GSK | Pharma Strategy Blog

Update on RAF resistance in metastatic melanoma

“RAF inhibitors (vemurafenib and dabrafenib) have profound clinical activity in patients with BRAF-mutant melanoma, but their therapeutic effects are limited by the emergence of drug resistance.”

Solit and Rosen (2014)

For today’s post on Science Fridays, I wanted to take a look at an overview paper, published in Cancer Discovery, from two researchers in the metastatic melanoma field who have been looking at multiple mechanisms of resistance. It’s an important topic because while we have seen incremental improvements in outcomes for this disease, the 5-year survival rate is still rather poor with only 10–20% of metastatic patients still alive by then. This is not to disparage the efforts of scientists, clinicians or companies working in this space, far from it, but there is is clearly a need for new therapies, strategies and combinations, given the high unmet medical need that exists.

We still have a long way to go in moving the survival needle dramatically.

It wasn’t until I searched for related blog posts to link to this one that I realised how much we have already covered on this topic! Regular readers will recall discussions here on PSB on various combinations such as:

RAF + MEK inhibitors (downstream resistance)
RAF + PI3K-AKT-mTOR inhibitors (cross resistance)
RAF + CTLA–4 checkpoint inhibitors (anti-tumour immunity)

to name a few examples.

We have seen that adding a MEK inhibitor to dabrafenib e.g. trametinib can overcome resistance temporarily and add a few extra months before the resistance sets in again. Similarly for PI3K inhibitors tested to date. Adding ipilimumab, an anti-CTLA–4 checkpoint inhibitor held much promise, but the combination was abandoned with the emergence of unexpected liver toxicity.

Results thus far suggest that something else is acting as an escape route, thereby enabling the tumour to continue driving oncogenic addiction to BRAF.

The $64K questions are what is happening and what can we do about it?

We also need to remember that clinical research advances piecemeal based on evidence from preclinical reseach, so we see the logical evolution of BRAF monotherapy -> combos with downstream (MEK) or upstream (NRAS) targets in same pathway -> combos with diagonal (PI3K) pathways etc.

What Solit and Rosen have done is put a nice summary together of the state of play in this disease and the paper (see References below) is well worth reading.

Their main assertion is interesting, namely:

“The common feature of each of these mechanisms of resistance is that they result in activation of ERK signaling that is insensitive to the RAF inhibitor. Thus, RAF inhibitor resistance is often associated with maintenance of activation of the oncogene-driven pathway.”

Two recent papers are cited in support of this theory from Shi et al., (2014) and Allen et al., (2014) – see References below for additional background reading. Both studies used patient samples to look at clonal evolution and the genetic landscape in advanced melanoma. It’s actually quite amazing what unbiased exome sequencing can uncover at the molecular level, not least are the development of new mutations and other functional alterations.

The Shi et al., (2014) study was briefly summarised by Solit and Rosen:

“Multiple biopsies were obtained at different times or from disparate locations from several patients, and more than a single lesion in the ERK pathway was identifi ed in multiple patients typically within
different tumor biopsies.”

They went to note:

“A detailed phylogenetic analysis of multiple progressive lesions from a subset of these patients suggested branching evolution of tumors in which the development of genetic diversity was not linearly associated with time.”

Previously, a case report found distinct mechanisms of BRAF inhibitor resistance were present in two different progressing lesions from a single patient, so the work of Shi et al., (2014) is consistent with this finding. It blows my mind that different lesions in the same patient might behave completely differently though – imagine trying to devise an appropriate and effective clinical strategy in these cases?!

Allen et al’s (2014) work also involved whole exome sequencing (WES) from patient samples:

“WES was performed on paired pretreatment and progression samples collected from 45 patients, of whom 14 developed resistance soon after initiation of therapy (within 12 weeks). They also detected several resistance mechanisms that had been previously identified to confer RAF inhibitor resistance, including mutations in NRAS , MAP2K1, and NF1 and BRAF amplification.”

A third important study in this area from Wagle et al., (2014) adds to the weight of evidence with new mutations developing. Solit and Rosen continued the story:

“Consistent with the preclinical studies highlighted above demonstrating that MEK1 and MEK2
mutations can confer RAF and MEK inhibitor resistance, a MEK2 Q60P mutation was identifi ed in 1 of 5 patients studied. Of greater surprise to the investigators, one patient had a BRAF splice variant lacking exons 2–10 and a second patient had BRAF amplification.”

By now, you can see the sheer variety of changes and adaptations taking place in different studies around the world in some of the top melanoma labs. What do they have in common though?

“One hypothesis to explain this result is that increased abundance of the oncogenic driver (in this case BRAF) in response to prolonged drug treatment results in increased flux through the ERK pathway and restoration of ERK activity above the threshold required for inhibition of cell proliferation.”

The next challenge is to figure how we can approach better therapeutic index and shutting down of the pathways?

“The results suggest that the early adaptive response of BRAF -mutant cells to ERK pathway inhibition may promote the selection of resistant clones that harbor additional genomic events that
confer higher levels of RAF inhibitor resistance. The data also support combinatorial approaches that attenuate the adaptive response, including the addition of a PI3K or AKT inhibitor to the RAF and MEK (or ERK) inhibitor combination.”

The problem with this approach though, is that the neither the BRAF nor PI3K inhibitors have been able to reach or go beyond the single agent dosing schedules:

“As previous attempts to combine MAPK and PI3K pathway inhibitors have been limited by overlapping toxicities, upfront testing of intermittent treatment schedules should be considered.”

This is the also approach that Das Thakur suggested in her work presented at AACR last year, and subsequently published in Nature, to delay the development of resistance to vemurafenib.

I do think this one area where we may well see new trials evolve in advanced melanoma, so we will have to wait for new data before we can see if the strategy is successful at delaying the emergence of resistant clones. It is good to see the evolution of solid preclinical and translational evidence from patient biopsies helping to inform future clinical trial strategies.

In the meantime, the next major milestone I’m waiting for is on Roche/Genentech’s MEK inhibitor, cobimetinib (GDC–0973), which is due to report combination data with vemurafenib (continuous dosing) later this year. It will be interesting to see if this inhibits MEK more completely than trametinib and whether the combination has a better initial outcome than dabrafenib plus trametinib, which added about two to three months of extra survival over dabrafenib alone.

References:

Solit DB, & Rosen N (2014). Towards a Unified Model of RAF Inhibitor Resistance. Cancer discovery, 4 (1), 27–30 PMID: 24402945

Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, Chodon T, Guo R, Johnson DB, Dahlman KB, Kelley MC, Kefford RF, Chmielowski B, Glaspy JA, Sosman JA, van Baren N, Long GV, Ribas A, & Lo RS (2014). Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy. Cancer discovery, 4 (1), 80–93 PMID: 24265155

Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, Whittaker S, Kryukov GV, Hodis E, Rosenberg M, McKenna A, Cibulskis K, Farlow D, Zimmer L, Hillen U, Gutzmer R, Goldinger SM, Ugurel S, Gogas HJ, Egberts F, Berking C, Trefzer U, Loquai C, Weide B, Hassel JC, Gabriel SB, Carter SL, Getz G, Garraway LA, Schadendorf D, & Dermatologic Cooperative Oncology Group of Germany (DeCOG) (2014). The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma. Cancer discovery, 4 (1), 94–109 PMID: 24265153

Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, Rosenberg M, Goetz EM, Sullivan RJ, Farlow DN, Friedrich DC, Anderka K, Perrin D, Johannessen CM, McKenna A, Cibulskis K, Kryukov G, Hodis E, Lawrence DP, Fisher S, Getz G, Gabriel SB, Carter SL, Flaherty KT, Wargo JA, & Garraway LA (2014). MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition. Cancer discovery, 4 (1), 61–8 PMID: 24265154

Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, Dummer R, McMahon M, & Stuart DD (2013). Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature, 494 (7436), 251–5 PMID: 23302800

Lapatinib boosts effects of apoptosis-inducing drugs in colorectal cancer

By MaverickNY on June 13, 2011

I’m a subscriber to Science Translational Medicine and one of the things I really like about it is finding little gems like this – shared by Science Magazine on Twitter:

Breast cancer drug lapatinib boosts effects of apoptosis-inducing drugs in colorectal cancer

On clicking the link, I was delighted to see it was from Dr Wafik El Deiry’s group at Penn State, Hersey – you can find him as @weldeiry on Twitter – he tweets interesting snippets from various cancer conferences that he attends, including ones in GI cancers.

Here’s the essence of the paper that caught my eye:

We found that lapatinib improved the proapoptotic effects of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and two TRAIL receptor agonists, the antibodies mapatumumab and lexatumumab.

Tumors from mice treated with a combination of lapatinib and TRAIL exhibited more immunostaining for cleaved caspase-8, a marker of the extrinsic cell death pathway, than did tumors from mice treated with lapatinib or TRAIL alone.

Mapatumumab (HGS via Cambridge Antibody Technology) and lexatumumab (HGS) are both monoclonal antibodies that target the TRAIL receptor 1 to induce apoptosis (programmed cell death) as shown in the cartoon below:

Source: Human Genome Sciences

Put simply, death receptors (DR) are cell surface receptors that transmit apoptotic signals initiated by specific ligands such as Fas ligand, TNF alpha and TRAIL. They play an important role in apoptosis and can activate a caspase cascade within seconds of ligand binding. Induction of apoptosis via this mechanism is therefore very rapid.

To date, few of the DR or TRAIL inhibitors have lived up to their promise and lexatumumab also seems to have disappeared from HGS’s pipeline after being returned by GSK in 2008. Interestingly, there were some data previously published at ASCO in 2007, showing activity in a phase Ib trial in solid tumours due to synergy with gemcitabine, pemetrexed, doxorubicin or FOLFIRI:

Severe adverse events considered at least possibly related to lexatumumab included anemia, fatigue and dehydration. Tumor shrinkage has been observed, including confirmed partial responses (PRs) in the FOLFIRI and doxorubicin arms.

It looks as though mapatumumab is the successor to lexatumumab. Early studies with mapatumumab have been reported in a phase Ib trial in HCC and phase II in NSCLC although the latter did not support further development in that indication.

What does the current research show?

I was wondering what the possible underlying mechanism for the synergistic effect might be, given that lapatinib (Tykerb) is known to be a HER2/EGFR inhibitor. It does seem that this main target is not involved here though:

Lapatinib up-regulated the proapoptotic TRAIL death receptors DR4 and DR5, leading to more efficient induction of apoptosis in the presence of TRAIL receptor agonists. This activity of lapatinib was independent of EGFR and HER2.

In other words, the effects are off-target and unrelated:

The off-target induction of DR5 by lapatinib resulted from activation of the c-Jun amino-terminal kinase (JNK)/c-Jun signaling axis.

Of course, another EGFR inhibitor, the monoclonal antibody cetuximab (Erbitux) has been shown to work in refractory colorectal cancer and is approved in EGFR+ mutated disease. Lapatinib, as far as I know, has not shown any clinical activity in colon cancer to date, but is approved for treatment of refractory HER2+ breast cancer in combination with capecitabine.

Sometimes, it can take a while to figure out the logical combinations and tumour types though. This new research shows that, at least preclinically, there may be value in combining mapatumumab with lapatinib in colorectal cancer:

This activity of lapatinib on TRAIL death receptor expression and signaling may confer therapeutic benefit when increased doses of lapatinib are used in combination with TRAIL receptor–activating agents.

Implications of this research

A quick check of current clinical trials with mapatumumab shows that there aren’t any ongoing in colorectal cancer, but this research may well offer a strong rationale for the novel combination with lapatinib to be considered.

Of course, there is some wry amusement that the original TRAIL inhibitor, lexatumumab, was returned by GSK and lapatinib is marketed by the same company.

References:

Dolloff, N., Mayes, P., Hart, L., Dicker, D., Humphreys, R., & El-Deiry, W. (2011). Off-Target Lapatinib Activity Sensitizes Colon Cancer Cells Through TRAIL Death Receptor Up-Regulation Science Translational Medicine, 3 (86), 86-86 DOI: 10.1126/scitranslmed.3001384

What causes resistance to BRAF inhibition in melanoma?

By MaverickNY on August 31, 2010

Last week there was lot of excitement and interest surrounding the blog post on Roche/Plexxikon's data on PLX4032 in metastatic melanoma published in the New England Journal of Medicine. A number of the discussions on Twitter and email centred around what is causing resistance to the BRAF inhibitor?

If we take a look at the BRAF pathway alone, we would get a sense of the flow from the PDGF ligand through RAS, RAF and MAPK, which essentially drives angiogenesis and proliferation, like this 2004 review article:

Source: Nature Reviews Cancer

However, what this sort of simple diagrammatic picture doesn't tell us though, is where cross-talk or feedback loops might interfere with the inhibition to enable cell signalling to continue, thereby guaranteeing the tumour's continued survival despite our efforts to shut it down.

Another way of looking at the problem is to consider how pathways related to RAS signalling might possibly interact with the process, like this:

Source: Reaction Biology

When we look at the cell signalling processes this way, we can see that inhibiting PI3-kinase or AKT at the same time as RAF might turn out to be a useful approach.

It was therefore with great interest while browsing my RSS cancer feeds that I spotted a paper by Shao and Aplin in the current Cancer Research journal entitled: "Akt3-Mediated Resistance to Apoptosis in B-RAF–Targeted Melanoma Cells" (see journal link below).

If we use a BRAF inhibitor such as PLX4032 in advanced melanoma, we are effectively trying to kill the cancer cells by inducing apoptosis, or programmed cell death, thereby reducing the tumour growth and proliferation. However, as the researchers put it very succinctly:

"Melanoma cells are highly resistant to anoikis, a form of apoptosis induced in nonadherent/inappropriate adhesion conditions. Depleting B-RAF or the prosurvival Bcl-2 family protein Mcl-1 renders mutant B-RAF melanoma cells susceptible to anoikis."

They therefore began looking at different approaches to dealing with anoikis using both inhibitors and RNA interference.

These concepts may help us better understand how mutant B-RAF protects melanoma cells from apoptosis, thereby providing insight into possible resistance mechanisms to B-RAF inhibitors by developing new mutations in AKT. It also paves the way for future therapeutic strategies, either in combination, or in sequence, with a V600E BRAF inhibitor such as PLX4032 and an Akt inhibitor. I'm also wondering what effect a PI3-kinase inhibitor might have, but clearly adding an Akt inhibitor to the mix may well be worth a try in the first instance.

There are a number of AKT inhibitors in development in various companies pipelines. This is where the challenges and hurdles begin if a company doesn't have a relevant inhibitor because traditional R&D focuses on developing one's own pipeline with or without the current standard of care rather than cross-development with other companies with novel combination treatments unless a partnership, particularly with a small biotech, is specifically sought out.

As far as I know, Roche/Genentech or Plexxikon don't have an AKT in their pipelines, but there are some currently in early clinical development with other companies. The PI3K-mTOR-AKT pathway has been discussed in more detail in previous blog posts.

The most interesting and promising compound in this class is probably Merck's MK-2206, currently in phase II development for a number of different tumour types.

Other Akt inhibitors in R&D include:

Keryx: perifosine in phase II development for myeloma and colorectal cancer
Rexahn: Archexin in phase II trials in pancreatic cancer
Nerium: oleandrin in phase I development for metastatic renal and colorectal cancers
GSK: GSK2141795 and GSK21110183 are both in phase I trials for either hematologic malignancies or solid tumours

GSK had an earlier Akt inhibitor in phase I, GSK690693, but I believe it may have been terminated due to problems with hyperglycaemia, a common problem associated with PI3K-IGF-1R feedback. This problem has since been addressed and managed in other trials associated with these agents by the simple addition of metformin in the protocol. GSK now appear to be focusing on the follow-on compounds instead.

All in all, it's interesting to see how our knowledge of the biochemical and molecular pathways helps us better understand how cancer works and how we can use the data to devise improved strategies for tackling melanoma in the future. I'll be watching how this field develops with close interest.

Dibb, N., Dilworth, S., & Mol, C. (2004). Opinion: Switching on kinases: oncogenic activation of BRAF and the PDGFR family Nature Reviews Cancer, 4 (9), 718-727 DOI: 10.1038/nrc1434

Shao, Y., & Aplin, A. (2010). Akt3-Mediated Resistance to Apoptosis in B-RAF-Targeted Melanoma Cells Cancer Research, 70 (16), 6670-6681 DOI: 10.1158/0008-5472.CAN-09-4471

Crouthamel, M., Kahana, J., Korenchuk, S., Zhang, S., Sundaresan, G., Eberwein, D., Brown, K., & Kumar, R. (2009). Mechanism and Management of AKT Inhibitor-Induced Hyperglycemia Clinical Cancer Research, 15 (1), 217-225 DOI: 10.1158/1078-0432.CCR-08-1253

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Chemoprevention in Prostate Cancer – do 5alpha-reductase inhibitors make things worse?

By MaverickNY on August 12, 2010

There's a lot of media coverage today surrounding use of 5alpha-reductase inhibitors such as finasteride (Merck) and dutasteride (GSK) and their generic equivalents for chemoprevention of prostate cancer following publication of a study on finasteride by the American Association of Cancer Research (AACR) and one earlier this year on dutasteride in the New England Journal of Medicine (see references below for sources and the journal articles).

So what do these drugs do?

The drugs in the 5alpha-reductase class were developed for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

Improve symptoms
Reduce the risk of acute urinary retention
Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.

Fair enough, but how does this relate to prostate cancer?

Well, testosterone is the major circulating androgen in men and is converted to the major intracellular androgen, dihydrotestosterone, by steroid 5alpha-reductase isoenzymes, designated as type 1 and type 2. Finasteride inhibits the type 2 isoenzyme, whereas dutasteride inhibits both.

Many of you will be aware that in early stage prostate cancer, most men are hormone sensitive and respond to androgen deprivation therapy (ADT), which effectively acts as chemical castration to suppress the growth of the tumour of the prostate. Later, when castration resistance sets in (CRPC), the disease is more advanced. These days, if they are asymptomatic or mildly symptomatic, then a vaccine called sipuleucel-T (Provenge) can be considered or if metastatic and symptomatic, then chemotherapy with docetaxel (Taxotere) can be considered as a first-line option or cabazitaxel (Jevtana) after docetaxel has failed.

The goal of using the 5alpha-reductase inhibitors early was therefore to prevent or at the very least delay the development of malignant prostate cancer, essentially reducing the risk of developing the disease later. Several studies have been published over the last decade to answer this question.

The big question is does this approach actually work?

My thinking was if it was that obvious, then surely urologists and primary care physicians would be rushing to prescribe either therapy? Trouble is, they're not, as this succinct AACR press release shows.

One of the problems is that the original Prostate Cancer Prevention Trial (PCPT) study back in 2003, a large randomized controlled trial consisting of 18,000 men, appeared to have conflicting results, since it showed:

a 25 percent reduced risk of prostate cancer.
a 27% increased risk in high-grade tumours, which was highlighted in the accompanying editorial.

This fact seems to have created doubt and concern amongst urologists and PCP's.

Subsequently, there have been other reported studies with finasteride in 2008 (reanalysis of the 2003 data) and with dutasteride in the NEJM earlier this year, suggesting in both cases that the risk did not exist. The doubt, however, still lingers as the AACR press release highlighted:

"64 percent of urologists and 80 percent of primary care physicians never prescribe finasteride for chemoprevention.

When asked for reasons for their decision, 55 percent said they were concerned about the risk of high-grade tumors and 52 percent said they did not know it could be used for chemoprevention."

Another issue is the conflicting consequence of PSA suppression, which is still used by many urologists as the main biomarker for diagnosis and ADT treatment. The NEJM editorial earlier this year noted the challenge:

"Among men without cancer, both finasteride and dutasteride treat lower urinary tract symptoms, produce dramatic prostate shrinkage, and reduce serum levels of PSA by 50% or more.

However, for the patient who believes that he is taking a drug to prevent prostate cancer, this decline in PSA level can lead to a false sense of security."

Why is this? The editorial went on to explain:

"Data from the PCPT indicate that finasteride produces a progressive suppression of PSA for the duration of treatment. To estimate what the “true” PSA level would be if finasteride were not taken, it is necessary to multiply the PSA level by 2.0 for the first 2 years, by 2.3 for years 2 through 7, and thereafter by 2.5.

However, if the PSA level ever begins to rise at all, a biopsy should be performed, because with an increase in PSA level, the risk of cancer is increased by a factor of 3 and the risk of high-grade disease is increased by a factor of 6.

In the Finnish study, men who received finasteride for more than 4 years had a risk of high-grade disease that was increased by a factor of 2.6."

After reading all of the evidence in the various studies (cited below), I can see why physicians might be:

Confused
Concerned

It's hard to make solid sense of the real impact of all the research, even as an unbiased scientist given the data that has emerged. My overall takeaway from all the articles was as follows:

Dutasteride and finasteride do not prevent prostate cancer.
They do shrink tumours that have a low potential for being lethal.
They do not reduce the risk of a positive biopsy in patients who have an elevated PSA level or an abnormal digital rectal examination.
Use of these drugs for prevention may be controversial because PSA levels are suppressed, giving a false sense of security.
If prostate cancer develops, the diagnosis may be thus delayed (by artificially low PSA levels) until they have high-grade aggressive disease that may be more difficult to cure.

My final observation is that perhaps we should be monitoring other markers of disease such as circulating tumour cells (CTCs) in the blood rather than PSA. Whether this would be a better measure of disease or not remains to be elucidated, but would certainly be worth looking at in future studies to see if it is a more accurate biomarker in early prostate cancer.

Hamilton RJ, Kahwati LC, & Kinsinger LS (2010). Knowledge and Use of Finasteride for the Prevention of Prostate Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699373

Andriole, G., Bostwick, D., Brawley, O., Gomella, L., Marberger, M., Montorsi, F., Pettaway, C., Tammela, T., Teloken, C., Tindall, D., Somerville, M., Wilson, T., Fowler, I., & Rittmaster, R. (2010). Effect of Dutasteride on the Risk of Prostate Cancer New England Journal of Medicine, 362 (13), 1192-1202 DOI: 10.1056/NEJMoa0908127

Walsh, P. (2010). Chemoprevention of Prostate Cancer New England Journal of Medicine, 362 (13), 1237-1238 DOI: 10.1056/NEJMe1001045

Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, & Coltman CA Jr (2003). The influence of finasteride on the development of prostate cancer. The New England journal of medicine, 349 (3), 215-24 PMID: 12824459

Lucia, M., Darke, A., Goodman, P., La Rosa, F., Parnes, H., Ford, L., Coltman, C., & Thompson, I. (2008). Pathologic Characteristics of Cancers Detected in the Prostate Cancer Prevention Trial: Implications for Prostate Cancer Detection and Chemoprevention Cancer Prevention Research, 1 (3), 167-173 DOI: 10.1158/1940-6207.CAPR-08-0078

Murtola, T., Tammela, T., Määttänen, L., Ala-opas, M., Stenman, U., & Auvinen, A. (2009). Prostate cancer incidence among finasteride and alpha-blocker users in the Finnish Prostate Cancer Screening Trial British Journal of Cancer, 101 (5), 843-848 DOI: 10.1038/sj.bjc.6605188

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Evidence for role of microRNA in Melanoma

By MaverickNY on July 16, 2010

Twitter is great for highlighting interesting journal articles, as I found when Edward Winstead from the NIH shared this paper from PLOSone on the importance of microRNA in melanoma in his Twitter stream (thanks, Ted!).

There has been a lot of interest in melanoma lately, with the rise of a couple of interesting new compounds targeting different mutations or kinases including CTLA4 by ipilimumab (BMS) and B-RAF by PLX-4032 (Plexxikon/Roche).

You can see some of the recent data I've blogged about here, here and here.

At the moment, we're waiting for the new data from PLX-4032 at a melanoma conference later this year and BMS may be filing their phase III data in ipilimumab by the end of this year after some promising reactions to the data presented last month in the plenary session at ASCO. In addition, GSK also have some compounds in earlier development that are generating interest.

How does the new data in PLOSone connect with melanoma?

Well, it's an aggressive and highly malignant cancer and scientists have long wondered how melanoma cells travel from primary tumours on the surface of the skin to the brain, liver and lungs, where they become more aggressive, resistant to therapy, and deadly. This ultimately makes treatment and control of the disease very challenging.

In Feb 2009, an article in PNAS (see reference below) suggested that the culprit might be a short strand of RNA called microRNA (miRNA) that is over-expressed in metastatic melanoma cell lines and tissues. It is also known that the Microphthalmia associated transcription factor (Mitf) is an important regulator in melanocyte development and has been shown to be involved in melanoma progression.
The new data reported in PLOSone this month takes our understanding a little further and shows that microRNAs are also involved in regulating Mitf in melanoma cells.

The authors concluded that:

"miR-148 and miR-137 present an additional level of regulating Mitf expression in melanocytes and melanoma cells. Loss of this regulation, either by mutations or by shortening of the 3′UTR sequence, is therefore a likely factor in melanoma formation and/or progression."

What this means is that the microRNA's involved may offer new therapeutic targets in order to either reduce the development of resistance or aggressive progression and metastasis (ie spread of melanoma) to other organs. In order words, future research may involve the addition of microRNA therapy to optimise outcomes.

For now, microRNA is very much a research on the rise but it won't be long before we start seeing the first RNA based therapies in the clinic based on a solid scientific research rationale. As our understanding of the complex biology improves, so does the chances of developing a multi-factorial strategy to combat the devastating disease.

For those of you interested in this exciting field, I'll cover a more basic primer on microRNA and RNA therapeutics in development in a future blog post.

Photo Credit: Wikipedia

Haflidadóttir, B., Bergsteinsdóttir, K., Praetorius, C., & Steingrímsson, E. (2010). miR-148 Regulates Mitf in Melanoma Cells PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011574

Segura, M., Hanniford, D., Menendez, S., Reavie, L., Zou, X., Alvarez-Diaz, S., Zakrzewski, J., Blochin, E., Rose, A., Bogunovic, D., Polsky, D., Wei, J., Lee, P., Belitskaya-Levy, I., Bhardwaj, N., Osman, I., & Hernando, E. (2009). Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor Proceedings of the National Academy of Sciences, 106 (6), 1814-1819 DOI: 10.1073/pnas.0808263106

Malcolm Gladwell on cancer research

By MaverickNY on May 10, 2010

I was reading an article from the New Yorker this morning by Malcolm Gladwell on the Annals of Innovation. You can read the abstract here.

The article centres around the story of Synta/GSK's elesclomol in melanoma in 2007. The drug, like many others, started off promisingly but the final results showed that the patients did more poorly in the treatment arm. What the researchers didn't know at the time was that the target in melanoma was actually different from the one they were aiming at. The understanding of the biology had yet to evolve beyond chemotherapies at that time and our understanding of biomarkers in melanoma was sketchy at best.

Essentially, the author concluded:

“When will we find a cure for cancer?” Gladwell writes, “implies that there is some kind of master code behind the disease waiting to be cracked. But, so far as we can see, there isn’t a master code. There is only what can be uncovered, one step at a time, through trial and error.”

In some sense Gladwell's right, the process of finding new cancer drugs based on the biology of the disease goes one step at a time, science and research is necessarily iterative, after all. But he missed the reason why.

It's because cancers are heterogeneous.

Photo Credit: Cnet

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BIO 2010: A place for new biotech deals emerging?

By MaverickNY on May 6, 2010

I've been following the annual Biotechnology Industry Organisation (BIO) Conference being held in Chicago remotely on Twitter (check out the hashtag #BIO2010) while busy with client work this week and secretly thanking my lucky stars that I'm office bound and not whinging about sore feet myself as McCormick Place has hard floors and miles of corridors! Much of the lifestream seems to be a lot of moaning about the limited/almost non media access to the keynotes and grumbling about the general lack of social media savvy of the organisation. No surprises there.

Still, in a world where life seems to be increasingly on 24/7, this interesting little snippet from the San Francisco Business Times was much more revealing:

"Big drug makers are ready to make a deal.

With some facing a multibillion-dollar patent cliff and others just trying to expand their focus, big biotech and pharmaceutical companies are reaching out to capture potential products from other companies.

That played out at the recent Biotechnology Industry Organization convention in Chicago. While smaller, privately held companies continued to dominate the number of 15-minute pitches, South San Francisco-based biotech biggie Genentech Inc. and German goliath Bayer Schering Pharma AG also spun out appeals to smaller companies to sell out or partner up.
The list of big companies taking time slots to make similar pitches included the likes of Pfizer, Merck AstraZeneca, Eli Lilly and GlaxoSmithKline."

It's a few weeks post AACR and a month before the run-up to ASCO, also oddly in Chicago, and thus companies interested in oncology will have been evaluating the latest AACR data and thinking about whether or not to make a move before the competition do.

Of course, with many companies facing a potential perfect storm of patent cliffs and a shortfall in the in-house pipelines over the next few years, everyone is desperately hunting for 'breakthroughs'. These are never a sure fire thing and are very hard to predict.

Increased activity and competition for licensing deals also means good news for the little companies as supply and demand may well drive prices up. It will certainly be interesting to see who pounces over the next few weeks and many investors will be scanning their crystal balls hard for clues.

Who do you think will be snapped up?

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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!

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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.

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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