Avastin | Pharma Strategy Blog

More phase III cancer trials flop: Pfizer (Sutent) and Roche (Avastin)

By MaverickNY on March 12, 2010

The last 18 months have seen a lot of failed cancer studies in phase III development after early promising phase II results, teaching us that sometimes rushing full steam ahead without fully understanding the issues is not always the smartest strategy.

Let's start with Pfizer's figitumumab, an IGF-1R antibody, which we have previously discussed in non-small cell lung cancer (NSCLC) (here and here). There was one phase II trial at MD Anderson that led to what many of us thought was a rather cavalier, aggressive and hasty phase III program, without really seeking to understand the underlying biology behind the pathway first. Interestingly, other competitors have taken a much slower and more methodical approach to thinking through the various issues and may well come out ahead as a result.

Given the front-line trial produced a negative response, I think many of us were expecting the 2nd line study to eventually go the same way. The endocrine and biochemical interactions happening around IGF-1R will need more careful reflection before the concept has a real chance of working. There are various things happening around cross-talk between receptors, interaction with the insulin receptor and AKT may well turn out to have an important role to play. All in all, manipulating the biochemistry of the pathways needs a little more sophistication than a mere sledgehammer to crush a grape approach.

Pfizer also announced that two phase III trials with sunitinib (Sutent) also failed to meet their primary endpoint. Sutent is approved for the treatment of renal cell cancer and gastrointestinal stromal tumours (GIST) and as an oral VEGF/KIT inhibitor that was originally developed by Sugen before it was snapped up by Pharmacia, I think it has done pretty well. It is unrealistic to expect every drug to work in every indication and there may be differences between how monoclonal antibodies such as bevacizumab (Avastin) work compared to small molecules such as Sutent and Bayer's sorafenib (Nexavar).

Like Pfizer, Bayer recently announced promising phase II results in breast cancer. Given that Pfizer previously announced last year that a Sutent trial in breast cancer was negative (see previous post), I wasn't expecting the two current trials to be positive. Had they done so, it would have been akin to a miracle.

Roche's Avastin has had a string of good results and also a few setbacks. The original program focused on breast cancer rather than colorectal cancer before the trial was negative. To give Genentech credit though, they went back to the drawing board to figure out what worked and where the issues were before eventually having another success in breast cancer much later. This is probably what Pfizer need to do now too, scientific and clinical reflection is sometimes a necessary part of the pain on the journey.

Avastin has been now approved in colorectal, lung, breast, renal and brain cancers, so a setback in prostate cancer, as Genentech announced this morning, is probably not going to matter too much. This is unfortunate because there really aren't that many options for advanced stage patients who have become hormone resistant. All is not completely lost for men with prostate cancer though, as sanofi-aventis (a client) have reported that their next generation taxane, cabazitaxel, increased survival in this population, so hopefully we will see more of the data at this year's ASCO meeting in June.

One thought we should perhaps reflect on. 'Oncogenic addition' is a phrase bandied around quite a bit these days, and for sure, some approaches have been very successful. We need to remember though, that targeting kinases and enzymes is only going to work if the enzyme is actually critical to the survival of the tumour, which will rarely happen in isolation. The way forward is most likely going to need a more sophisticated approach that combines multiple inhibitors in a logical fashion. To achieve that approach though, will require more iterative phase II trials to really determine exactly what is going on.

Pfizer and Roche/Genentech both have smart scientists and clinicians in their organisations, so my feeling is that they will go back to the drawing board and evaluate these trials and the data very carefully. You can't have a home run every time, but you can sometimes figure out ways to see if an agent can be made to work by tweaking things. Often, we're limited by our knowledge of the biology and sometimes negative trials can actually help us understand things better.

Photo Credit: Stuck in Customs

What can we learn from the Oscars?

By MaverickNY on March 8, 2010

Last night many people in the NY-NJ-CT region missed the Oscars beamed from the Academy Awards after an argument over money between CableVision and ABC. If a Biotech company and their big Pharma partner has a spat, it is rarely as public or has as much impact as TV deals do, but the shock waves can certainly be felt through the investor community every time a high profile predatory shareholder such as Carl Icahn gets their teeth into a biotech such as Genzyme or Biogen IDEC.

It was interesting that the year’s biggest grossing, most expensive and stunning film, ‘Avatar’, lost out to a smaller, niche film about the Iraqi war, ‘The Hurt Locker’, with a stronger plot, storyline and superb acting.

It’s a bit like a baby Biotech producing a string of new products with solid efficacy doing well, much as Genentech did with Herceptin, Tarceva and Avastin or Amgen did in their early days with Neupogen and Epogen. Eventually, of course, the new kid on the block becomes household name and new companies rise behind them with new science and a solid underpinning.

After the austerity of last year’s Awards ceremony, this year’s Oscars were a little more lavish by comparison. I wonder if that is a metaphor for the economy in general, with less doom and gloom and some signs that things are picking up?

Art ultimately reflects life.

The big question is, who are the next generation of big Biotech's in the making?

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Roche on a roll with positive data for Avastin in ovarian cancer

By MaverickNY on February 25, 2010

After yesterday's news regarding the negative data for bevacizumab (Avastin) in gastric cancer, I wasn't expecting to hear any more from Roche this week, however, the opposite happened and this morning positive data was sitting waiting for me in my inbox today!

What's new?

Well, results from phase III study demonstrated the combination of bevacizumab and chemotherapy followed by maintenance use of bevacizumab increased the time women with advanced ovarian cancer lived without their disease worsening as measured by progression-free survival (PFS) compared to chemotherapy alone. Advanced ovarian cancer generally has a poor prognosis, so new therapy options are much needed.

Roche's press release declared that:

"This is the first positive phase III study of an anti-angiogenic therapy in advanced ovarian cancer and continues to support Avastin and anti-angiogenesis as a fundamental pillar of cancer treatment today."

What does the data show?

The Gynecologic Oncology Group (GOG) completed a three-arm trial in women with newly diagnosed advanced ovarian cancer who already had surgery to remove as much of the tumour as possible were randomised to receive one of the following:

Placebo in combination with commonly-used chemotherapy (ie carboplatin (AUC 6 IV) and paclitaxel (175mg/m2) for 6 cycles), followed by placebo for a total treatment duration of up to 15 months.
Bevacizumab (5mg/kg for 5 cycles starting at cycle 2) in combination with carboplatin and paclitaxel (6 cycles), followed by placebo for a total treatment duration of up to 15 months.
Bevacizumab in combination with carboplatin and paclitaxel, followed by the continuation of bevacizumab alone as maintenance therapy, for a total treatment duration of up to 15 months.

Overall, the trial showed that women who continued maintenance use of bevacizumab alone, after receiving bevacizumab in combination with chemotherapy (Arm 3), lived longer without the disease worsening compared to those who received chemotherapy alone. Women who received bevacizumab in combination with chemotherapy, but did not continue maintenance therapy with bevacizumab (Arm 2), did not live longer without the disease worsening compared to chemotherapy alone.

The full results will be presented at ASCO in June.

Meanwhile this is an interesting development in ovarian cancer, given that J&J have a filing for trabectedin (Yondelis) with the FDA for the same disease, although ODAC expressed concerns about the risk-benefit profile given the side effects associated with the chemotherapy.

Time will tell what will happen later this year but at the moment it's looking more promising for Roche/Genentech than J&J.

Roche’s Avastin fails in stomach / gastric cancer

By MaverickNY on February 24, 2010

Things were so busy in the Icarus office yesterday I didn’t get a moment to post on the Roche/Genentech news that the latest topline phase III trial analysis for bevacizumab (Avastin) were disappointing. The company announced the findings in a press release:

“Avastin (bevacizumab) in combination with Xeloda (capecitabine) or fluorouracil and cisplatin chemotherapy in patients with inoperable, advanced or metastatic gastric cancer (stomach cancer). The study, known as AVAGAST, did not meet its primary endpoint of extending overall survival in patients treated with Avastin in combination with chemotherapy compared to the same chemotherapy plus placebo.”

The full data will be presented at ASCO in June.

Now, while initially disappointing, anyone who was at ASCO last year will remember the stunning data from the ToGA trial, presented by Eric van Cutsem. This study looked at the benefit of adding a different Roche drug, trastuzumab (Herceptin), to standard chemotherapy in patients with HER2 positive gastric cancer, and found a significant benefit of approximately 2.5 months compared to chemotherapy alone.

What is the significance of these two trials for gastric cancer?

Well, Avastin targets VEGF, Herceptin targets HER2, the first was negative, the second positive, which may tell us something useful about the biology of the disease and what mechanisms are driving the tumour growth.

Sometimes a negative result tells us more than we may realise at first. It helps define what really matters.

Why did Roche's Avastin lose steam in 4th quarter 2009?

By MaverickNY on February 5, 2010

This snippet from Reuters posted earlier this week while I was listening to the Roche earnings call in Basle, which was a nicely put together presentation:

"Roche Holding AG overhauled the sales efforts for its best-selling drug, the Avastin cancer treatment, after the company “lost steam” during the fourth quarter.

Sales of the medicine were hurt by a focus on selling it as a treatment for breast tumors, Pascal Soriot, the head of the pharmaceuticals division, said in an interview today. The company beefed up marketing by assigning the sales team responsible for the Herceptin breast cancer drug to also promote Avastin, while the group that sells the Xeloda therapy will promote it for use against colorectal cancer, he said.

“We focused on breast and then kind of lost steam on lung cancer a little bit,” Soriot said at Roche headquarters in Basel, Switzerland. “We’ll increase the promotional effort and I think we’re going to turn this around.”"

Sadly, though, this is not something that was unexpected, as many of us industry observers were secretly wondering how Genentech would fare once absorbed in the more conservative Roche system. One is very science based and the other is more corporate.

Just take a look at the two management teams and you get the big picture:

In the top picture, you see the Roche management team individually taken and in suits, but look like they have taken their ties off just for the photoshoot to make them a little less stiff and formal, perhaps.

In the bottom picture, the Genentech management team, taken as a team in fairly casual attire, with the CEO, Ian Clark, even wearing a fleece!

A tale of two very different cultures in one quick glance.

What impact does this have on the physicians? I asked around. Now, lung cancer doctors are fairly academic and science based, many also do translational research, for example. Underneath they are generally approachable, fun and always willing to answer questions or help people understand a complex topic. They're much more easy going than some of the other cancer specialties.

Which group do you think they would most likely mix with?

Therein lies the rub.

Corporate suits may look sharp, but do they engage and have fun with the scientists, or even understand their world? How much of a subtle impact might that have in the long run? While it is true that in the end, all marketing is ultimately about sales, the intangibles such as how you approach it and engage with customers along the way is often crucial to success.

Time to stop drinking the corporate Kool Aid and focus on the science, methinks.

#AACR Personalized therapy in lung cancer – part 3

By MaverickNY on January 19, 2010

After writing the first two posts in the series, I was much amused to see this tweet in my Twitter stream from one of buddies:

When you've been blogging on science, marketing, PR and cancer topics for several years you begin to wonder if it actually beneficial to anyone, so today's post is dedicated to Miguel in Barcelona for making me smile :-). If you're on Twitter, please do follow him because he's a great guy and shares a lot of very interesting pharma related links. Give him some Twitter love!

Today's topic is about a new generation flavanoid, ASA-404, from Novartis. Of course, under FTC guidelines, I should disclose that as many of you know, I'm a former employee and have also done consulting work for the company, but not on this particular product.

ASA-404 is an interesting agent in phase III development. It's a vascular disrupting agent (VDA) with a tubulin dependent mechanism of agent. Unlike taxanes, which target the microtubulin in DNA, this agent is also part anti-angiogenic agent because it selectively disrupts the tumour vasculature with both direct and indirect effects. In simple terms, I think of it as a kind of hybrid cross between an anti-angiogenic such as bevacizumab (Avastin) and a taxane such as paclitaxel or docetaxel.

Dr Mark McKeage presentation at the AACR lung cancer meeting was focused on the phase II that has been published to date, including a publication in the British Journal of Cancer (see bottom of article).

The drug was well tolerated in phase I trials, achieving an MTD of 3700 mg/m².

In a phase II trial, paclitaxel and carboplatin (pc) therapy was used as the reference arm, and ASA-404 added to the standard chemotherapy in the other arm to determine if the agent added any extra benefit for newly diagnosed patients with non-small cell lung cancer (NSCLC) with either a squamous or non-squamous histology. They looked at 2 different doses of ASA-404 – 1200mg/m² was used in the randomised comparison with carbo-tax and 1800mg/m² with out the comparator arm but in combination as before. 36 patients were accrued into the reference pc arm, 37 in the lower dose ASA-404 arm and 31 in the higher dose ASA-404 arm. This gave a total of 104 patients in the pooled phase II study.

Overall, similar rates of adverse events (AE's) were seen in the squamous and non-squamous patients, except for a slight increase in AE's related to blood/lymphatic effects. No serious AE's associated with vascular effects of bleeding, hemorrhage or hemoptysis were seen. There was an increase in hematologic toxicities (anemia, neutropenia and thrombocytopenia) but these were not significant and none rose above 20%. There was no apparent increase in neutropenia related sepsis.

In terms of efficacy and median overall survival, McKey reported:

PCA vs. PC

14.0 vs. 8.8 mos for 1200mg/m²

14.9 for 1800mg/m²

Thus we can clearly see that adding ASA-404 to standard carboplatin-paclitaxel therapy improved median overall in frontline NSCLC by 5 months.

Recently, the FDA has approved several therapies in NSCLC in different histologies, due to either issues with side effects (bevacizumab and bleeding issues) or lack of efficacy (pemetrexed), while others such as erlotinib have been shown to be particularly effective in non-smoking female asians with an adenocarcinoma histology, although the approval is not based on histology.

Let's take a look at the ASA-404 histology data:

Squamous: Non-Squamous: Overall:

PCA PC PCA PC PCA PC

ORR (%) 40.0 14.3 31.7 25.0 34.4 22.2

One third of the patients had a squamous histology, but experienced no bleeding issues seen with VEGF agents.

While the results are higher for those with a squamous histology, there was also a trend towards higher efficacy in the non-squamous patients. The positive results provided support and evidence for the drug's effectiveness and rationale for beginning the phase III triala, ATTRACT-1 in first line and ATTRACT-2 in second line NSCLC without restriction on histology.

To put the 5 months improvement in median OS with ASA-404 in context, I checked out the PI for other therapies. Bevacizumab was approved on the basis of 12.3 months vs. 10.3 months, ie a 2 month improvement, while pemetrexed was approved on the basis of non-inferiority when comparing pemetrexed plus cisplatin to gemcitabine plus cisplatin (ie 10.3 months of overall survival in each arm).

The front-line trial has completed accrual and is ongoing, but the ATTRACT-2 trial for patients who have had prior chemotherapy is still enrolling. You can find it here: ATTRACT-2.

Of course, these are early days yet and positive phase II data does not always translate to phase III success, but they are a hopeful sign of good things to come. If the data are repeated, it will be good news for patients with NSCLC.

McKeage, M., Von Pawel, J., Reck, M., Jameson, M., Rosenthal, M., Sullivan, R., Gibbs, D., Mainwaring, P., Serke, M., Lafitte, J., Chouaid, C., Freitag, L., & Quoix, E. (2008). Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer British Journal of Cancer, 99 (12), 2006-2012 DOI: 10.1038/sj.bjc.6604808

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Clinical trial results show Denosumab is superior to Zometa in breast cancer patients with bone metastases

By MaverickNY on July 13, 2009

Amgen’s recent announcement of phase III trial data showing that it’s monoclonal antibody, denosumab was superior to Novartis’ Zometa (zoledronic acid) for the treatment of breast cancer patients with bone mestastases is further news that scientifically driven drug development can yield exciting results.

Denosumab is in essence a targeted therapy like Gleevec, Avastin or Herceptin. It’s development came about from basic research that discovered the cellular control of bone remodelling and regulation of bone density is reglated by the RANK Ligand pathway.

RANK Ligand is a TNF famly member, a protein that is expressed on the sufrace of marrow, stromal cells and osteoblasts (the cells responsible for bone formation). When RANK-L binds with its receptor RANK it stimulates the activity of osteoclasts (cells responsible for bone resorption). In the body, RANK-L production is naturally regulated by the protein Osteoprotegerin (OPG), which binds with RANK-L thereby preventing it from binding to its receptor, RANK. When there is insufficient OPG, or too much RANK-L produced, excess bone loss occurs. This occurs in post-menopausal women or in cancer related bone loss.

Denosumab acts by attaching itself to RANK-L, thereby inhibiting its action. Deprived of RANK-L, osteoclasts cannot form, function or survive. The result is less bone destruction and bone loss. Understanding the RANK Ligand pathway has been a breakthrough step in understanding bone biology.

Many cancer patients end up with bone metastases that not only causes pain, but also bone destruction. Roodman, in a 2004 New England Journal article, proposed the “vicious cycle” hypothesis to explain this: Tumor cells produce parathyroid hormone-related peptide (PTHrP), which stimulates osteoblasts to produce RANK ligand leading to less production (downregulation) of osteoprotegerin (OPG), thereby stimulating osteoclasts to resorb more bone. At the same time, production of PTHrP promotes tumor growth directly. Therefore, it should come as no surprise that denosumab would be effective in cancer patients with bone mets and skeletal related events.

What does the future hold for denosumab? In the postmenopausal osteoporosis market, a once or twice yearly injection is extremely attractive given its ease of use. Compliance is a real issue with bisphosphates such as alendronate or risedronate where a daily pill must be taken. Many primary care physicians are not set-up to administer an infusion, which is what Novartis’ once a year osteoporosis treatment, Reclast requires.

However, despite impressive clinical data, Amgen does not yet have a home run. It lacks a large sales force and infrastructure to sell to primary care physicians. Also with generic fosamax (alendronate) available, the cost/benefit trade off is going to be a key factor in uptake. The cost of denosumab will need to be carefully considered for Amgen to enter this competitive market. The FDA advisory board meets on August 13 to discuss Amgen’s BLA application and consider whether to recommend approval for the treatment and prevention of osteoporosis, and treatment of bone loss in patients undergoing hormone ablation for prostrate and breast cancer. Given the positive data from the phase III pivotal studies, a positive recommendation is expected with approval by the FDA expected in October.

For cancer patients, denosumab could become the gold-standard for treatment of bone metastases given its superiority over Novartis’ Zometa. For oncologists, the fact that denosumab only requires an injection while Zometa requires an infusion is less of an issue. The key to success for oncology drugs is based solely on the data. If the positive results continue, Amgen are likely to take market share from Zometa once approval for the treatment of bone metastases is obtained in 2010 or 2011.

So, my take on this is that denosumab is a real winner for Amgen. Whether it will capture the market for postmenopausal osteoporosis remains to be seen, but it is an exciting new drug that will benefit cancer patients. Further data on denosumab can be expected from the September meeting of the American Society of Bone and Mineral Research (ASBMR) in Denver.

Treating triple negative breast cancer

By MaverickNY on September 29, 2008

The American Cancer Society estimates 183,000 new cases of breast
cancer will be diagnosed in the United States this year with more than
40,000 dying from the disease. A portion of these are women who have triple negative breast cancer, which confers a poorer prognosis.

Triple negative breast cancer occurs where the tumour does not express
estrogen (ER) or progesterone (PR) receptors or HER2 protein. This means that standard
treatment with hormone blocking agents and agents that target HER2
such as tamoxifen and Herceptin respectively, are ineffective weapons against this subtype of breast
cancer. Women with triple negative breast cancer generally have shorter survival than those who are ER/PR positive. Identifying better combinations of chemotherapy
and novel biologic agents that are effective in this disease is
therefore critical.

Here in New Jersey, at the Robert Wood Johnson Cancer Center, they are starting a new trial aimed at previously untreated women with triple negative breast cancer using triple combination therapy of doxil, carboplatin, and the anti-angiogenic therapy, Avastin.

Extensive research has suggested that the formation of new blood
vessels plays an important role in the establishment of distant sites
of breast cancer by providing nutrients needed for cell growth to reach
a tumour. Avastin has been found to interfere with the production of
new blood vessels, thereby interfering with cell growth and survival at
distant sites.

Doxil and carboplatin are potent chemotherapies that have been found to prevent the
growth of cancer cells by inhibiting cancer cell reproduction. Overall, this important
study seeks to determine the response of the patient's tumour to this
novel combination and to assess the side effects.

The new trial is part of the CINJ Oncology Group (CINJOG), which involves physicians throughout New Jersey from the CINJ Network of
hospitals. For additional information on how to participate,
individuals should call (732) 235-7251.

According to a recent report from the American Cancer Society,
the death rate from breast cancer went down 2.2 percent per year from
1990 to 2004. Much of that improvement has come as a result of clinical trials and new therapies being developed to treat the disease.

This article is part of the Cancer Research Blog Carnival being hosted by the
Sciencebase Science Blog last week.

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Hot oncology drugs – what's new at ASCO?

By MaverickNY on May 16, 2008

The annual American Society of Clinical Oncology (ASCO) conference begins later this month and the data has just been released. Here are some key abstracts prior to the presentations:

Eli Lilly’s Alimta (pemetrexed) slowed the spread of non-small cell lung cancer in patients with advanced disease. It’s approved for use in patients who have failed chemotherapy; this study suggests it may be added to treatment earlier in the course of disease. Lilly are reportedly filing the early data in patients with select histology later this year. It was recently approved for first-line use in the EU.

Novartis' RAD001 (everolimus/Afinitor); nearly two-thirds of renal cell cancer patients taking had progression of their disease delayed by a year, a significantly better result than in those taking placebo. The disease did not progress for one year in 65 percent of patients taking RAD001, taken once daily orally, compared to 37 percent in those taking placebo, according to detailed results from a late-stage trial, which was stopped early because it met its main target.

GSK 's Tykerb (lapatinib) demonstrated positive data from the first-ever randomized, multi-center, open label Phase III trial of the combination of two targeted agents, lapatinib and trastuzumab (Herceptin), in women with HER2-positive metastatic breast cancer who had previous been heavily pre-treated with taxanes and anthracyclines.

Genentech's Avastin (bevacizumab) showed improved survival for patients with recurring brain cancer. The Phase II trial compared Avastin with irinotecan chemotherapy to Avastin alone in patients with relapsed glioblastoma multiforme (GBM), the most common and aggressive type of brain cancer. Median survival was 9.2 months in the Avastin-only arm and 8.7 months in the Avastin and irinotecan arm. According to historical estimates, only 15 percent of patients with relapsed GBM would be expected to live without their cancer advancing for six months.

ImClone/BMS's Erbitux (cetuximab) new gene findings indicate a simple gene test could allow doctors to predict in advance which patients are likely to benefit from the therapy, ie those without KRAS mutations, since there is evidence that they are more likely to respond to treatment. The same approach would also apply to Amgen's Vectibix (panitumumab).

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