Genentech | Pharma Strategy Blog

Roche's ocrelizumab and AstraZeneca's cediranib bite the dust

By MaverickNY on March 8, 2010

This week kicked off with some interesting emails and alerts in my inbox.

You may well be wondering what on earth rheumatoid arthritis and colorectal cancer have in common. The answer is that yet more agents in development have bitten the dust.

Firstly, it seems that Roche and Biogen Idec have announced that they are suspending the development of their humanised anti-CD20 monoclonal antibody, ocrelizumab, for treatment of rheumatoid arthritis (RA) and Lupus.

This follows a recommendation of the independent Data and Safety Monitoring Board (DSMB) based on their assessment of the studies in RA. The review detected an infection related safety signal which included serious and opportunistic infections, some of which were fatal.

According to the Roche press release:

"As previously announced, the FILM study in MTX-naïve RA patients was placed on clinical hold following an assessment of benefit to risk in this specific RA patient population. In addition, the BELONG study in lupus nephritis patients was previously halted due to serious and opportunistic infection signals."

The trials in multiple sclerosis appear to be ongoing. Their other CD20 antibody, rituximab, has been on the market for several years for the treatment of cancers such as non-Hodgkins Lymphoma (NHL) and more recently, chronic lymphocytic leukemia (CLL). There have been no safety issues with this product.

Oddly, the second agent that flopped today went up against Roche's Avastin and was found to fall short of the required hurdle in a large phase III trial. AstraZeneca's cediranib (Recentin), is a oral small molecule VEGF inhibitor that was being evaluated for the treatment of colorectal cancer (CRC).

According to AstraZeneca's press release this morning:

"This study, HORIZON III, assessed the efficacy of cediranib compared with bevacizumab, both in combination with chemotherapy. Clinical activity was observed in the cediranib arm of the study and there was no statistically significant difference between treatment arms on the efficacy endpoints examined. However, the efficacy did not meet the pre-specified criteria for the primary endpoint of non-inferiority in progression-free survival."

Ouch!

However, these results are not entirely surprising given the previous failure of Novartis' vatalanib in CRC, another small molecule inhibitor, in phase III trials for colorectal cancer. There may well be some quirk in the mechanism of action in colorectal cancer that preferentially allows monoclonal antibodies to work more effectively than small molecules. The half life, dosing schedules or inhibiting the ligand differently could all play a crucial part in the process.

For AstraZeneca, though, their run of bad luck in oncology continues with Iressa, Zactima and now Recentin all struggling to make a major impact.

Photo Credit: Kiragon

1 Comment

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?

1 Comment

Why do some Pharma companies do well in oncology and other's don't?

By MaverickNY on March 3, 2010

A chance email yesterday from Matthew Herper of Forbes Health got me thinking. He was interested in whether a company, who have been successful in other therapeutic areas, could do well in cancer.

A question like that can quietly sit in the back of your mind for days percolating and brewing until you sit down and really think about it.

I've had some great opportunities to work in several different therapy areas including cardiovascular, dermatology, immunology, CNS, hematology and oncology. The last two have much in common, the others less so. But what makes them different, what factors are important to take into consideration and how do make it work?

Two of the big differences are data and science.

Cancer is much more technically complex than many diseases and the understanding of how the biochemistry and the drug interact can make or break a product. One of the first oncologists I ever met, a dour academic chap who did a lot of leukemia transplants and research in equal measure, memorably advised me in a most stern manner to "forget the fluff and puff, just show me the data!"

Cardiologists and dermatologists always seemed to ask 'how' questions… how much does this cost, how soon will you have slides for a lecture series, how many papers do you have published so far etc.

Oncologists are a different breed. They ask a lot of why and where questions… why should I use this drug, where is the evidence to show X or Y etc.

For me, it's about learning a completely different mindset and adjusting to a new customer focus. If your drug isn't better than what an oncologist has already, especially in efficacy, no amount of hype is going to give you a hook or an advantage. Risk-benefit trade-offs in a serious disease that may lead to deaths forces people to think about the treatments in another light.

Think about it, the most common questions an oncologist is going to hear from people who visit are:

Will I be cured?
Will it make me live a little longer?
Will the treatment make me feel better?

Intuitively, people with cancer focus on the most important things and for doctors hearing that many times during the course of a week, they will subconsciously be thinking that way too.

Going back to Matt's broad question, I was thinking about all these things yesterday while interviewing an oncologist about how he treats a certain cancer, which in rare cases is curative but in most situations 2) and 3) more clearly applied. My focus was a little sharper than usual because I found myself automatically asking why questions about a range of different regimens.

Now, some of the companies for the treatments he mentioned have indulged in typical marketing hype, with fancy programs, e-details and branded campaigns that could well have applied to an anti-hypertensive or skin cream. As the doctor walked through his treatment algorithm, I could almost imagine the critical survival charts on the wall in from of my desk. Finally, it became clear that he ranked them by the survival curves, with one exception that was reserved for a small, rare subset that had aggressive disease because the consequences of managing the concomittant myelosuppression were too high.

And there in is the rub.

Success in the oncology arena boils down to data and how well you stack up against the competition. Being first to market gives you a huge advantage too, since a hurdle is set and the ones afterwards are forced to demonstrate why they are better.

This is way many good marketers I've met avoid or dislike oncology: it's data driven, not marketing driven.

In oncology new products, the best thing you can do is focus on the data and find areas or niches where you can do well. It requires a more analytical approach to understand the science, work with the clinical and research teams and patiently build a blockbuster niche by niche. If a drug fails in an indication, either find another one quick or ditch it. Spend money wisely on more smaller phase I and II studies experimenting with different tumour types to match the biology of the disease with the drug's target. This is critical, but it also takes money and time with a high risk attached to it because more drugs fail than succeed.

Of course, once you get a drug to market, that's not the end. You have to practice 'kaizen' and continually invest more dollars in new indications. If you're too slow doing this, the second to market drug can be equivalent but have the advantage of a broader clinical program while you sat on your laurels for several years. Life cycle management means planning ahead for the second and third indications before you finish the first cancer type. If the first one fails, this also means you have a backup in advanced stages and that's a smarter strategy than everyone trying to get senior management's attention for resources and dollars if you put all your eggs in one basket.

Not every company has the scientific mindset and willingness to invest research dollars to succeed in cancer. Management by consensus doesn't work very well either, that just drags things down to the lowest (and often slowest) common denominator. You need passionate driven product champions who fight to the end and generate resources, focus and high priorities to get things moving by corralling the collective energy to get things moving at pace faster than the proverbial snail.

With regards to cancer pipelines, Roche/Genentech and Novartis probably have two of the most promising at the moment and are significantly ahead of the pack in my view. They invest heavily in science and research, as well as broad clinical programs that creates a continuous buzz. The mindset is clearly to accept a few negatives that are easily over shadowed by the many successes. This creates a groundswell and positive energy. Pfizer, Merck and BMS all have interesting pipelines, but also have to fight the internal entropy for execution as well.

Data matters. Execution matters.

Forget the hype in oncology and think about making a real difference to the lives of people with cancer and intelligent ideas around the concept of artisanal marketing, which my buddy Morgan Brown described in an intelligent and thought provoking post this week:

"Thoughtful, insightful, honest, embracing complexity and celebrating the craft of the product or products themselves."

4 Comments

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.

Chronic Leukemia is a hot topic right now!

By MaverickNY on February 19, 2010

Last night and this morning brought some topical news on the leukemia front.

Just before 5pm EST yesterday, the FDA announced they had approved Roche/Genentech's rituximab (Rituxan) in chronic lymphocytic leukemia (CLL). Rituxan is already approved for non-Hodgkins Lymphoma (NHL) and rapidly the standard of care when combined with CHOP chemotherapy in this disease. CLL is the most common adult leukemia and tends to affect older patients.

According to the Roche press release this morning, the FDA approval was for:

"Rituximab plus fludarabine and cyclophosphamide (FC) chemotherapy for people with either previously untreated (first-line) or previously treated (relapsed or refractory) CD20-positive chronic lymphocytic leukemia (CLL)."

The CLL data was presented last year at ASH, showing that FCR led to improved survival compared to FC alone. FDA's press release highlighted the results:

"The safety and effectiveness of Rituxan was evaluated in two studies that measured progression-free survival, defined as the time a patient in the study lived without the cancer progressing.

In one study of 817 patients who had not received any prior chemotherapy, progression-free survival was eight months longer for those receiving Rituxan plus chemotherapy than for those who received chemotherapy alone. In another study of 522 persons whose cancer had progressed following other chemotherapy drugs, progression-free survival was five months longer for those who received Rituxan plus chemotherapy.

The FDA analyzed the data on patients 70 years of age and older who had received Rituxan and found no evidence that adding the drug to chemotherapy benefitted elderly patients compared to receiving chemotherapy alone. However, there was also no evidence that Rituxan was harmful to elderly patients."

This approval affects several companies in the CLL space.

Late last year, GSK received approval for their CD20 antibody, ofatumumab (Arzerra) in CLL in the refractory setting but are likely to be impacted by rituximab's approval in both first and second line CLL. My guess would be that physicians will be very comfortable and experienced using the Roche/Genentech monoclonal antibody and therefore using it in CLL as well as NHL will not be a difficult stretch.

Bendamustine (Treanda), from Cephalon, is an old drug that has been making a comeback in NHL and after the success of the bendamustine-rituximab (BR) combination in NHL that was presented at ASH, it may well become the new standard of care there instead of R-CHOP. Trials are ongoing with BR in CLL and if positive, I can see that becoming a solid option in CLL in the not too distant future. For now, FCR looks like being the most efficacious first-line option in CLL, replacing FC. It may not be long before BR offers similar or better efficacy than FCR with fewer side effects. We will have to wait and see.

The other news that was interesting in my inbox is that Novartis (a client), announced that nilotinib (Tasigna) received FDA priority review for newly diagnosed patients with early-stage chronic myeloid leukemia (CML):

"FDA priority review status is granted to therapies that offer major advances in treatment or provide a treatment where no adequate therapy exists. This status accelerates the standard review time from 10 to six months. Tasigna demonstrated that significantly fewer patients progressed to more advanced stages of the disease than the standard of care Glivec® (imatinib)* at 12 months. Tasigna also showed a statistically significant improvement over Glivec in every other measure of efficacy in the trial, including major molecular response (MMR) and complete cytogenetic response (CCyR) at 12 months."

Novartis and BMS were in a race to file for the front-line indication for their second generation tyrosine kinase inhibitors (TKIs) with comparative trials versus the standard of care, imatinib (Gleevec/Glivec). Novartis presented the initial Tasigna results at ASH in December in a late breaking abstract that pointed to earlier and deeper responses with nilotinib compared with imatinib.

BMS didn't presented any data from their randomised registration trial at the meeting, but recently announced at the JP Morgan Healthcare conference last month, that they expected data to be available at ASCO. I'm not sure whether they submitted a regular abstract or a late breaker, but it will be interesting to see what the data looks like and the big question now is when will they be filing Sprycel with the FDA for the front-line indication?

It going to be an interesting few months ahead in leukemia, that's for sure!

2 Comments

San Francisco: A hotbed of oncology Biotechnology

By MaverickNY on February 15, 2010

We spend a lot of time researching biotechs in the oncology space and thus it occurred to me that many of them are located around the San Francisco bay area as a hub, in a landscape dominated by Genentech, now part of the Roche empire. San Francisco has good logistic connections, a lot of roomy office space, active research in several universities and provides a pleasant haven for science, academia, research and industry to all flourish.

There are far to many to mention in one blog post, but here is a quick update on some of the companies we’ve been following over the last couple of years in the cancer market (in no particular order):

Sunesis ($SNSS): Got off to a rocky start with the early development of voreloxin, but have refocused the clinical trial designs with some interesting phase I and II results to date in AML. The compound, a quinolone derivative that acts as DNA damaging agent, is also being developed in platinum resistant ovarian cancer. I’d like to see some comparative data in AML at some point, or at least a study with just a standard chemo in it compared to the standard + voreloxin, otherwise it will be hard to see exactly what the agent actually adds.

Poniard ($PARD): Poniard are developing a new generation platinum agent, picoplatin, that seeks to offer equivalent efficacy as existing platinums, but with less neuropathy that is common to existing treatments such as oxaliplatin.

Picoplatin got off to a good start with trials starting in small-call lung cancer (SCLC) and colorectal cancer (CRC). Early results looked promising. However, results from the pivotal Phase 3 SPEAR (Study of Picoplatin Efficacy After Relapse) trial of in the second-line treatment of SCLC did not meet its primary endpoint of overall survival. The analysis, based on 320 evaluable events (patient deaths), showed a hazard ratio of 0.82 with a p value of 0.089. The company felt that the main reason for the discrepancy lay in pateints in the placebo arm receiving more chemotherapy than the picoplatin arm after relapse occurred.

A randomised, controlled Phase 2 trial of picoplatin in metastatic CRC patients is ongoing. The study recently met its primary objective. Picoplatin, in combination with 5-fluorouracil and leucovorin (FOLPI regimen), was associated with a statistically significant reduction in neurotoxicity (p <0.004) compared to oxaliplatin given in combination with 5-fluorouracil and leucovorin (FOLFOX regimen). The results also suggested that FOLPI had similar efficacy to FOLFOX. More data is expected at ASCO in June.

Nodality: Is an interesting technology company that is developing next generation diagnostics by characterising cell signalling pathways. The concept is based upon proprietary flow cytometry technology, originally developed in the laboratory of Professor Garry Nolan and licensed from Stanford University.

Flow cytometry has been widely used to characterise cell surface markers on hematologic cells. Nodality are now utilising advanced quantitative flow cytometry to define the signalling networks within individual cancer cells, in order to enable biologically-driven clinical decision making for cancer treatment. Essentially, this technology can be used to determine changes before and after cancer treatment, eventually leading to the identification of appropriate biomarkers for treatments.

BiPar Sciences: Are developing BSI-201, a PARP inhibitor for the treatment of triple negative breast cancer and ovarian cancer. They signed a deal with sanofi-aventis last year and are now a wholly owned subsidiary. It looks to be a promising agent, albeit with a short patent life. The race to market against KuDos/AstraZeneca will be an interesting one to watch over the next couple of years. How will the two PARP inhibitors stack up? Time will tell. They also have a follow on PARP inhibitor (BSI-401) in development, and an anti-tubulin compound.

Exelixis ($EXEL): Have been in the news frequently over the last few years as they license out their in-house compounds to companies such as BMS, GSK, sanofi-aventis and Genentech. Their stated goal is to develop first in class or best in class compounds through their own discovery and clinical programs. The pipeline runs an interesting gamut of targeted agents to various pathways, including MET, VEGF, PI3-kinase, IGF-1R, MEK, RAF and others.

The most advanced agent (XL184) is in phase III development for metastatic medullary thyroid cancer (MTC) with BMS (aka BMS-907351). This is a very slow growing cancer, so a rapid development is unlikely. The compound is a multi-kinase inhibitor of VEGFR, MET and RET. It is also being tested in phase I/II trials for recurrent glioblastoma (GBM), non-small cell lung cancer (NSCLC) in combination with erlotinib and a phase I trial in advanced malignancies is also ongoing.

BMS probably have the biggest investment in Exelixis, having licensed at least 5 of their compounds in cancer. Time will tell if this proves to be a smart decision or not.

Plexxikon: Are a private Berkeley based company who focus on the discovery and development of small molecules in several therapeutic areas including cardio-renal disease, CNS, inflammation, metabolic disease and oncology. They are most known for their BRAF inhibitor, PLX4032, which is being developed for the treatment of malignant melanoma. BRAF is thought to be mutated in approximately half of melanomas and may be one of the drivers of the disease.

Plexxikon signed a deal to develop the agent with Genentech, now Roche, and phase III trials in melanoma were announced last month. This is definitely a promising agent to watch out for.

Facet Biotech ($FACT): have been in the news recently after Biogen Idec tried to purchase the company, but offers have been repeatedly rebuffed and dismissed as inadequate. The company was launched as a spin-off from PDL BioPharma, Inc in December 2008.

Facet are developing several compounds in the multiple sclerosis and cancer markets, including volociximab (solid tumours) and elotuzumab (myeloma). The MS agent in phase II, daclizumab, has received most attention but the oncologic agents are too immature to determine how effective they might be yet. Definitely one to watch out for though, if a white knight in the form of a big pharma with cash descends in the near future. The most obvious companies with cash and a declared growth by acquisition strategy are BMS and Celgene, but I’m not sure Facet would be a good fit for either. On paper, Biogen Idec was probably a better option.

There are plenty of other interesting cancer companies in the Bay Area, but these are a few that I’ve been watching. More will be covered in the next update of the cancer market in the area. New data will no doubt be presented at the forthcoming American Society of Clinical Oncology (ASCO) meeting in June.

3 Comments

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.

Dual HER2 inhibition improves survival benefit in advanced breast cancer

By MaverickNY on January 21, 2010

Updated Survival Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy.

Blackwell KL, Burstein HJ, Sledge GW, Stein S, Ellis C, Casey M, Baselga J, O'Shaughnessy J

Background: The synergistic interaction of lapatinib combined with trastuzumab was established in HER2-positive preclinical models, hence providing the rationale to evaluate this combination in a clinical setting. Progression-free survival (PFS) from study EGF104900 revealed the combination of lapatinib plus trastuzumab was superior to lapatinib alone in women with HER2-positive metastatic breast cancer (MBC) that progressed on multiple lines of trastuzumab-based therapy. Preliminary data showed a trend in overall survival (OS) favoring the combination therapy; however, data were not mature. Updated OS analyses are reported.

Methods: Women with HER2-positive MBC progressing on prior trastuzumab-containing regimens were randomized to receive either lapatinib 1500 mg once daily or lapatinib 1000 mg once daily in combination with trastuzumab 2 mg/kg (after a 4-mg/kg loading dose). If objective disease progression occurred on or after 4 weeks of lapatinib alone, crossover to the combination arm was permitted. OS was summarized using Kaplan-Meier curves and compared between treatment arms using stratified log-rank tests. Analyses adjusting for baseline prognostic factors and crossover were also performed.

Results: 296 women were randomized (148 per arm). The median number of prior trastuzumab-containing regimens for MBC treatment was 3. Of the women randomized to lapatinib alone, 52% (77/148) crossed over to the combination arm. At data cut-off for updated OS, 218 deaths (74%) had occurred. Median OS following treatment with lapatinib plus trastuzumab was 60.7 weeks compared with 41.4 weeks for lapatinib alone. A significant improvement in OS was demonstrated with combination therapy compared with lapatinib monotherapy (HR: 0.74; 95% CI: 0.57, 0.97; P=.026). The survival benefit was maintained after adjusting for baseline prognostic factors (HR: 0.71; 95% CI: 0.54, 0.93; P=.012). A trend toward a clinically relevant 25% reduction in risk of death (P=.080) was also observed after adjusting for crossover.

Conclusion: A statistically significant OS benefit was observed in women with heavily pretreated, HER2-positive MBC treated with lapatinib in combination with trastuzumab compared with those treated with lapatinib alone. The actual survival benefit of the combination therapy may be underestimated due to the high frequency of crossover.

Source: SABCS.org

This data from the Sam Antonio Breast Cancer Symposium last month showed that heavily pre-treated patients including prior trastuzumab (Herceptin) who received a combination of two HER-2 inhibitors, trastuzumab and lapatinib (Tykerb) improved their survival by 4.5 months over lapatinib alone:

The EGF104900 study included 296 women and resulted in an overall survival rate of 56% in patients randomized to lapatinib (1,000mg/day) plus trastuzumab compared to 41% in those assigned to lapatinib (1,500mg/day) alone.

Presently, trastuzumab is approved for first treatment of HER-2 positive breast cancer and lapatinib is given in second line once Herceptin fails. It is interesting that there wasn't a Herceptin only arm, only a lapatinib only arm, but then the patients had previously progressed on trastuzumab therapy.

Previous studies with Herceptin and anthracyclines have shown an increase in cardiotoxicity associated with mainly with doxorubicin. There was no suggestion of a cardiac safety issue with the HER-2 combination therapy in this study.

Lapatinib and trastuzumab target HER-2 through different mechanisms, which may account for the apparent additive effect in combination. Previous preclinical and animal studies have suggested synergistic benefits for the combination, including enhanced apoptosis, anti-proliferative effects and downregulation of survivin.

This is the first study to show a survival improvement for any anti-HER2 agent taken beyond first line therapy. It validates the concept that trastuzumab is an important drug to maintain through disease progression beyond initial therapy in patients who have previously done well on combined chemotherapy and HER-2 regimens before developing disease progression.

#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

1 Comment

Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘Genentech’

Roche's ocrelizumab and AstraZeneca's cediranib bite the dust

What can we learn from the Oscars?

Why do some Pharma companies do well in oncology and other's don't?

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

Roche’s Avastin fails in stomach / gastric cancer

Chronic Leukemia is a hot topic right now!

San Francisco: A hotbed of oncology Biotechnology

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

Dual HER2 inhibition improves survival benefit in advanced breast cancer

#AACR Personalized therapy in lung cancer – part 3