Pharma Strategy Blog

The growing importance of KRAS in ovarian cancer and its impact on pipelines

We've heard a lot about the impact of KRAS in colorectal cancer as a useful biomarker for determining whether or not to treat with EGFR therapy, depending on whether the mutation is wild-type or mutated, but now new evidence has emerged for it's possible role in ovarian cancer.

A paper by Ratner et al., from Yale University, looked at the relationship between an increased risk of OC and a KRAS variant.

Overall, the data demonstrated that a variant of the KRAS oncogene was present in 25% of all ovarian cancer patients. The same variant was also found in 61% of ovarian cancer patients with a family history of breast and ovarian cancer. Up until now though, it has proven impossible to tell which women with a strong family history of breast and ovarian cancers would go on to develop the disease. These results therefore offer some new clues in the puzzle.

Related research from another team from the UK, Denmark and US, published last year, looked at tagging single-nucleotide polymorphisms (SNPs) in candidate oncogenes and the susceptibility to ovarian cancer in approx. 1,800 women with invasive ovarian cancer compared with controls (n=3,000). The goal was to identify moderate/low-risk susceptibility alleles of the proto-oncogenes BRAF, ERBB2, KRAS, NMI, and PIK3CA, but no evidence of ovarian cancer association was found with these SNPs. When stratified by histologic subtype, however, one common variant allele have borderline evidence of association with epithelial ovarian cancer.

What was interesting to me in the latest research from Yale is that all the women in the study had a strong family history of cancer, but only half had known genetic markers of ovarian cancer risk such as BRCA1 or BRCA2 mutations. The results, albeit from a small sample (n=157), suggest that the KRAS variant may offer a more sensitive than currently available. 

The Yale group had previously established that the KRAS-variant is not somatic but germline, meaning it is identical in person's normal and tumour tissues, thereby enabling the researchers to collect primarily germline DNA from either blood or saliva, rather than from tumour biopsy samples.  This is huge from a patient perspective and physician point of view in terms of ease of use and convenience.

This study is important because ovarian cancer is the single most deadly form of women's cancer and is usually diagnosed in advanced stage disease.  Part of the reason is because of the lack of known risk factors or genetic markers of risk.  To this end, the authors concluded:

"Our findings strongly support the hypothesis that the KRAS-variant is a genetic marker for increased risk of developing ovarian cancer, and they suggest that the KRAS-variant may be a new genetic marker of cancer risk for hereditary breast and ovarian cancer families without other known genetic abnormalities."

What we now need is validation in large scale clinical trials to determine whether the genetic marker can be used commercially to determine prognostic risk for ovarian cancer earlier.  If the results ultimately prove useful in clinical trials, then this finding relating to the KRAS variant may well have important implications for future therapeutic strategies and pipeline development in ovarian cancer as well as for prognostic testing and earlier detection for improved outcomes. 

Ratner, E., Lu, L., Boeke, M., Barnett, R., Nallur, S., Chin, L., Pelletier, C., Blitzblau, R., Tassi, R., Paranjape, T., Hui, P., Godwin, A., Yu, H., Risch, H., Rutherford, T., Schwartz, P., Santin, A., Matloff, E., Zelterman, D., Slack, F., & Weidhaas, J. (2010). A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk Cancer Research DOI: 10.1158/0008-5472.CAN-10-0689 

Quaye, L., Song, H., Ramus, S., Gentry-Maharaj, A., Høgdall, E., DiCioccio, R., McGuire, V., Wu, A., Van Den Berg, D., Pike, M., Wozniak, E., Doherty, J., Rossing, M., Ness, R., Moysich, K., Høgdall, C., Blaakaer, J., Easton, D., Ponder, B., Jacobs, I., Menon, U., Whittemore, A., Krüger-Kjaer, S., Pearce, C., Pharoah, P., & Gayther, S. (2009). Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer British Journal of Cancer, 100 (6), 993-1001 DOI: 10.1038/sj.bjc.6604947

Chin, L., Ratner, E., Leng, S., Zhai, R., Nallur, S., Babar, I., Muller, R., Straka, E., Su, L., Burki, E., Crowell, R., Patel, R., Kulkarni, T., Homer, R., Zelterman, D., Kidd, K., Zhu, Y., Christiani, D., Belinsky, S., Slack, F., & Weidhaas, J. (2008). A SNP in a let-7 microRNA Complementary Site in the KRAS 3' Untranslated Region Increases Non-Small Cell Lung Cancer Risk Cancer Research, 68 (20), 8535-8540 DOI: 10.1158/0008-5472.CAN-08-2129

Aeterna Zentaris and Keryx's Perifosine gets fast track designation for colorectal cancer

Last month at the ASCO GI Symposium, Keryx and Aeterna Zentaris reported statistically significant benefit in survival from updated results of a randomized, double-blind, placebo-controlled phase II study of KRX-0401 (perifosine) for the treatment of advanced metastatic colorectal cancer. 

The study was based on 35 evaluable, but heavily pre-treated patients, with relapsed or refractory metastatic colon cancer were randomized to receive capecitabine (Xeloda) from Roche at 825 mg/m2 BID on days 1 - 14 every 21 days plus either perifosine (P-CAP) or placebo at 50 mg daily (CAP).

The results showed that the P-CAP arm had 1 PR and 8 SD for an overall response rate of 64%, while the CAP arm had 0 PR and only 3 SD for a response rate of 27%.

In addition, looking at the overall survival, the data favoured the P-CAP arm a MOS of 15.3 weeks compared with 6.8 weeks for CAP alone.

Typical adverse events reported appeared to be relatively mild:

"The P-CAP combination was well-tolerated with Grade 3 and 4 adverse events of > 10% incidence for the P-CAP arm versus CAP arm as follows: anemia (15% vs. 0%), fatigue (0% vs. 11%), abdominal pain (5% vs. 11%), and hand-foot syndrome (30% vs. 0%)."

Perifosine is also being developed for the treatment of multiple myeloma, which is currently in phase III development.  The compound is an inhibitor of Akt and phosphoinositide 3-kinase (PI3K), as well as other pathways such as JNK and MAPK. These pathways are associated with programmed cell death (apoptosis), cell growth, cell differentiation and cell survival as shown in the diagram below:

Source: Aeterna Zentaris

Interestingly, this morning's news brought an announcement that the FDA have granted Fast Track Designation for the perifosine in advanced, refractory colorectal cancer.  Based on the phase II data, a randomised phase III trial is expected to begin this quarter based on a similar trial design.

Clearly, it will be a little while before the data is available, but definitely one to watch out for in the future given new therapy options are always needed in the refractory cancer setting.

Merck KGaA reviewing cardiac data for Erbitux in lung cancer trials

"Merck KGaA is reviewing heart risks of its tumor-fighting Erbitux drug in several types of cancer after European regulators asked for more information on the treatment’s safety. 

The European Medicines Agency requested the review after rejecting Erbitux for use in lung cancer patients, according to a report published online on March 12. The drug regulator identified an “increased incidence of cardiac events” in lung cancer patients age 65 years or more, in particular high-risk patients with a history of heart problems."

Source: Bloomberg

This was an interesting snippet of news that I saw in the mass of alerts this morning, and no obvious press release from any of the companies involved with the drug, Merck KGaA (in Europe), BMS or Imclone (US partners).  

Part of the problem here is that many people with lung cancer also tend to have cardiac co-morbidities and thus the two may go hand in hand. To be fair, similar side effects have not apparently been reported in other cancers, such as colon cancer.

If the analysis reveals negative findings, then it may lead to changes in the prescribing information, which will not be good news.  Of course, the company are hopeful that will not happen, because changes in the EU labelling for Erbitux (cetuximab) may subsequently impact the US one too.  

Merck are already having a rough week on the issues management and communications front with the suspension of the Stimuvax trials after a patient being treated with the vaccine developed encephalitis. At least the current issue didn't get reported on a Friday!

Bench to Bedside: How can we speed up cancer drugs to the clinic?

After yesterday's post about the I-SPY trials in neoadjuvant therapy for breast cancer and how they may speed up the process of bringing new innovative cancer drugs to the clinic faster, I was reflecting on my own experiences with imatinib (Gleevec).   

The Philadelphia Chromosome was first identified in 1960 by Nowell and Hungerford. Gleevec was finally approved by the FDA in May 2001, 41 years later.   

Between 1999, when I arrived in the US and working in New Product Development at Novartis until 2001 when Gleevec was launched, I attended scientific meetings including AACR, ASH and ASCO. Often, Dr Judah Folkman, a scientific researcher from Harvard, would talk about angiogenesis and hypothesised that was the principal mechanism by which tumours grew. I listened to his ideas many times because I was curious and found the concept both fascinating and intuitive. There was a long line of drugs that failed to work though, and every meeting seemed to bring yet more negative results.

Now, Folkman first advanced the angiogenesis theory in 1971 in the New England Journal of Medicine, but it wasn't until 2002, when bevacizumab (Avastin), a VEGF inhibitor that prevented angiogenesis from happening, was finally approved for the treatment of colon cancer.   At that point you go, 'oh wow' and realise that Folkman's theory was indeed proven correct.

Thus a tale of two incredible cancer drugs that both took a relatively long time to evolve from scientific idea to effective treatment in people with cancer.  Or perhaps they were actually relatively 'quick' compared to others, but why it takes this long is something we can surely do better at. 

Last night I was researching ideas for drug development and innovation since the concept of bench to bedside fascinates me and came across this enlightening video from a lunchtime talk that Dr Susan Desmond-Hellmann gave last year at UCSF. Oddly, she seems to have trodden similar thought processes and asked why and how can we speed things up as well. 

The short lecture is well worth listening to for those interested in drug development - the good doctor explains the bench to bedside concept far better than I: 

Sources for scholars and clinical scientists:

The NEJM doesn't appear to go back beyond 1993 online, but the original reference to Folkman's article is at: 

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186.

A more recent one from 1995, which provides an update is available online at: NEJM

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

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

Cancer biology is becoming very complex #AACR

As we learn more about the biology of cancer, I'm finding that rather becoming simpler, it actually seems much more complex and sophisticated than we may have first realised.

Sometimes, we don't know what we don't know.

Take for example, the recent AACR meeting on the molecular origins of lung cancer that I attended and wrote a few summary posts on (with more to come!) 

There was a particularly fascinating lecture from Robert Kerbel, who looked at the role of tyrosine kinase inhibitors (TKIs) in metastatic cancer.  He noted that there have been many successful trials with TKI's, with a two month improvement in survival being typical.  There have also been failures, such as bevacizumab (Avastin) in 1st line pancreatic cancer, 2nd and 3rd line breast cancer and adjuvant colorectal cancer. 

Numerous theories associated with how anti-angiogenic agents work, including the normalisation of blood vessels, allowing more drug to be delivered to the tumour and several other hypotheses have also been floated around.

What struck me though, was that the switch to a different concept, one where there are early indications that anti-angiogenic therapy actually promotes invasion and metastasis, for example in glioblastoma.  Dr Kerbel then showed some scans clearly showing disease progression and growth and asked whether bevacizumab actually increases the aggressiveness of a metastatic tumour over time?

ie

The evidence for this concept came from an paper published in Cancer Cell in 2009 by Paez-Ribes et al.,:

"The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies."

This invasion effect has been shown in bevacizumab and sunitinib (Sutent), both potent inhibitors of VEGF, so clearly the effect is a class one.

Kerbel discussed what else could explain the results other than increased tumour hypoxia? 

Another idea looked at dose dependent circulating levels of plasma VEGF, which Ebos et al., proposed and was subsequently noted with sunitinib in phase II human breast cancer trials reported by Harold Burstein.

The issue then becomes one of potential consequences.  Thus, plasma VEGF levels may explain drug resistance seen with anti-angiogenic agents, rapid tumour regrowth and rebound revascularisation may occur once therapy is stopped and an increase in malignant aggressiveness may be seen as invasion and metastasis increases.

The other question on my mind is why is there differences observed in adjuvant and metastatic disease as we have discussed previously with the negative bevacizumab results in adjuvant colorectal cancer.  It is possible, based on these observations that treatment with anti-angiogenic agents may have the opposite effect to that intended by hastening progression and thus such therapies may be better suited to the metastatic setting.

The big question now is figuring out how to overcome the drug resistance seen with these agents while minimising the vascular stimulation effects seen.

 

Pàez-Ribes, M., Allen, E., Hudock, J., Takeda, T., Okuyama, H., Viñals, F., Inoue, M., Bergers, G., Hanahan, D., & Casanovas, O. (2009). Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis Cancer Cell, 15 (3), 220-231 DOI: 10.1016/j.ccr.2009.01.027

Ebos, J., Lee, C., Cruz-Munoz, W., Bjarnason, G., Christensen, J., & Kerbel, R. (2009). Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis Cancer Cell, 15 (3), 232-239 DOI: 10.1016/j.ccr.2009.01.021

Loges, S., Mazzone, M., Hohensinner, P., & Carmeliet, P. (2009). Silencing or Fueling Metastasis with VEGF Inhibitors: Antiangiogenesis Revisited Cancer Cell, 15 (3), 167-170 DOI: 10.1016/j.ccr.2009.02.007

Ebos, J., Lee, C., Christensen, J., Mutsaers, A., & Kerbel, R. (2007). Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy Proceedings of the National Academy of Sciences, 104 (43), 17069-17074 DOI: 10.1073/pnas.0708148104

Burstein, H., Elias, A., Rugo, H., Cobleigh, M., Wolff, A., Eisenberg, P., Lehman, M., Adams, B., Bello, C., DePrimo, S., Baum, C., & Miller, K. (2008). Phase II Study of Sunitinib Malate, an Oral Multitargeted Tyrosine Kinase Inhibitor, in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane Journal of Clinical Oncology, 26 (11), 1810-1816 DOI: 10.1200/JCO.2007.14.5375

Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, & Kerbel RS (2009). Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer cell, 15 (3), 232-9 PMID: 19249681

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Erbitux improves survival in patients with metastatic colorectal cancer and wild type KRAS tumours

The American Society of Clinical Oncology (ASCO) held their annual symposium on Gastrointestinal cancers over the weekend in Fort Lauderdale, FL.  I was unable to attend the meeting, but it was interesting to follow it remotely via various people at the event. 

In 2008, van Cutsem first presented the interim phase III data from the front line trial of cetuximab (Erbitux) with FOLFIRI in metastatic colorectal cancer (mCRC) in a plenary session at the ASCO annual meeting.  The data demonstrated that biomarker data suggested that the presence of wild type rather than mutant type KRAS predicted response to cetuximab in mCRC.

The updated CRYSTAL data was probably the most anticipated abstract at this meeting.  Here's a snapshot from the abstract:

The data above clearly shows a superior response rate, progression-free survival (PFS) and overall survival (OS) in favour of cetuximab in wild type KRAS.

What was also interesting is that BRAF, another mutation that has been shown to increase resistance to EGFR inhibitors, was not predictive of cetuximab activity, based on pooled data from the CRYSTAL and OPUS trials presented by Prof Kohne.

Overall, these data indicate that testing for KRAS mutational status is a valid way of deciding which patients should receive EGFR inhibitors such as cetuximab for the treatment of metastatic colorectal cancer.  Patients with mutant KRAS or BRAF mutations are less likely to do well on such therapy.

It will be interesting to see whether future trials with a RAS/RAF inhibitor such as sorafenib (Nexavar) with cetuximab are being considered in combination to overcome resistance.

{Updated: I should clarify that the wt KRAS effect is an EGFR class effect as you can see from similar data on panitumumab (Vectibix) in the second line setting in this abstract. 

The presenter, Peeters, noted that in patients with wild type KRAS:

• PFS was 5.9 months for panitumumab plus FOLFIRI vs. 3.9 months for FOLFIRI alone (HR=0.73). 
• Median OS was 14.5 months for the study arm vs. 12.5 months for FOLFIRI alone (HR=0.85). 
• Response rate for the panitumumab arm was 35% compared with 10% for patients assigned to FOLFIRI alone. 

As with cetuximab, there was no difference in PFS, OS or response rate in patients with mutant KRAS tumours.  The study met its primary endpoint, so it will be interesting to see if regulatory approval will be forthcoming in the second line setting for panitumumab.}

Acknowledgement:  Many thanks to Kerri Wachter who was at the meeting and provided information and tips that lead to this post.

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Science and medical conferences - is there value in going?

One of the great things about travelling to scientific conferences around the world, is catching up with old friends, meeting new people, learning new things and also seeing some wonderful sights when least expected.

Here's a quick shot I took at dusk on my 3G iPhone took walking from the bus stop to the hotel I was staying in for the recent AACR meeting on molecular origins in lung cancer. 

It was nice to get out at the end of the day for some fresh air, but the sunset was certainly an added bonus and a heartening welcome after the chill of the East coast winter!

Some meetings you can get a decent flavour of what's going on from the press releases and reports coming out from good science writers, reporters and analysts such as Brooke Wang, Kerri Wachter, Mike Huckman and Roxanne Nelson.  You can't attend every conference, but you can trust in a few good men (and women) to tell the stories in a straightforward and accurate way.

After a while, I can tell who is actually reporting live from the meeting and who is just rehashing a press release or media briefing - the quality of the reporting and analysis shines through beyond mere data repetition :>}.

One of the biggest things I personally gain from being on the spot is the chance to interact with key opinion leaders and ask them questions.  Of course, you can do this by email or phone too, assuming you can track them down in a timely fashion, but checking the nuances on the spot is extremely valuable both for greater understanding and immediacy.

Right now, I'm following the ASCO Gastrointestinal Cancer Symposium from Fort Lauderdale on Twitter via the #GICaSymp hashtag.  Kerri is tweeting and reporting from there and several Pharma buddies are also attending and sending updates by email.  I'm particularly keen to hear what Dr Eric van Cutsem has to say in his update about KRAS and biomarkers from the CRYSTAL trial in colorectal cancer.

Amgen's Vectibix is dead in colorectal cancer

The stunning press release from Amgen today announcing that Vectibix did not meet statistical significance for overall survival (OS) in the 1st line colorectal cancer (CRC) trial with patients who had wild type KRAS mutations was a total shock after it had previously met it's primary endpoint of progression free survival (PFS) earlier this year based on the data presented at the ECCO/ESMO conference.

It has previously been shown that CRC patients with mutated KRAS do not respond to EGFR kinase inhibitors whereas those with wild type mutations do, so one would expect the selected patients to do well and chances of success are increased.  However, although the Vectibix arm did better, the result was not significant:

"The prospective analysis of the 203 study showed that Vectibix, when added to a FOLFOX chemotherapy regimen in patients with KRAS wild-type mCRC, resulted in a median overall survival of 23.9 months compared to 19.7 months for patients treated with FOLFOX alone. The median overall survival difference of 4.2 months in the Vectibix arm did not reach statistical significance (HR=0.83, p=0.072)."

Interestingly, according to the newswires some analysts appear to be claiming that regulatory approval and successful sales growth was still possible:

"We believe the positive trend coupled with a robust [progression free survival] benefit will be adequate to support regulatory approval," J.P. Morgan analyst Geoffrey Meacham wrote in a note to clients.

He said that "modest" use of Vectibix in new patients, and an increase in patients who failed previous treatment, could boost his 2012 sales view of $445 million by about $300 million.

Neither Vectibix, nor Erbitux, another EGFR inhibitor from ImClone, are approved for the treatment of newly diagnosed colorectal cancer.

We'll see what the regulatory authorities have to say about the Amgen data.  Strategically, however, given that most medical oncologists look at OS as the gold standard that was not met in the patient population most likely to respond, I think it will be hard for Vectibix to gain any real traction in the first-line setting for this disease against Genentech's Avastin even if it is approved, especially when you factor in a more costly therapy and a very nasty rash as a potential side effect. 

My own view is that the negative OS result is likely to be more of a death knell in newly diagnosed colorectal cancer for Amgen, but time will tell.

Watch this space!

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What's hot at the ESMO conference this week?

This week I'm snowed under with work, so was unable to attend the ECCO/ESMO conference, but have been following the key updates on Twitter and via press releases.  Here are a few snippets of data I found interesting and some analysis/commentary:

1) Bayer announced some updated Phase II data with Nexavar (sorafenib) in breast cancer.

They found that when combined with Roche's capecitabine, it makes a significant difference to the time women live without their disease worsening.

Pfizer's Sutent (sunitinib) also had positive Phase II data in breast cancer in the past, before concluding that the Phase III data was unlikely to show a significant effect. We should therefore probably wait for the phase III sorafenib data before getting over excited.

2) The PI3K pathway might be as a factor in poor response or resistance to HER2-inhibitors such as trastuzumab.

"Of the 8,000 genes tested, we found that only knock down of PTEN conferred resistance to Trastuzumab. Decreased PTEN expression results in hyper activation of the PI3K pathway. Significantly, activating mutations in the gene encoding the p110a catalytic subunit of PI3K (PIK3CA) have been identified in some 25% of primary breast cancers potentially mimicking the effects of PTEN loss. Indeed, overexpression of the breast cancer-derived mutant PIK3CA (H1047R) also conferred resistance to Trastuzumab in cell culture. These findings are consistent with a major role of the PI3K pathway in the development of resistance to trastuzumab."

It makes sense to consider a) predict whether patients are likely to respond to therapy upfront and b) consider multiple therapies to overcome the development of resistance.

3) Impact of microsatellite instability (MSI) positivity and the presence of KRAS and BRAF mutations on colon carcinoma patients.

It has been observed in the past that stage III colon carcinoma patients with the BRAFV600E mutation had a significantly worse prognosis, based on the results of a study that aimed to assess the impact of microsatellite instability (MSI) positivity and the presence of KRAS and BRAF mutations on colon carcinoma patients.

The current study reported on 258 patients with stage III colon cancer who were treated with surgery followed by a 5-fluorouracil-based adjuvant therapy.  KRAS mutations in codons 12 and 13 were determined by PCR followed by direct sequencing, and MSI status was determined by typing the BAT 26 marker (positive in 99% of MSI-positive white patients). It was concluded that tumor mutational status should be determined to predict survival more accurately in patients with colon carcinoma.

We will probably hear more about BRAF as a predictive marker in CRC, in addition to the KRAS mutation that was all the rage at ASCO earlier this year.  Predicting responses to therapy is one thing, but the real need for patients going forward, is to find new therapies that will overcome the resistance induced by these mutations.

4) Is Iressa (gefitinib) making a comeback in NSCLC?

Two interesting abstracts (O9002 and O9003) demonstrated that analysis of four phase III trials comparing gefitinib monotherapy (250 mg orally per day) versus chemotherapy (docetaxel alone or carboplatin/docetaxel) produced marked efficacy of gefitinib in NSCLC patients with EGFR mutations. The benefits of gefitinib in prolonging progression-free survival (PFS) were even greater in Asians with mutations than in non-Asians with mutations.

It is good sense that EGFR testing should be performed in NSCLC patients in order to select for therapy and ensure that those most likely to respond are treated. There is little point in giving a drug to patients who are unlikely to respond, so the value of biomarkers is clearly demonstrated in this setting.

5) Bayer's shows activity in renal cell carcinoma

In addition to sorafenib, Bayer also have an oral multikinase inhibitor, regorafenib (BAY 73-4506), in development, which produced disease regression or stabilization in 81% of patients in 1st-line treatment of patients with metastatic or unresectable RCC

"Of 48 patients evaluable for efficacy, preliminary data indicate a partial response (PR) in 33% (23% confirmed PR) and stable disease in 46% of patients."

Renal cell carcinoma is fast becoming a) a useful tumour type for testing proof of concept for new drugs in development, but that also means that b) that the market is becoming very competitive for such a small indication.  I'm not sure what Bayer would usefully gain by having two such products on the market in the same tumour type, since it potentially cannibalises their sorafenib market share.

6) Amgen's motesanib (AMG-706), a VEGF inhibitor looks active in metastatic breast cancer

"Motesanib in combination with P (paclitaxel) or D (docetaxel) appears to be tolerable and shows evidence of antitumor activity in pts with advanced breast cancer. Coadministration with either P or D had no major effect on motesanib PK."

I've been following this agent for a little while as it started cropping up in searches for clinical trials in multiple tumor types.  It appears to target VEGF, KIT and PDGF.  Poster PD-5029 is a dose finding study, so the emphasis is on adverse events and tolerability rather than efficacy, but 28-29% response rates this early are interesting at this stage.  This is one agent I'll be following more closely as more results are published in the future. 

There are probably some other interesting abstracts out there, but those are the ones that caught my eye in the news this week.  Anyone who saw some other data is welcome to mention or discuss them in the comments below!

Cancer in Wildlife May Signal Toxic Dangers

The white whales were victims of intestinal cancers caused by industrial pollutants released into the St. Lawrence River by nearby aluminum smelters.

Now research points to environmental pollutants as the cause of deadly cancers in several wildlife populations around the world. Normally rare in wildlife, cancers in California sea lions, North Sea flounder and Great Lakes catfish seem to have been triggered or accelerated by environmental contaminants.

Other animals, including Tasmanian Devils, sea turtles, woodchucks, eels and sperm whales, also have been stricken with cancers, although they appear to stem from natural causes, including viruses, spontaneous tumors, or genetic factors.

In some cases, the survival of a species and the stability and biodiversity of an ecosystem is jeopardized. The cancers also highlight the dangers that industrial activities pose – not just to animals, but to people in the same areas, exposed to the same compounds.

via scientificamerican.com

Cancer is very rare in animals, it's pretty much a man-made disease in various guises.

What then, of the people who worked in the surrounding region in Quebec? Well, it seems people who worked in smelters near the cancer-stricken belugas have reported many cases of lung and bladder cancers linked to coal tar exposure at the factories. Other residents have high rates of digestive tract and breast cancers.

This is an interesting SciAm article worth reading and reflecting on.

Posted via web from sally church's posterous

Pfizer discontinues Sutent in colorectal cancer

That was the lead headline screaming from my intelligence database this morning, from several sources.  On checking the Pfizer website, to verify the information, I found the following in a terse press release:

"Pfizer Inc announced today the discontinuation of the SUN 1122 Phase 3 trial that evaluated Sutent^® (sunitinib malate) plus FOLFIRI (irinotecan plus infusional 5-fluorouracil and leucovorin) versus FOLFIRI alone for the first-line treatment of metastatic colorectal cancer (CRC).  The independent Data Monitoring Committee (DMC) found that the addition of sunitinib to the chemotherapy regimen FOLFIRI would be unable to demonstrate a statistically significant improvement in the primary endpoint of progression-free survival (PFS) compared to FOLFIRI alone, in this study.  No new safety issues were identified."

It would therefore seem that small molecule TKI's are not the way to go with this disease given that Novartis' vatalanib also failed in phase III trials of a similar nature.  Genentech's Avastin acts differently, targeting the outside of the receptor as a monoclonal antibody.

For Pfizer, this represents another major setback with Sutent after the recent failure in breast cancer studies.  Prior to that, the company terminated two other compounds in phase III development, namely, esreboxetine for fibromyalgia and PD 332,334 for generalized anxiety disorder (GAD) so 2009 is not turning out to be a stellar year for them.

Chasing blockbusters is clearly not all it is cracked up to be. 

Contrast Pfizer's experiences with Novartis approach by following the science rather than the money in a Business Week article.  Ilaris, an IL-1 inhibitor, has just been approved by the FDA for a rare autoimmune condition known as Muckle Wells disease.  This development follows a similar strategy to that taken by the company with the development of Gleevec, ie focusing on the biology of the disease and finding a targeted drug aimed at the critical mutation.  The result?  Over 90% of children and adults suffering from the immune disorders that the drug was designed to treat experienced rapid, sustained remissions.

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• Pfizer discontinues Sutent in breast cancer (pharmastrategyblog.com)

VEGF update from ASCO 2009

After the recent success of Genentech's Avastin (bevacizumab) in metastatic colorectal, lung, breast and brain cancers, it was a little surprising to hear that the adjuvant data in colorectal cancer missed the mark, with the survival data not showing a significant benefit to the Avastin arm.  The Genentech press release announced:

"Results from a phase III study of Avastin® (bevacizumab) plus six months of chemotherapy following surgery in patients with early-stage (adjuvant) colon cancer (NSABP C-08). The study showed the addition of one year of Avastin to chemotherapy did not result in a statistically significant improvement in overall disease-free survival (DFS), the primary endpoint, compared to chemotherapy alone after surgery. Patients who received Avastin plus chemotherapy had a lower risk of the cancer returning during the year of treatment, however, the improvement diminished over the course of the study. No new safety signals for Avastin were observed."

At the Genentech ASCO press briefing, the lead investigator, Carmen Allegra noted that six events separated the study from meeting the early-stopping rule at one year.  It was that close.  The one year data showed plenty of hints of significant survival but by the pre-specified three-year endpoint, when there were 603 events, disease-free survival had ceased significance. The end result for Avastin was 77.4% versus 75.5% for standard chemotherapy alone.

The difference between taking a look at the interim data and the final analysis clearly shows the benefit of long term follow up in the adjuvant setting because things may not always be as they seem.  It will be interesting to see futher analyses to see if any particular subsets responded better to the combination treatment with Avastin.

Meanwhile, VEGF as a pathway has had a somewhat chequered history since Judah Folkman first elucidated angiogenesis as a potentially important pathway in how tumours grow and survive.  Numerous compounds have entered the clinic with great fanfare, but successfully navigating the treacherous R&D waters through to phase III/IV has proved problematic.  The latest interesting molecule is AstraZeneca's Zactima (vandetanib, ZD6474), a dual-acting TKI that targets VEGF receptor-2 (KDR) and EGFR.  It is currently in phase III development for lung cancer and phase I/II trials are ongoing in colorectal cancer, medullary cancer and others.

The big news with this agent at ASCO earlier this month was the ZODIAC, ZEAL and ZEST trial data in advanced NSCLC. 

ZODIAC is a randomised, double-blind, placebo-controlled Phase III study evaluating the combination of vandetanib 100mg with docetaxel versus docetaxel alone.  The study enrolled 1391 patients previously treated with one prior anti-cancer therapy for advanced NSCLC.  Results presented by Roy Herbst et al., showed that the study met its primary endpoint and the addition of vandetanib to docetaxel resulted in a statistically significant improvement in progression-free survival (PFS), the length of time a patient lives without their cancer growing:

PFS 14.0 weeks vs. 17.3 weeks (HR 0.79; P<0.001) in favour of vandetanib. 

An update on the survival data is expected be available later this year.

ZEAL (ZACTIMA Efficacy with Alimta in Lung cancer) is a randomised, double-blind, placebo-controlled Phase III study evaluating the combination of vandetanib 100mg with pemetrexed versus pemetrexed alone in patients with locally advanced or metastatic NSCLC, treated with one prior anti-cancer therapy.  It enrolled 534 patients at 160 centres across 23 countries.

The data from ZEAL followed the same trend of ZODIAC, although the primary endpoint did not reach statistical significance in the study, despite median PFS of 11.9 weeks vs. 17.6 weeks in favour of the  vandetanib plus pemetrexed arm (HR 0.86, P=0.108).

Secondary endpoints in the ZODIAC and ZEAL studies were also reported.  They showed that addition of vandetanib to chemotherapy significantly improved objective response rate, a measurement of tumor shrinkage:

ZODIAC: 17.0% vs. 10.0%, P<0.001

ZEAL:     19.1% vs.  7.9%, P<0.001

The studies also demonstrated that adding vandetanib to standard chemotherapy resulted in a significantly longer time to deterioration of disease related symptoms:

ZODIAC: HR 0.78, P=0.002

ZEAL: HR 0.61, P=0.004

Overall survival in both studies showed a positive trend, although they had not yet reach statistical significance:

ZODIAC: HR 0.91, P=0.196

ZEAL:     HR 0.86, p=0.219

Adverse events reported in both studies was consistent with previous studies with vandetanib in NSCLC. The most common adverse events associated with vandetanib included rash, diarrhea and hypertension (ZEAL); rash, diarrhoea and neutropenia (low white blood cell count) (ZODIAC). Incidence of protocol-defined QTc prolongation was <2.0 percent in both studies and was not associated with symptoms.

The ZEST (ZACTIMA Efficacy Study versus Tarceva) trial is a Phase III randomised, double-blind, multi-centre study to assess the efficacy of vandetanib 300mg versus erlotinib 150mg in patients with locally advanced or metastatic NSCLC after failure of at least one prior anti-cancer therapy.  It enrolled 1240 patients at 171 centres across 22 countries.

Results from the ZEST phase III study were also presented at ASCO.  Again, the primary objective of demonstrating a statistically significant prolongation of PFS for vandetanib was not met in this study.  In a pre-planned non-inferiority analysis, vandetanib was shown to have similar efficacy to erlotinib for PFS and OS:

PFS: HR 0.98, P=0.721

OS: HR 1.01, P=0.830.

The objective response rate (ORR) and symptom control were also similar for both treatments ie ORR was 12% in both arms.  The most common adverse events observed in the ZEST study were rash, diarrhoea and hypertension. Incidence of protocol-defined QTc prolongation was 5.1 percent in the vandetanib arm.

On the basis of these results, AstraZeneca are expected to file with the FDA in the first half of 2009.  Other trials ongoing include ZEPHYR and ZETA.  Results from ZEPHYR (300mg monotherapy study in EGFR failures in advanced NSCLC) and ZETA (300 mg monotherapy in advanced medullary thyroid cancer) phase III studies are expected be available during the second half of 2009.

Overall, aside from the Avastin data in glioblastoma following on from the recent FDA approval, I thought this batch of trial results with VEGF inhibitors rather dispiriting, but it may be the almost constant rain in New Jersey over the last 8-10 days that has influenced that sentiment.

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• Avastin Shows No Benefit Against Early Stage Colon Cancer (nlm.nih.gov)
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Recent news from American Association of Cancer Research

After attending the recent annual AACR meeting in Denver, where the weather went on a wild ride from arriving in a snowstorm dumping a foot of snow to 74F and glorious sunshine, I thought it was time to capture a few thoughts on the new trends emerging there.  Normally, I would have updated this blog on the conference much earlier, but the demands of client meetings and proposals have intervened somewhat. 

Image by bridgepix via Flickr

It was my first time in Denver and Colorado, so I wasn't really sure what to expect at all but after spending nearly a week there, it's definitely somewhere I would think about visiting again, mainly because every where one went, the people were exceedingly nice and polite, adding to the positive experience.

The organisers were also on Twitter (@aacr) and that helped tremendously with little things like getting the sound up in Hall A or wherever, as the acoustics  was rather faint and fuzzy at times.  Kudos to their marketing team for their engagement, interaction and responsiveness, they really added to the overall positive experience.  More organisations can listen and learn from their approach, because it not having problems that is the issue but how you handle them.  AACR handled things with ease and aplomb.  Nice one guys, very professional job!

Ok, you're all wondering what about the science and oncology data?

Well, what struck me as general trends and interest was the wealth of information on mTOR, IGF-1R, PI3K/Akt, c-Met and HDACs, plus miRNA seemed to be in just about everything.  Sirtuins came up a few times, but the concept is still very early before we can make any conclusions. 

Of course, Novartis' mTOR inhibitor, Afinitor, was approved in renal cell carcinoma just before the meeting so there was inevitably a lot of interest in the drug class and where it might be going given that there are now two on the market.  Anticipating the concomittant interest a product launch may bring is one bane of conference scheduling - the small room was full to overflowing.  I stood outside the double doors and managed to capture a few notes of the session standing up, but some parts of the chicken scratch defy even my interpretation. 

Suffice to say, it was clear that investigators see both mTORi and HDACi as an exciting opportunity to add either drug to standard of care and produce wither an additive effect or possibly reduce the resistance that occurs by blocking an important pathway, thereby making the regimen work more effectively for longer.  Merck's HDACi, (vorinostat or Zolinza), was another drug with a similarly bright future in this respect, because while efficacy may be limited as a single agent, it could well be a good drug for multiple combinations.  Many of these ideas were discussed at different sessions and checking out clinicaltrials.gov showed over 100 trials already underway or planned with the therapy.  That's not bad going for a drug approved for a rare form of lymphoma so far, ie CTCL.

It was interesting that the established medical news reported on some odd things at the meeting such as a urine test to predict smokers risk of lung cancer, drug combinations in pancreatic cancer (a deadly disease) and the impact of the Stimulus Package on cancer research.  There was very little on the basic scientific research and progress with biomarkers.  Yet virtually every session I went to, including the poster sessions, covered biomarkers in considerable depth. 

Biomarkers can be used for different things - as a marker of activity, as a marker of outcome or as a marker for patient selection amongst other things.  The field is really only just getting going and will have an increasing impact on healthcare over the next few years.  As more targeted agents are developed at great expense, patients, physicians and payers alike want to know which patients are most likely to respond and why?  This exciting approach is great news for diagnostic companies such as Nodality, who help pharma companies identify and track critical biomarkers in clinical trials.

Predicting which patients will respond to which therapies will increase the chances of success, reduce costs and improve confidence.  The idea of treating everyone with a given cancer to get 10% response rate is old hat now.  Why not figure out which 10% are likely to respond to EGFR therapy and just treat those?  The ongoing story of the impact of KRAS/BRAF and loss of PTEN in CRC is fascinating; we can now identify 70% of the non-responders and treat those patients more appropriately. 

The role of histology is also becoming important in some cancers, especially in NSCLC.  For example, it appears that patients with squamous, non-squamous and even non-smoking Asians with adenocarcinoma can each be treated differently.  The discussions in the corridors and poster sessions were very much focused on this and more on this topic is expected at ASCO, when Genentech announce the full data for Avastin and Tarceva in first line NSCLC.  Alimta also appears to be more effective in non-squamous NSCLC, whereas Avastin is considered for squamous patients to avoid the increased risk of GI bleeds. 

All of this information and much more, such as the Erbitux front-line data in CRC will make for a fascinating ASCO later this month.

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Tumour suppressor genes and ATOH1 in colorectal cancer

An interesting pair of papers on tumour suppressor genes in colorectal cancer was just published in PLoS Biology.  According to the researchers,

"Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1Atoh1, (also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors."

What does that mean in reality?

Well, essentially they may have found a master switch and activating a specific gene (Atoh1), which is  common to fruit flies, mice and humans, may allow cancer to be "switched off".

Why colorectal cancer, you may ask? 

The research demonstrated that colorectal cancer and Merkel cell carcinoma patients show genetic and epigenetic ATOH1 loss-of-function mutations, meaning that switching off the ATOH1 gene function lead to cell differentiation and growth of those tumours.  In addition, mice lacking ATOH1 developed bowel cancer, and the gene was also frequently inactivated in human patients with the disease.

Time will tell, but undoubtedly new compounds will be developed targeting the oncogene to re-activate it and slow down tumour progression to determine whether the basic research offers proof of concept in human cancer.  In a few years time, we may even see some therapeutic developments in Pharmaceutical pipelines targeting ATOH1 as a viable and valid target in human colorectal cancer.

Thanks to Sarah Arrow of Arrow Light Haulage for bringing this research to my attention.

Wouter Bossuyt, Avedis Kazanjian, Natalie De Geest, Sofie Van Kelst, Gert De Hertogh, Karel Geboes, Greg P. Boivin, Judith Luciani, Francois Fuks, Marinee Chuah, Thierry VandenDriessche, Peter Marynen, Jan Cools, Noah F. Shroyer, Bassem A. Hassan (2009). Atonal homolog 1 Is a Tumor Suppressor Gene PLoS Biology, 7 (2) DOI: 10.1371/journal.pbio.1000039

Wouter Bossuyt, Natalie De Geest, Stein Aerts, Iris Leenaerts, Peter Marynen, Bassem A. Hassan (2009). The Atonal Proneural Transcription Factor Links Differentiation and Tumor Formation in Drosophila PLoS Biology, 7 (2) DOI: 10.1371/journal.pbio.1000040