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ASCO 2013 Highlights Part 2

It’s that time of the year when the annual meeting of the American Society of Clinical Oncology (ASCO) hurtles around with alarming speed out of nowhere and everyone in Pharmaland goes, “ASCO, what already? Is it really June?!” Suddenly the month becomes the focus for many frantic hives of activity.

Immunotherapy

The last two years have seen some unprecedented changes in new therapies emerging to treat several different tumour types, both liquid and solid. One of the new trends that has begun to emerge is the new class of immunotherapy agents called checkpoint regulator inhibitors. These include:

CTLA-4 (ipilimumab)
PD-1 (nivolumab and lambrolizumab)
PD-L1 (RG7446)
OXO-40 inhibitors (more about those in another post).

This year at ASCO brings forth a lot of new data from the four compounds mentioned. In the video preview we have also attempted to explain how these antibodies work and why they are an important development beyond melanoma. There are data in several tumour types including melanoma, RCC and head & neck cancer at Chicago. In the recent thought leader interview with Dr Robert Motzer (MSKCC), he mentioned PD-1 as a hot topic to watch out for in renal cancer. However, I’m particularly looking forward to seeing the lung cancer data, which has the potential to be really stunning.

In this year’s ASCO video preview, we have included some graphics and an MOA video explaining how these immunotherapies are thought to work. Check it out below!

CLL

Another area that I’ve been watching for a while is chronic lymphocytic leukemia (CLL), which has languished a little in the shadow of it’s CML cousin. Not for long though!

There are a lot of exciting developments here beyond Pharmacyclics BTK inhibitor, ibrutinib. These include new CD-20 antibodies such as Roche’s GA-101 (obinutuzumab) and SYK inhibitors (whatever happened to fostamatinib, one of the hematology highlights of the 2010 ASCO?) where Gilead are now developing an early compound, potentially for combining with their PI3K-delta inhibitor, CAL-101, now known as idelalisib.

In addition, Infinity also have a PI3K-delta inhibitor, although they are further behind in development. We don’t know yet whether greater in vivo potency will translate to the clinic or whether also targeting gamma will add to the efficacy or introduce off-target kinase toxicities. Either way, it’s good to see so many targets and exciting new agents being explored for this disease.

Breast and Lung Cancers

On the solid tumour front, I was delighted to see new data in HER2+ breast cancer and ALK+ lung cancer. Interestingly, in both of these cancers, Pfizer and Novartis in particular are making inroads with a number of compounds including everolimus (Afinitor), palbociclib (PD-0332991) a selective inhibitor of cyclin dependent kinases (CDK) 4 and 6, LDK378 and PF-05280014, a trastuzumab biosimilar.

Pancreatic Cancer

My final topic that has some interesting developments is pancreatic cancer. Since the phase III Abraxane data from the MPACT study was presented at ASCO GI, Celgene have filed with the FDA and received Priority review, with a PDUFA date of September 21st. An update is expected at ASCO, along with tumour marker data and prognostic biomarker data. Threshold are presenting their phase III study design for TH-302 in the Trials in Progress section, but given the standard of care may well have changed by the time the data is mature, this may well be a day late and dollar short.

All in all, a good year can be expected for new data emerging at this year’s ASCO.

You can learn more about these topics, including insights on how PD-1 and PD-L1 immunotherapies work from the video highlights by clicking on the image below:

My ASCO preview video was freely available for several months but is now part of Biotech Strategy Blog Premium Content.

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ASCO 2013 Highlights PD-1 and PD-L1 immunotherapy

One of the hot topics at this year’s annual ASCO meeting is clearly going to be PD-1 and PD-L1 immunotherapies, following on from the success of BMS’ PD-1 agent highlighted in my ASCO video last year. By now, we know that it has a generic name, nivolumab, and is being studied in combination with ipilimumab (Yervoy) in metastatic melanoma. You can find the many nivolumab abstracts here.

Understanding how PD-1 and PD-L1 immunotherapy works.

Source: Roche

Interestingly, BMS also now has competition from other big pharma companies, including Roche’s PD-L1 antibody, MPDL3280A, and Merck’s lambrolizumab. Roche appear to be developing a companion diagnostic, which could mean the responses are different for PD-L1 positive and negative patients. At least, that would be an intuitive conclusion and a potentially good way to preselect patients who are most likely to respond to the therapy.

In addition, the FDA have already picked up on this class of agents, conferring the almost ubiquitous Breakthrough Therapy status on some of them already, so solid data in the next year or so could mean a fast track to market strategy is possible in this category.

In the battle of the abstracts and sheer depth of data in the PD-1/PD-L1 segment, you can see that Merck are already the poor cousins to BMS and Roche in execution. Just one? That’s pitiful! Never a good sign.

What factors need to be considered in looking at the immunotherapy data?

Last night I was searching the abstracts on my iPhone after the local broadband inconveniently went down and also watched the conversations on Twitter, usually a fun experience fishing for and discussing the diamonds in the rough. A couple of things struck me, however, around the immunotherapy data mining and chatter:

Firstly, there’s way too much focus on ORR (overall response rate) and the minutiae of the differences between the different PD-1/PD-L1 agents. It’s far too early to tell much, as we all know that what matters are the randomized phase III trials, trial design and patient selection (specific, catch-all etc). These can all have a huge impact on the final outcomes in large scale randomised studies.

Secondly, ORR is a measure of disease control – it tells us how much shrinkage there is going on at the time of measurement and is based on RECIST. This is partly a hangover form old chemo days, and partly a lack of available biomarkers of response. Let’s not also forget that immunotherapies usually have a delayed effect and while waterfall plots at six months or so are useful, they don’t tell us what the long term effects will be. How durable will the responses be beyond 6-8 months? Is there adaptive resistance developing? What sort of logical combinations and sequencing options can be considered? So many questions to which we have no answers yet.

Thirdly, be very careful when interpreting the abstract data for ORR – sometimes the data is given for all the patients, irrespective of whether they responded or not, and sometimes it is given as a percentage of the patients who actually had some sort of response. You need to compare apples with apples when looking across studies or the conclusions drawn can end up being a little off.

Fourthly, I don’t think ORR is the ideal endpoint. So what? What really matters is how long do patients live, do they feel better (or worse) and will they have a better quality of life as a result of taking the medication? Other obvious but important questions we need to evaluate going forward include:

How much of a prolonged effect with PD-1/PD-L1 immunotherapies have over 5 years?
What will be their effect on subsequent therapies?
Will they boost or hinder sequencing and in which tumour types?
Is there a biomarker of response?
Is a diagnostic necessary?

Fifthly, combination studies are nice if they lead to improved outcomes, but at what cost will this be achieved? By this, I mean both in terms of safety (remember ipi and vemurafenib were thought to be a logical combo in melanoma until the unexpected AEs scuppered that concept) and also cumulative cost of treatment. None of the new oncology therapies can or will be considered inexpensive these days, especially when the benefit might be measured in only a few months or less.

Overall:

I’m really looking forward to these presentations on PD-1/PD-L1 and will write about them in more detail at the meeting. It continues to be an exciting area in oncology, as long as the results live up to the expectations. It’s still unclear which tumour types will benefit most and what the durability will be. Right now, I have more questions than answers, but as a concept it’s definitely one well worth watching over the next couple of years.

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Will vemurafenib receive early approval for metastatic melanoma?

By MaverickNY on August 9, 2011

A Reuters press release on vemurafenib (Zelboraf) caught my eye this morning, suggesting that it might be approved in BRAFV600E metastatic melanoma by the FDA might be “imminent” according to an unnamed source and much earlier than the expected PDUFA date in ~~November~~ October 28th (now confirmed by Roche/Genentech).

If so, that’s very good news.

However, what really caught my eye was a quote from a spokesperson at Roche Diagnostics, suggesting that the BRAFV600E test would could around $150. That’s lower than I was expecting, although no doubt it will be considerably offset by the cost of vemurafenib itself.

It was also good to hear recently that Roche and BMS, the manufacturers of ipilimumab (Yervoy), have now met to discuss and finalise the much anticipated combination trial of Zelboraf and Yervoy. It will be interesting to see if the combination will extend survival even further in patients with the V600E mutation. There’s a long way to go before the results bear fruit, as an early dose finding and tolerability study will be the first step in the process.

Of course, pricing and reimbursement will be key, given that Yervoy was launched recently with a $120K price tag for four infusions. On the 2Q earnings call the other week, BMS announced that the launch was going well and uptake was strong. It is given as a 3mg infusion every three weeks for 4 cycles, over a 3 month period. It will be interesting to see what the Zelboraf monthly price will be, assuming it successfully garners approval. Should the combination work out in the future, the cost of treating metastatic melanoma will likely become even more expensive despite only small incremental survival benefits.

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BMS and Roche join forces in metastatic melanoma

By MaverickNY on June 2, 2011

Two of the most dynamic cancer markets at the moment are prostate cancer and metastatic melanoma, which is great news considering that neither has had much attention over the last decade compared to breast and lung cancers.

My colleague has posted an overview of what’s going on in advanced prostate cancer today, which you may be interested in checking out pre-ASCO. However, what excited me this morning were announcements from BMS and Roche declaring their intent to pursue combination trials in BRAF metastatic melanoma with their therapies ipilimumab (Yervoy) and vemurafenib (PLX4032).

This is really great news, and a very logical approach that is well worth evaluating.

I’m delighted to see the two companies seeking to work together on this to see if the combination can improve outcomes further than what we have seen for vemurafenib alone, which already showed impressive responses in poor prognosis patients.

Vemurafenib has been shown to target the BRAF V600E mutation, as you can see in the graphic.

Ipilimumab is an immunotherapy that targets the CTLA-4 antigen and was approved by the FDA in March as a treatment option for newly diagnosed patients with metastatic melanoma.

A phase I/II trial is planned initially, which is a relatively low risk study – if the results look good we will hopefully see a larger scale phase III trial emerge. If not, at least we will know a quick answer on the combination.

Meanwhile, these two drugs will be presented in the plenary session at ASCO this weekend comparing either to the current standard of care, dacarbazine (DTIC), in advanced newly diagnosed metastatic melanoma.

I’m really looking forward to writing more on those trials on Monday morning – so do check back then for an update of the phase III data!

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Update on PARP inhibitors including olaparib, iniparib and veliparib

By MaverickNY on January 28, 2011

Now that the dust has settled on the news from sanofi-aventis yesterday that iniparib did not achieve it’s primary survival endpoints in the phase III trial in newly diagnosed triple negative breast cancer (TNBC), it’s time to take stock of this class.

Yesterday was another major snow shovelling day in New Jersey so I missed the AstraZeneca year end conference call. A Pharma Strategy Blog reader kindly filled me in with some relevant information – the company discontinued the development of their PARP inhibitor, olaparib, in BRCA breast cancer – scroll down to the discontinued section to see the note.

Our source also listened to the Q+A and in response to questions on olaparib from the analysts, Martin Mackay, the Head of R&D observed that:

“We decided to focus on serious ovarian cancer, and really focus our attention to that in the first instance and wait to see how those results play out in Phase III. Then we’ll revisit… breast cancer.”

This raises some interesting questions about PARP inhibitors in general.

Yesterday, we noted the fine line that needs to be trod between potency/efficacy and tolerability. Last ASCO we saw how challenging it was to manage the toxicities with olaparib in combination with chemotherapy. Iniparib doesn’t appear to add to the adverse event profile in combination, but missed its efficacy endpoints.

Meanwhile, Abbott’s PARP inhibitor, veliparib, is being tested in the I-SPY breast cancer trial, so while it will be a while before we see any data, it will be interesting to see how it pans out given that it is also more potent than iniparib. Pfizer, BMS and Merck are also potential players in the PARP class, but their inhibitors are in earlier stage development. Based on the latest news with iniparib and olaparib it will be fascinating to see what they decide to do.

The latest developments in triple negative breast cancer also raise other critical issues:

Was the olaparib decision based on toxicities, lack of efficacy or being behind iniparib, since they recently announced their phase II results?
How will neliparib fare in the neoadjuvant setting and what toxicities might be expected?
TNBC are mainly basal cell histology so many will also be BRCA1 or 2 positive – did these women do better in the olaparib trial?
Will the Pfizer and Merck compounds have a better risk:benefit profile?
What biomarkers will emerge to indicate subsets or predict response to therapy?
If (5) does evolve, how will this develop from a diagnostics perspective?
What will happen in ovarian, lung and prostate cancers, all of which have a very small proportion of people who have the BRCA1 or 2 mutation.

The current situation with iniparib and olaparib raises more questions than answers, so it will be interesting to see what learnings emerge from the data and whether the once promising class is salvageable or dead.

All in all, 2011 is turning out to be an interesting year and we have yet to get past January.

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Metastatic melanoma – what’s new on the horizon?

By MaverickNY on November 3, 2010

Metastatic melanoma is quite a hot topic right now with a rich pipeline of products in development after a decade of little or no progress. Of course, it is a bit like three London buses coming along at once after an hour long wait in the winter weather, but better late than never.

Many of you will remember the recent data from ipilimumab (BMS), an immunotherapy that showed increased survival, albeit with some severe adverse events, from the phase III trial in newly diagnosed metastatic melanoma presented at ASCO in the plenary session earlier this year, followed by a publication in the NEJM. The FDA filing was subsequently submitted on the basis of the positive data.

Yesterday, BMS announced that the FDA have moved the PDUFA date back 3 months from Dec 25th to March 26th, 2011. A precise reason for the delay wasn’t given , but the company did say:

“In response to an FDA request, Bristol-Myers Squibb submitted further analysis of data pertaining to the current application for pre-treated advanced melanoma and the agency considers this to be a major amendment to the drug’s BLA.”

I’m not going to speculate on the reasons for the extra review time or what the new data was, but it is an interesting and unexpected development.

Meanwhile, there’s also been a lot of buzz around targeted BRAF inhibition in melanoma lately, specifically around the initial stunning results seen with PLX4032 (Plexxikon & Roche). So far, it seems that responses of around 6-12 months, with a median of around 8 months are possible with an kinase inhibitor that specifically targets the V600E mutation associated with BRAF, although there two problems:

The responses are not durable as resistance (eg associated with MEK or AKT amplification) sets in.
Inhibiting CRAF as well as BRAF appears to lead to an unwanted excess proliferation of squamous cells, which is reversible on withdrawal of treatment.

In the first case, a couple of recent papers have looked at mechanisms of resistance around BRAF inhibition that give us some clues of where to go next.

MAPKpathway Gopal et al., (2010) decided to see what happened with AZD6244 or selumetinib (Array and AstraZeneca), a MEK and MAP/ERK inhibitor, and whether it would have any impact in mitigating BRAF resistance, given the potential close interaction within the RAS-RAF-MAPK pathway and downstream events that could be impacted through cross-talk and feedback loops:

“We analyzed a panel of Braf mutant human cutaneous melanoma cell lines for their sensitivity to growth and survival inhibition by AZD6244. We compared these effects with the baseline activation status of signaling pathways in the cells, and with AZD6244 treatment–induced changes in signaling networks.

These studies have identified the phosphoinositide 3-kinase (PI3K)-AKT pathway as a critical regulator of the efficacy of AZD6244 in Braf-mutant melanomas, including in cells without baseline activation of the pathway.”

In order to determine possible mechanisms of resistance in the cell lines, they compared the effects of AZD6244 treatment on their signaling pathways with effects in sensitive cell lines and found:

“Although all four of these Braf-mutant cell lines showed similar degree and duration of MAPK inhibition and several other proteins, the resistant cell lines increased their P-AKT levels following exposure to AZD6244, which was not observed in the sensitive cell lines.”

They went on to note:

“The functional significance of AKT activation is supported by the fact that inhibition of AKT activity, either by AKT knockdown or concurrent treatment with the mTORC1/2 inhibitor AZD8055, resulted in synergistic cell killing in the resistant cell lines.”

AstraZeneca and Merck have an ongoing partnership with their MEK (AZD6244) and AKT (MK-2206) kinase inhibitors, so combining them in a clinical trial to try and reduce resistance via feedback loops here would be an interesting approach worth trying. Such a combination trial is currently recruiting in advanced solid tumours, not melanoma per se. It is, however, a classic catch-all phase I study to see what kinds of cancers might respond and determine the MTD, but I would be very interested to see the data from patients with metastatic melanoma if they are enrolled.

Now, it has been shown in breast cancer cell lines showed that MEK inhibition resulted in cross-activation of the EGFR tyrosine growth factor receptor, but EGFR has not been shown to be relevant in melanoma, so Gopal et al., considered what other receptors might be responsible for mediating the effects. In the discussion, an interesting snippet caught my eye:

“AZD6244 treatment induced a slight increase of IGF-I secretion by the cells, and knockdown of IGF-I also blocked P-AKT induction by AZD6244. Supporting a specific role for the pathway in cell survival, recombinant IGF-I treatment blocked AZD6244-induced cell death, but not growth arrest, in the sensitive WM35.”

This might also suggest another useful combination approach to consider in clinical trials.

Previously, it has been shown that targeting BRAF can not only inhibit the important driver in melanoma, the V600E mutation, but it can also stimulate cellular signaling through the MEK-ERK pathway by activating the related family member C-RAF. This may explain the squamous cell proliferation seen in some patients with PLX4032. The more ideal BRAF inhibitor would therefore specifically target BRAF V600E, without activating CRAF at the same time.

Related to the subject of malignant melanoma, Kamata et al., (2010) just published a paper that looked at the relationship between BRAF and CRAF in the disease. Previously it has been shown that D594A BRAF lacks kinase activity, but can induce the related gene product CRAF in addition to the mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway. What they found was really interesting. In a nutshell:

“We show that the aneuploid phenotype is dependent on Craf. Treatment with the MEK inhibitor U0126 did not attenuate the emergence of aneuploidy but prevented the growth of aneuploid cells. These results provide a previously unidentified link between Craf and chromosomal stability, with important implications for our understanding of the development of cancers with driver mutations that hyperactivate Craf.”

Aneuploidy is an abnormal number of chromosomes and can lead to genetic instability, a key cancer hallmark. It’s an important concept here because Kamata et al., have offered a different reason for the CRAF proliferation observed with some BRAF inhibitors:

“Impaired activity BRAF mutants are frequently coincident with oncogenic RAS mutations in human cancers (26) and in these, albeit rare, cancers, we may expect the hyper-activated CRAF induced by the combination of both oncogenes to enhance the aneuploidy response compared with mutation of either oncogene alone. Such a situation is likely to be highly detrimental to the individual and, indeed, this mechanism may well account for the highly aggressive melanomas we observed following the combined expression of D594A Braf and G12D Kras in melanocytes.”

All in all, this is a very complex yet fascinating area of research and for those of you interested in this field, I would highly recommend reading the latest papers.

Photo Credit: Wikipedia

References:

Boni, A., Cogdill, A., Dang, P., Udayakumar, D., Njauw, C., Sloss, C., Ferrone, C., Flaherty, K., Lawrence, D., Fisher, D., Tsao, H., & Wargo, J. (2010). Selective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function Cancer Research, 70 (13), 5213-5219 DOI: 10.1158/0008-5472.CAN-10-0118

Garnett MJ, Rana S, Paterson H, Barford D, & Marais R (2005). Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Molecular cell, 20 (6), 963-9 PMID: 16364920

Gopal, Y., Deng, W., Woodman, S., Komurov, K., Ram, P., Smith, P., & Davies, M. (2010). Basal and Treatment-Induced Activation of AKT Mediates Resistance to Cell Death by AZD6244 (ARRY-142886) in Braf-Mutant Human Cutaneous Melanoma Cells Cancer Research, 70 (21), 8736-8747 DOI: 10.1158/0008-5472.CAN-10-0902

Kamata, T., Hussain, J., Giblett, S., Hayward, R., Marais, R., & Pritchard, C. (2010). BRAF Inactivation Drives Aneuploidy by Deregulating CRAF Cancer Research, 70 (21), 8475-8486 DOI: 10.1158/0008-5472.CAN-10-0603

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Inhibition of mutated, activated BRAF in metastatic melanoma

By MaverickNY on August 25, 2010

Hot on the heels of last week's New England Journal of Medicine article on ipilimumab (BMS) comes another article on metastatic melanoma, this time from Keith Flaherty's group in Pennsylvania and Boston on BRAF inhibition with PLX4032, an exciting compound being developed by Plexxikon/Roche (see link below in the references for the article).

I've written a few posts on this interesting compound recently (e.g. here and here), for those interested in getting up to speed on the concept and data.

The basic concept is that a while back it was noticed that some tumours such as melanoma develop the V600E BRAF mutation and induce resistance or a poorer prognosis, so common sense says why not find a targeted agent to inhibit the activity to see what happened?

In the August 26th edition of the NEJM, Flaherty et al., described the updated phase I results in two phases:

55 patients (49 with melanoma) in the dose escalation phase
32 additional people with metastatic melanoma who had BRAF with the V600E mutation in the extension phase

Now, remember, a phase I trial usually seeks to define the maximum tolerated dose (MTD), which is used in the phase II studies and looks at the general tolerability and side effects. Efficacy is not the primary end point, but of course, we all secretly look at the activity to see if there is any sign of a response!

First things first. After some palaver with the crystalline formulation, it was finally settled on a "micro-precipitated bulk powder" since that offered superior bioavailability. I'm paraphrasing a bit and taking liberties here, but no doubt regular readers will sense my excitement and tendency to skip to the bottom line and find out what it all means, although we have all been there with those kind of challenging problems, especially as they add delays and frustrations all around!

Anyway, as a result of these changes, the final recommended dose that emerged for the phase II studies was 960mg BID, with increases in the dose limited by grade 2 or 3 rash, fatigue or arthralgia. These kind of side effects are fairly typical of oral TKI's and very different from what we saw with last week's NEJM article on immunotherapy with ipilimumab in a similar population.

Potentially, the biggest concern is the appearance of squamous-cell carcinoma that appeared in 10 of 32 patients (31%) in the dose escalation cohort. While normally well differentiated and of low invasive potential, it is something to note. The authors noted that recent data earlier this year (see references below) suggest BRAF inhibitors can activate the MAP kinase pathway in cells that lack a BRAF mutation and may explain some of the peculiar side effects seen with PLX4032.

Previously, Flaherty et al., reported nine responses in the second PLX4032 cohort and median PFS of 6 months. For comparison with the updated data, see the last report before reading on. Over half of the people in both cohorts had received 2 or more therapies, so these are a mix of relapsed and refractory patients:

In the first cohort of 55 people, there were 16 with the BRAF V600E mutated melanoma and received 240mg or more of PLX-4032. The efficacy? Well, there were 10 partial response and 1 complete response (69%).
In the extension cohort of 32 people, 24 were partial responders and 2 had a complete response (81%), which is pretty impressive all around. No wonder Dr Flaherty was very excited when interviewed for an article in the NY Times earlier this year!

My first reaction was slight disbelief, after all, this is a very difficult to treat and highly aggressive disease, thus sadly, people do tend to relapse early. In short, if there were three cancers I absolutely wouldn't want to get, this would be one of them.

On closely checking the data carefully including the 81% response rate in the second cohort (yes, it's correct!), I noticed that the researchers reported across all patients in the phase I study, the median progression free survival (PFS) was now improved to 7 months. That means that 50% did worse and 50% did better than 7 months, way better than one might expect so early in a trial. I did double check again and pinch myself, as it was late on Tuesday night when I penned the draft.

If you are interested in this area, do check out the link to the article below because the water plots and anti-tumour responses over time are well worth looking at, especially as some people are clearly achieving responses approaching a year, despite having advanced disease.

"Responses were observed at all sites of the disease, including the bone, liver, and small bowel."

Yes, it is still very early, but how awesome is it to read that?

As an aside, a number of readers have written asking why sorafenib hasn't shown to be effective in melanoma, despite inhibiting BRAF. Flaherty et al., had an answer for that. They suggested that because it also inhibits other pathways, it may well be that the non-BRAF effects of the drug mediate side effects that limit the ability to achieve enough drug concentration and thus the drug concentration isn't high enough to effectively inhibit the V600E BRAF mutation. An interesting theory that also speak to the idea that several specific inhibits may be more effective that more promiscuous multi-kinase inhibitors.

The good news is that for now at least, we seem to be on the right track with PLX4032 and ipilimumab in metastatic melanoma. It will be interesting to see what the mechanisms of resistance are down the road, and whether we have some options in the works for either combination or sequencing of different targeted agents for this disease.

Flaherty, K., Puzanov, I., Kim, K., Ribas, A., McArthur, G., Sosman, J., O'Dwyer, P., Lee, R., Grippo, J., Nolop, K., & Chapman, P. (2010). Inhibition of Mutated, Activated BRAF in Metastatic Melanoma New England Journal of Medicine, 363 (9), 809-819 DOI: 10.1056/NEJMoa1002011

Heidorn, S., Milagre, C., Whittaker, S., Nourry, A., Niculescu-Duvas, I., Dhomen, N., Hussain, J., Reis-Filho, J., Springer, C., & Pritchard, C. (2010). Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF Cell, 140 (2), 209-221 DOI: 10.1016/j.cell.2009.12.040

Poulikakos PI, Zhang C, Bollag G, Shokat KM, & Rosen N (2010). RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature, 464 (7287), 427-30 PMID: 20179705

Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B., Anderson, D., Alvarado, R., Ludlam, M., Stokoe, D., Gloor, S., Vigers, G., Morales, T., Aliagas, I., Liu, B., Sideris, S., Hoeflich, K., Jaiswal, B., Seshagiri, S., Koeppen, H., Belvin, M., Friedman, L., & Malek, S. (2010). RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth Nature, 464 (7287), 431-435 DOI: 10.1038/nature08833

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Improved survival with ipilimumab in metastatic melanoma

By MaverickNY on August 19, 2010

The latest New England Journal of Medicine dropped in the mail yesterday afternoon, it has some interesting articles on how palliation plus chemotherapy offers improved survival over chemo alone and a small study on the positive impact of T'ai Chi on fibromyalgia. My attention, however, was drawn to the ipilimumab data in advanced metastatic melanoma.

We saw the first major presentation of this phase III trial recently at ASCO, and my pre-ASCO notes can be found here. At the BMS investor meeting held during the conference, the executives were clearly very excited about the prospects for the agent. It would seem that the FDA agrees with them, as it was announced yesterday that Priority review status has been granted in previously treated people with melanoma. The PDUFA action date is estimated as December 25th, 2010, so I think we can safely assume that it will likely happen a bit before that 🙂

Going back to the NEJM paper, what can we expect?

The complex study design looked at the impact of ipilimumab, which targets CTLA-4 antibodies resulting in anti-tumour effects, with and without gp100, a vaccine based on melanoma vaccine, versus ipilimumab alone in a phase III trial of 674 patients. In short, here's how the median overall survival results stack up:

Ipilimumab + gp100: 10.0 months
gp100 alone: 6.4 months
Ipilimumab alone: 10.1 months

There was no difference in survival between the two ipilimumab groups, suggesting that the gp100 vaccine isn't adding anything to the mix. I'm not really convinced, however, of the arguments for using gp100 as an unconventional control over dacarbazine (DTIC) in patients who had previously failed IL2 therapy. From this data, we have no idea how ipilimumab stacks up versus dacarbazine in the second-line setting, but given there is no standard of care in the refractory setting for patients who have failed dacarbazine, it presented a tricky issue in trial design. Still, the overall survival advantage in favour of ipilimumab alone speaks for itself.

It will be interesting to see what BMS do with this commercially, if the FDA approve it and they most likely will. Based on this data, it appears to make sense to market ipilimumab alone without the extra costs and potential toxicities associated with adding gp100.

Four months improvement in advanced refractory melanoma is a relatively big jump, and like many I'm excited to see that, despite the low responses rates seen in the ipilimumab groups (6-11%). The editorial by Hwu also noted that:

"… the true importance of this drug lies in the long-term benefit that was seen in a subgroup of patients. Follow-up from the earliest cohort of patients that received the anti–CTLA-4 drug shows that ongoing complete responses in some patients with metastatic melanoma can continue past 6 years."

The biggest downside of this trial though, was the side effect profile. Whereas we recently saw few fatal toxic side effects associated with the Provenge vaccine in castrate-resistant prostate cancer, immunotherapy with ipilimumab is an entirely different kettle of fish, as the NEJM article demonstrated:

Grade 3-4 immune related adverse events:

10-15% of ipilimumab treated patients
3% treated with gp100 alone

Deaths in study:

14 related to study drugs (2.1%)
7 associated with immune-related events

Now, we need to remember that people entering clinical trials at Academic centres are not the typical patients seen in the Community setting. They tend to be younger and have a much better performance status for a start, so it is likely that there will be some nervousness associated with management and complications in older, more frail patients. The authors noted that:

"Adverse events can be severe and long-lasting, or both, but most are reversible with appropriate treatment."

It reminds me somewhat of the situation with another immune-related therapy a few years ago with alemtuzumab (Campath), an monoclonal antibody that binds to CD52 in chronic lymphocytic leukemia (CLL), where the occasionally urgent side effect management and rare complications that can arise (CMV activations, severe infections etc) were so resoundly disliked by the Community, that most avoid using it where at all possible. Urgent medical attention of severe and, potentially fatal, complications is much easier to handle in a hospital than an office setting, especially on a Friday afternoon or over the weekend.

Ipilimumab looks to be an efficacious therapy that extends life, but at a cost. I can therefore see that it will mostly likely get used in Academic settings, where there is more comfort and familiarity in dealing with the potential complications, especially in advanced, relapsed disease. I could be wrong in that assessment, but that is what instinct tells me.

Most doctors will try something once, especially in the refractory or salvage setting, but the first sign of potentially fatal complications requiring urgent medical attention creates an environment that is fraught with stress and worry, busy Community practices may well decide it will be easier to refer appropriate patients in that situation.

In an accompanying editorial (see below for reference link), Patrick Hwu summed up the trial and new directions in metastatic melanoma admirably:

"Despite dramatic effects in a subgroup of patients receiving the anti–CTLA-4 drug, the majority of patients with metastatic melanoma do not respond to this agent, and further work is vital to improve these results.

Future efforts should include the rational combination of anti–CTLA-4 agents or alternative checkpoint inhibitors with targeted therapies or other immune agents. Instead of attempting to marginally increase the median survival, the primary goal of these new combination therapies should be to enhance the percentage of long-term survivors, thereby elevating the “tail” of the survival curve."

{Disclosure: Long on BMS}

Hodi, F., O'Day, S., McDermott, D., Weber, R., Sosman, J., Haanen, J., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J., Akerley, W., van den Eertwegh, A., Lutzky, J., Lorigan, P., Vaubel, J., Linette, G., Hogg, D., Ottensmeier, C., Lebbe, C., Peschel, C., Quirt, I., Clark, J., Wolchok, J., Weber, J., Tian, J., Yellin, M., Nichol, G., Hoos, A., & Urba, W. (2010). Improved Survival with Ipilimumab in Patients with Metastatic Melanoma New England Journal of Medicine DOI: 10.1056/NEJMoa1003466

Hwu, P. (2010). Treating Cancer by Targeting the Immune System New England Journal of Medicine, 363 (8), 779-781 DOI: 10.1056/NEJMe1006416

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Patterns of expression of DNA repair genes and relapse from melanoma

By MaverickNY on August 17, 2010

Someone kindly sent me this paper on how gene expression can be used to track insufficient DNA repair, which can lead to relapse in melanoma, making it potentially useful as both a prognostic and predictive biomarker for the disease. Regular readers will notice that I am slowly changing my opinion of gene expression studies as a result of articles like this one :-).

According to the researchers:

"Over-expression of DNA repair genes was shown to be associated with reduced relapse-free survival, thicker tumors and tumors with higher mitotic rate.

Preliminary data are also reported suggesting that DNA repair genes are overexpressed in tumors from patients who do not respond to chemotherapy."

Resistance to treatment is one of the biggest ongoing problems associated with treatment of melanoma, both with approved therapies and also pipeline drugs, so finding ways to detect it earlier (and the reasons why) would potentially help in sequencing with different drugs.

So what was involved in this study, which is the largest gene expression study to date in melanoma? The authors decided to see whether formalin-fixed tissue analysis would be useful:

"Gene expression profiles were identified in samples from two studies (472 tumors). Gene expression data for 502 cancer-related genes from these studies were combined for analysis."

The findings were quite interesting.

Basically, the increased expression of DNA repair genes most strongly predicted relapse, and was associated with thicker tumours. Increased expression of RAD51 was the most predictive of relapse-free survival (RFS). In addition, RAD52 and TOP2A were independent predictors of RFS in the analysis.

The authors concluded:

"Over-expression of DNA repair genes (predominantly those involved in doublestrand break repair) was associated with relapse. These data support the hypothesis that melanoma progression requires maintenance of genetic stability."

In the past, we have discussed synthetic lethality and DNA repair on this blog in breast and ovarian cancers, with respect to PARP inhibitors seeking to repair damaged DNA and prolong survival outcomes. Based on the current analysis, it looks as though a similar approach may be useful in melanoma. This may give clues for future pipeline development of new therapeutics designed to tackle the specific underlying biology of the cancer.

It should be noticed, though, that the results are describing the factors contributing to relapse from chemotherapy (dacarbazine, DTIC) rather than current pipeline drugs in development for melanoma such as PLX-4032 (Roche/Plexxikon) or ipilimumab (BMS).

I would be very interested to see whether the biomarkers identified in this research for chemotherapy would also apply to the targeted therapies. It is possible that they may not, or possibly they could help reverse or repair some of the changes occurring. Either way, finding ways to address the DNA repair may be a fruitful area of study.

Jewell, R., Conway, C., Mitra, A., Randerson-Moor, J., Lobo, S., Nsengimana, J., Harland, M., Marples, M., Edward, S., Cook, M., Powell, B., Boon, A., de Kort, F., Parker, K., Cree, I., Barrett, J., Knowles, M., Bishop, T., & Newton-Bishop, J. (2010). Patterns of Expression of DNA Repair Genes and Relapse from Melanoma Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-10-1521

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

Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘BMS’

ASCO 2013 Highlights PD-1 and PD-L1 immunotherapy

What factors need to be considered in looking at the immunotherapy data?

Overall:

Will vemurafenib receive early approval for metastatic melanoma?

BMS and Roche join forces in metastatic melanoma

Update on PARP inhibitors including olaparib, iniparib and veliparib

Metastatic melanoma – what’s new on the horizon?

Inhibition of mutated, activated BRAF in metastatic melanoma

Improved survival with ipilimumab in metastatic melanoma

Patterns of expression of DNA repair genes and relapse from melanoma

Evidence for role of microRNA in Melanoma