.8 and 10 months.

In study 101-09, patients received approximately 4 prior regimens (maximum was 12) and are therefore more comparable to the ofatumumab study in terms of prior therapy. Interestingly, 65% also received bendamustine in addition to rituximab and alkylating agents, while 63% received an anthracycline.

Instead of an ORR in the expected 20-30% range, the actual number was an impressive 53.6%.

What about the DOR you may be thinking? 11.9 months.
Progression-free survival (PFS) was 11.4 months.

The waterfall plot tells a bigger picture:

Idelalisib iNHL study 101-09

Source: Gilead

 

Side effects were similar to those previously reported, with diarrhea, fatigue, cough and nausea being the most common. The only grade 3 event in double figures was diarrhea (10%). Almost half (48%) saw raised liver enzymes (ALT or AST), with 13% experiencing grade 3 or more. Hematologic events were mainly decreased neutrophils (53%) with a quarter (26%) experiencing grade 3 or more.

The company also has three phase III trials in CLL ongoing.

In particular, Study 116 (idelalisib plus rituximab versus rituximab alone in patients unfit for chemoimmunotherapy) is nearly enrolled. The interim analysis is expected in the fourth quarter this year.  This trial is a similar population to the German CLL11 study in patients with co-morbidities that compares obinutuzumab and rituximab with chlromabucil to chlorambucil alone.

No doubt if the interim analysis is promising, then further Health Authority discussions will ensue with regards to the CLL approval path for idelalisib.

What does all this mean?

Gilead have gathered solid phase II data for idelalisib in refractory iNHL, an area of high unmet medical need.  Whether this would be considered for Accelerated or full approval isn’t yet clear, since there are no surrogate endpoints.  It will be interesting to see how the FDA view the data and make an informed decision.  No doubt we will hear more later in the year pending discussion with the FDA and their perspective on the data.

My experience from extensive market research and KOL interviews in CLL is that patients with co-morbidities tend to be treated with either chlorambucil or rituximab, both as single agents. Thus having two new therapies ie obinutuzumab and idelalisib (in different combinations) potentially available in the near future would transform this particular disease segment, create new standards of care, offer more therapeutic options and raise the bar for future entrants.

Pharmacyclics and J&J are also in the mix in CLL and NHL with their BTK inhibitor, ibrutinib, having Breakthrough designation and FDA filings have also begun for that compound.  These markets will soon become very competitive and it will be interesting to see how the landscape plays out given the lack of biomarkers available to help with decision making.  Obviously, the labelled indications will drive initial usage.  After that, no one is clear yet on how oncologists will ultimately decide on three different therapies, each with good data.  I do think it’s good to see clear progress, that’s ultimately the important thing from a clinical perspective.

Roche/Genentech have Priority Review and a PDUFA data of December 20th for obinutuzumab in front-line CLL, as well as Breakthrough Designation.  This could be very timely for the company given the ASH meeting in early December.  Pharmacyclics’ ibrutinib is expected to receive rapid approval for CLL and refractory mantle cell lymphoma (MCL).  In the meantime, if Gilead file for iNHL by year end, then idelalisib could be commercially available in the first half of 2014.

In addition, both idelalisib and ibrutinib appear to have decent efficacy in CLL patients with 17p deletions, a small subset that tend to have a poorer prognosis.

All of these exciting developments will make it more challenging for other possible agents in development by demonstrating good activity in areas that might have previously appeared attractive as a fast track to market strategy.  For patients and oncologists, a surfeit of riches is no bad thing!

AACR 2013 – some initial thoughts on the emerging trends

This year’s American Association for Cancer Research (AACR) annual meeting grew by 8% to approximately 18,000 attendees with 25% from 75 foreign countries, it is truly becoming a more global event for cancer researchers.

Over the next few days I plan to cover some of my highlights (basic, translational and clinical) in depth here on the blog and also with additional notes for email subscribers.  If you haven’t signed up for the PSB email alerts, there’s still time before the AACR notes go out.

Cherry Blossom in Washington DC by the Monument during AACR 2013With around 6,000 posters and many oral presentations from leading researchers, there is usually some interesting early data coming out from AACR.  This year was no exception.  My pile of poster handouts is over 6” thick with more already coming in my email!  My fervent wish for next year is that more scientists take to the QR code method of sharing their posters – aside from being green and saving trees, it’s also considerably easier on the back!  Another welcome development would be putting the posters online for later download as many of the European meetings already do.

I’m a little tired today as the event only just finished yesterday with a very good plenary session involving Jeff Engelman (MGH), Neal Rosen (MSKCC), Todd Golub (Broad Institute) and René Bernards (Netherlands Cancer Institute).  More on this later, but what a way to end the meeting with a fairly packed hall despite it being the last day.

One of my favourite activities at AACR is talking with young researchers in the poster hall, and a few of these will be highlighted in separate posts.  Many took the time to explain some complex biology and answer my many questions on a variety of topics.  Some of this information was really helpful in improving my own understanding of why I don’t like some therapeutic approaches (e.g. targeting hypoxia) others reinforced my enthusiasm for some immunotherapies such as PD-1 and PD-L1 inhibition.

What about the emergent themes from this year’s AACR meeting?

Every year brings new developments in some shape or form, but here are some of the trends I observed based on the posters and oral sessions I attended:

  • Identifying and developing strategies for overcoming resistance was MUCH more noticeable this year
  • New combination strategies (including more novel-novel approaches) was also very much to the fore
  • Increased pace of research into biomarker identification for clinical trial design
  • Continuing rise of epigenetics as a viable approach for cancer therapeutics
  • New targets emerging (more about these later)
  • Second generation agents to CDK 4/6 and 7, chimeric antigen receptor technology (CART), Polo-like Kinase (PLK1) and many others.

Over the next few days I’ll be writing more about these topics after wading through my many pages of chicken scratch notes from the oral sessions (largely driven by ones I know likely won’t be on the webcast, which goes live for the majority of sessions on May 1st) and that huge poster pile – watch this space!

 

 

J&J unblind Zytiga phase 3 trial in pre-chemotherapy castrate-resistant prostate cancer

By on March 8, 2012

The big cancer news that hit the news wires this morning was not entirely surprising:

“Janssen Research & Development, LLC today announced that it has unblinded the Phase 3 study of ZYTIGA (abiraterone acetate) plus prednisone for the treatment of asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer (CRPC) who have not received chemotherapy.”

Source: Press Release

Given the accelerated approval of abiraterone in the post-chemotherapy setting last year, the results in the pre-chemotherapy setting were widely expected to:

  1. Be even better in earlier stage than the 3.9 months OS advantage already seen
  2. Likely to have an early study halt

Zytiga already has Compendia listing through mention in the NCCN Guidelines with level 2a evidence in the pre-chemotherapy setting, essentially listed with ketoconazole.  Several industry friends with access to market data have mentioned that the pre-chemotherapy share for abiraterone is already around 20-25%, not bad at all given it doesn’t have full approval prior to docetaxel use and has been on the US market less than a year.

No clinical details were provided by the Data Science Monitoring Committee (DSMC), but the data are expected to be presented at a clinical meeting later this year (Adam Feuerstein of The Street speculated that ASCO was a likely target).  I do hope so, but that would suppose an abstract was sent in with no data by the late breaking deadline of Feb 1st.

The company did state that:

“The company plans to submit for regulatory approval in the United States and around the world beginning in the second half of 2012.”

At this rate, J&J should receive the new indication in the first half of 2013, based on the 302 trial data, depending on whether the filing is accepted as an accelerated, priority or regular review.  No doubt this information will be apparent after filing has taken place.

One challenge with early stoppage of trials based on progression-free survival (PFS) is that determining whether patients truly live longer, as judge by overall survival (OS), becomes much more difficult, if not impossible.  Once patients on placebo are offered the active drug, there is a crossover effect confounding any subsequent data analysis.

The news today will impact several other companies in the advanced prostate cancer landscape

Medivation and Astellas are expected to file MDV3100 in the post chemotherapy setting soon based on the phase 3 AFFIRM study.  This agent has several attractive advantages over abiraterone in that:

  • no concomitant prednisone or steroid administration is required (hence less puffiness and related side effects) and
  • it targets splice variants as well as the AR, which may lead to less drug resistance.

Based on the post-chemotherapy data we’ve seen so far (MDV3100 saw a slightly longer improvement in OS, which may be related to the above), we can expect that the phase III PREVAIL trial prior to docetaxel to also show a similar trend to the Zytiga study.  It won’t surprise me at all if the interim analysis also leads to the DSMC recommending early unblinding.  Based on the Zytiga data, it wouldn’t surprise me if the interim analysis for MDV3100 came up as early as mid next year, which would be earlier than expected.

Two drugs that will be impacted by these developments with hormonal agents are Dendreon’s Provenge, which is approved prior to docetaxel and Sanofi’s Jevtana (cabazitaxel), which is approved after docetaxel.

The immunotherapy sipuleucel-T (Provenge) is an unlikely partner for combination with abiraterone given that steroids suppress the immune system, while many older men with metastatic would much rather take a pill than undergo the debilitating side effects of myelosuppressive cytotoxics such as the taxanes.  Certainly my Dad was in that category, as are many men in their 70’s.  Once approved, Alpharadin (radium-223) may well offer a useful option for that subset of patients, especially of they have already tried ADT and seen biochemical relapse with rapidly rising PSA levels.  Provenge is likely to be negatively impacted by Zytiga approval pre-chemotherapy.

Approval of Zytiga in the pre-chemotherapy setting will likely increase its share there, since many oncologists are somewhat sceptical about Provenge in terms of how it works, how effective it is, how to monitor patient progress on it (it doesn’t seem to affect pain, PSA or any of the usual markers of disease) and the hefty price tag ($93K for 3 infusions) doesn’t help either.  MDV3100 would likely have an even stronger impact, since urologists dislike using steroids and managing the complications, plus Astellas have a solid franchise in urology already.

At this rate, Jevtana will be pushed further out down the treatment paradigm and reserved for salvage therapy in the younger, fitter patients.  Its biggest challenge is competing with it’s fellow taxane, docetaxel, since many oncologists will re-challenge with the generic if the patient previously did well on it.  Any delay (through improved survival with newer, earlier treatments) will delay time to cabazitaxel uptake.  This will likely get worse once MDV3100 is approved, and oncologists can sequence them.

At what point will we see placebo trials go away?

I’m not a big fan of placebo-controlled trials, except where there are no standard of care or alternative clinical options for patients.  Until recently, the advanced prostate cancer market was relatively immature with few approved therapies, so placebo trials were de rigeur.  Going forward though, new entrants to the market will face the ethical dilemma of how can placebo-controlled trials be justified in a market where drugs such as abiraterone (or MDV3100 and Alpharadin, if approved) have a proven survival advantage?  It will push the bar for new market entries higher (and more costly).  Millennium’s TAK-700 (orteronel), which is similar to abiraterone but may or may not need steroids, may well have just made it into clinical trials in time before that window shuts off.

And finally…

The good thing is that after a decade of not much happening in the advanced prostate cancer market, we are seeing a lot if new therapies, often with different mechanisms of action, being developed for this disease.  There are others I haven’t mentioned here, including custirsen (Oncogenex) and cabozantinib (Exelixis) which are also undergoing clinical trials and we await those results too.

As more drugs for castrate-resistant prostate cancer (CRPC) are approved, sequencing and combinations will also come to the fore to determine optimal strategies for improving outcomes for men with prostate cancer.  It’s an exciting market to be following given the rapid progress over the last year or so, but hopefully, this is just the beginning and there will be much more yet to come.

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FDA approves Roche hedgehog inhibitor vismodegib/Erivedge in basal cell carcinoma

By on January 30, 2012

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

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

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

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

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

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

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

Links:

FDA Press Release

Genentech Press Release 

 

ASH 2011 Update #3 – Multiple Myeloma

By on January 4, 2012

Most new developments in cancer research tend to occur in increments, thus we see a fair number of improvements in survival (whether PFS or OS) in the 1-4 month range over the existing standard of care. However, as we saw recently at European Conference for Clinical Oncology (ECCO) in September and the San Antonio Breast Cancer Symposium (SABCS) last month with the BOLERO-2 nad CLEOPATRA trials, every once in a while something comes along that shifts the efficacy curve by six or seven months and people rightly get very excited about this.

Imagine then, an improvement in median overall survival by 13 months? Or rather, 13.3 months to be precise? That’s both very exciting and huge for patients and physicians alike.

What was the drug that produced this stunning seismic shift?

Velcade.

VISTA in newly diagnosed elderly patients with MM

At the 2011 American Society of Hematology (ASH) meeting, Professor Jesús San Miguel (Salamanca, Spain) presented the five year results of the VISTA (VELCADE as Initial Standard Therapy in Multiple Myeloma) study. This trial compared triple therapy with bortezomib, mephalan and prednisone (VMP) to the current standard of care, melphalan plus prednisone (MP) in previously untreated multiple myeloma (MM) patients (N=682) who were ineligible for high-dose therapy.

The analysis demonstrated that after a median follow-up of 60.1 months, the median OS was 56.4 versus 43.1 months for patients randomised to VMP and MP, respectively, giving a significant survival advantage of 13.3 months for the VMP arm (p=0.0004).

This is how the survival curves look:

Source: Image courtesy of Millennium

Unfortunately, I wasn’t able to see the actual presentation live as it clashed with so many concurrent presentations on the ‘manic Monday’ of the meeting, but I did talk to Prof San Miguel, who excitedly described the findings as “impressive” despite the fact that “the control arm did very well,” however, “we now know that VMP is the best option in this patient population.”

This was one of those rare times when I thought that ‘impressive’ was perhaps an understatement, especially as the majority of patients could be considered elderly, in the 65-75 age range. Based on this eagerly anticipated data and talking to several myeloma thought leaders at the meeting, there is no doubt that VMP will become the new standard of care for upfront treatment in those patients who are ineligible for high dose treatment and a transplant.  It’s a result that is full of win all around.

Secondary Primary Malignancies and Revlimid

The other interesting thing about the data was the incidence of secondary primary malignancies (SPM), a topic that was very much to the for last year for Celgene’s lenalidomide (Revlimid).

Dr San Miguel observed that the background incidence in this elderly population is 1.92, based on SEER data. He also noted that in the VISTA trial, the incidence of SPM was 1.66 SPM per 100-patient-years for the VMP arm versus 1.30 for MP alone. This difference wasn’t significant and in fact, both arms were lower than expected from the SEER data, which is reassuring.

Talking of SPMs, I attended Dr Antonio Palumbo (Torino, Italy) presentation on the last day on a retrospective multifactorial analysis of newly diagnosed patients with MM (N=2,283) who had received Revlimid in European clinical trials (N=9).  They sought to try and address if we can anticipate when SPMs were most likely to occur and in which combinations. The median follow-up time for in their analysis was 29 months and the median age was 69 years.

Overall, they found 48 secondary cancers including 10 blood cancers and 38 non-blood cancers.

The data clearly showed that the incidence of SPM with IMiDs was higher in melphalan-based regimens than others:

Revlimid:
Dexamethasone ± cyclophosphamide 0.40
Melphalan                                             0.95

Thalidomide:
Melphalan                                             1.05

Melphalan only:                                     0.42

We can see from this analysis that while the IMiDs per se don’t appear to cause SPMs, there is clearly an interaction occurring between the IMiDs and melphalan that increases the risk, although the mechanism for this phenomenon is unknown.

The future is bright for MM

Multiple myeloma is now becoming a very dynamic area of clinical research beyond Velcade, thalidomide and Revlimid.

Other emerging agents include carfilzomib, pomalidomide, MLN9708, perifosine, HDACs (panobinostat, romidepsin, vorinostat) and many others.

No doubt we will hear more about these new agents in development going forward either as new combinations or sequencing of multiple therapies, all of which may lead to a cumulative increase in survival for patients with multiple myeloma.

 

 

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What’s hot at the American Society of Hematology 2011?

By on December 9, 2011

Palm trees in downtown San Diego

Greetings from the annual American Society of Hematology (ASH) meeting in San Diego!

The palm trees and warm sunshine here were a most pleasant welcome after the bitter chill in Texas.

Having just arrived here from the San Antonio Breast Cancer Symposium, I thought it would be a nice idea to do a quick preview of some of the new and interesting data that I’m interested in at this conference and share some of the hot topics that I’ll will be following over the weekend:

  • Ponatinib in refractory CML
  • In myelofibrosis, rixuluximib and CYT-387
  • Velcade and pomalidomide in multiple myeloma
  • Obinutuzumab, PCI-32765 and alisertib in lymphomas

Let’s take a quick look at these topics in turn.

CML

The updated phase II PACE trial is expected to be presented at this meeting. Ponatinib is a potent second generation BCR-ABL inhibitor that also targets FLT3 and FGFR. The initial indication is expected to be in relapsed, refractory CML after prior treatment with a minimum of two TKIs, although many are likely to have received imatinib, dasatinib and nilotinib, so a heavily pre-treated population. Patients with advanced CML or Ph+ ALL received ponatinib in a single arm open-label trial. The other thing to note is that this agent is the only TKI so far shown to target the rare T315I mutation and these patients were included in the study.

If the results continue to hold up for durability with no additional safety signals since FLT3 and FGFR may induce off-target side effects, then I’m expecting Ariad to file ponatinib for accelerated review with the FDA, based on phase II data in relapsed and refractory CML, sometime in 2012. This is an exciting new agent and it will good for patients with CML to have an additional option in this setting.

MYELOFIBROSIS

This year has seen a lot of interest in myelofibrosis with Incyte’s ruxolitinib (Jakafi) receiving FDA approval recently. The drug was approved largely on the basis of its ability to reduce spleen size, which is one of the complications of the disease. The updated phase III COMFORT-1 data is being presented on Monday and my assumption is that we will see an improvement in overall survival with ruxolitinib.

There has been a lot of interest in YM Bioscience’s agent, CYT-387, which caused a stir at ASCO after initial data suggested that it may be able to reverse anemia associated with the condition.

Now, I’m not sure of the exact mechanism behind this phenomenon, since both compounds target JAK1 and JAK2, so the anemia response may be an artifact or a real effect. If the anemia effect is real, then I’m expecting to see the hemoglobin levels to go up rather than down, as we saw with Jakafi. The poster on Monday may well tell us more about what’s happening here and also I’m hoping to speak to some myelofibrosis thought leaders to see what their perspective is.

MYELOMA

Multiple myeloma has seen real improvements in overall survival over the last 10 years with the introduction of bortezomib (Velcade) in the upfront setting and lenalidomide (Revlimid) in the refractory and maintenance settings. Currently, a new kid on the block, Onyx’s carfilzomib, is currently being reviewed by the FDA in the refractory population, although we likely won’t know the decision until 1Q next year. If approved, it may offer physicians a new option to extend outcomes even further in advanced myeloma.

There is another agent not far behind, pomalidomide, which is a third generation immunomodulatory agent similar to lenalidomide. Celgene are presenting key data at this meeting and I’m looking forward to seeing how the data is progressing. I’m expecting this compound to show good efficacy in advanced myeloma, as it is thought to be more potent than Revlimid.

The phase III multiple myeloma study that is of great interest is the VISTA trial, which will be presented on Monday and compares the combination of Velcade, melphalan and prednisone (VMP) with melphalan and prednisone alone (MP). The five year data in treatment naive multiple myeloma will inform us which combination has superior overall survival and side effect profile and what can be expected in terms of secondary primary malignancies (SPM) with the triple versus double combination over longer term follow-up.

LYMPHOMAS AND CLL

For me, the big lymphoma story at this ASH is probably going to be GA101, now named obinutuzumab. It’s a CD20 antibody similar to, but also different from, rituximab, making it ideal for testing in NHL since the proof of concept is already established for the CD20 target.

My critical questions related to this agent’s development are:

  1. Will it overcome rituximab resistance and work in refractory patients?
  2. Will it work more effectively than rituximab earlier and prolong outcomes further?
  3. Will it have fewer side effects than rituximab?

If any of the above are true, how does obinutuzumab work differently than rituximab and does that explain any of the differences?

Not all of these questions will be answered here at this ASH meeting, but I’ll discuss these issues in more detail once the data is available.

Finally, there are a couple of other compounds in early development for lymphomas that I’m really interested in.

The first is PCI-32765 (Pharmacyclics), a bruton kinase inhibitor (BTK), while the second is Millennium and Seattle Genetics’s aurora kinase A inhibitor, alisertib. These are relatively new mechanisms of action in lymphomas and intriguing scientifically.

I’ll write more about these particular agents in depth as the data becomes available, but they’re worth watching out for over the weekend as the wires hit the news sites.

Meanwhile, you can follow the conversations at the American Society of Hematology meeting on Twitter using the official hashtag of #ASH11.

Do check back for daily updates here in the blog for the hot (and sometimes not so hot) data. I’ll also be posting a video review of the important news next week.

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Video preview of San Antonio Breast Cancer Symposium 2011

By on December 7, 2011

What’s hot at the 2011 San Antonio Breast Cancer Symposium?

There is a lot of exciting data coming out at SABCS 2011 over the next three days, including the BOLERO2, CLEOPATRA and NEOSPHERE clinical trial data.

I previously wrote about the exciting BOLERO2 results that were presented at the European Multidisciplinary Cancer Conference (ECCO/ESMO 2011) in Stockholm in September. More data is expected at SABCS to coincide with a publication in the New England Journal of Medicine (NEJM).

The following video outlines some of the data that I think is hot at SABCS and why it’s worth watching out for. I will be writing more about it as it’s presented.

http://www.youtube.com/watch?v=t7bnqslE6mc

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Follow the conversation from 2011 San Antonio Breast Cancer Symposium

By on December 6, 2011

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

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

Excellent news in Advanced Prostate Cancer – Medivation's MDV3100 meets primary endpoint

By on November 3, 2011

It’s not often that you wake up to really exciting news in the cancer field, but that’s what happened this morning with Medivation’s announcement on the interim analysis of their androgen receptor (AR) antagonist, MDV3100:

“As reported by the IDMC, MDV3100 produced a 4.8-month advantage in median overall survival compared to placebo.

The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo. MDV3100 provided a 37 percent reduction in risk of death compared to placebo (Hazard Ratio=0.631).

The IDMC further determined, considering the observed safety profile, that MDV3100 demonstrated a favorable risk-to-benefit ratio sufficient to stop the study.”

The 4.8 month improvement in OS in post-chemo setting is superior to that previously reported for abiraterone (Zytiga), which had a 3.9 month advantage over placebo and received regulatory approval in the US and EU earlier this year.

This is great news for patients, for Medivation and also for Charles Sawyers at MSKCC who originally invented the MDV3100 compound. If you are interested in the MDV3100 story, you can read my interview with Dr Sawyers posted earlier this year.

There are several points to note about these results:

  • MDV3100 does not require concomittant steroid therapy as abiraterone does, this is huge for urologists who as surgeons do not generally want to manage side effects.
  • Given the excellent results in the post chemotherapy setting, I would expect the survival advantage in the pre-chemotherapy session for both therapies to be more than 6 months.
  • Ultimately, as hormone therapy, I can see the real advantage for MDV3100 being as a more potent and complete inhibitor of the AR than bicalutamide, so there is a huge potential for MDV3100 as ADT therapy in the earlier stages of disease.

With regards to filing, Medivation announced that:

“Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012 and will provide an update on regulatory timelines for MDV3100 subsequent to that meeting.”

At this rate, I would expect to see MDV3100 approved sometime in 2012.

The future is looking very bright indeed for patients with advanced prostate cancer – these new therapies offer the potential with sequencing to extend lives significantly.

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