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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘ipilimumab’

When is NICE is not so nice?

By on October 14, 2011

“Ipilimumab is not recommended for the treatment of advanced (unresectable or metastatic) malignant melanoma in people who have received prior therapy.

The Committee was satisfied that ipilimumab meets the criteria for being a life-extending, end-of-life treatment and that the trial evidence presented for this consideration was robust.

The Committee acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and ipilimumab could be considered a significant innovation for a disease with a high unmet clinical need.

Despite the combined value of these factors the Committee considered that the magnitude of additional weight that would need to be assigned to the QALY gains for people with advanced (unresectable or metastatic) melanoma would be too great for ipilimumab to be considered a cost-effective use of NHS resources.”

NHS NICE Guidance

In other words, it’s too expensive and the NHS doesn’t want to pay the £80K ($120K) sticker price. This news is no great surprise given the cost-benefit ratio when considering that there is no way to tell who might benefit most from treatment upfront.

The is, however, a huge difference between hope and false hope, as NPR Shots astutely noted when discussing Avastin in breast cancer earlier this week and in some ways that sentiment applies here too. By this I mean it would be much more compelling to both patients and NICE if an oncologist could talk about a new therapy in specific and useful terms.

Examples of doctor-patient conversations about treatment in the near future might look more like this….

Either:

“You have an 70-80% chance of responding to this therapy because you have X (mutation, translocation, biomarker etc), where this drug has been shown to be highly effective and extends life by over 2 years in many of our advanced patients with this disease to date.”

Or:

“This drug may do more harm than good in your case, as it has been shown to effectively target X (mutation, translocation, biomarker etc), which you do not have, and therefore, are unlikely to respond. I believe it would be better to consider these alternatives in your situation… “

We all know about heterogeneity – it’s the very underpining of what makes a cancer survive despite our best efforts to tame it until we can subset into more homogenous and predictable groups.  This means that offering a broad therapy to all patients with a given advanced cancer without any idea of its predictive value is fast becoming a misnomer in today’s world of emerging targeted therapies.  Now, manufacturers (marketers even) might think it’s better not to ‘limit’ their market opportunity, but the reality is many healthcare systems are looking at ways to limit treatments to where it’s needed most, not only for cost reasons, but also to direct resources where they are more likely to work. The current model is not sustainable in the long run.

Of course, if a predictive biomarker was available to determine which patients are more likely to respond to ipilimumab, then the QALY calculation would be considerably different, and possibility even within the realms of the current guidelines.

That’s a whole different ballgame, but hopefully one that will begin to emerge as we have seen with new targeted therapies such as vemurafenib (Zelboraf) in BRAF V600E malignant melanoma, crizotinib (Xalkori) in ALK-positive advanced lung cancers and everolimus (Afinitor) in combination with exemestane in ER/PR+ HER2- breast cancers that have relapsed after initial aromatase inhibitor therapy.

It will be interesting to see how NICE handles all of those situations in the future, since they are all targeted agents showing a significant impact on a patients ability to live longer,with a more precise, and therefore, limited patient definition.  As a Brit and a scientist, I may have reasonable expectations that NICE will make a rational and logical decision in the face of limited resources, but this is also tinted with a large dose of healthy scepticism after the trastuzumab (Herceptin) debacle in HER2-positive breast cancers that lead to the utterly ridiculous and unfair post code lottery in the UK.

We are not talking absolute costs here, but the relative costs of seeing real efficacy benefits of six months or more in those patients most likely to respond, while at the same time giving an offering that truly extends life in a meaningful fashion without exposing too many to the toxic side effects of a given treatment. Dealing with cancer is tough enough without being treated with a regimen that had absolutely no hope of helping people live longer and feel better.

Will vemurafenib receive early approval for metastatic melanoma?

By 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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European Hematology Association meeting 2011

By on June 8, 2011

Well, after just getting back from the American Society of Clinical Oncology (ASCO) meeting in Chicago, I’m heading off to Europe for the European Hematology Association (EHA) meeting – no rest for the wicked!

ASCO was a rather flat meeting this year – the stars were undoubtedly the imatinib 36 vs 12 month data in adjuvant GIST (clearly superior) and Roche/Plexxikon/Daiichi Sankyo’s vemurafenib in BRAF V600E metastatic melanoma. The ipilimumab data was strangely disappointing in the upfront setting – only 2 months improvement in survival when added to DTIC.

On the Sarcoma front, the catch-all nature of the study came back to haunt Merck with an improvement in PFS but no overall survival benefit for ridaforolimus as maintenance therapy after 1-3 cycles of chemotherapy. That filing will likely result in a highly charged ODAC meeting debating the merits of some awkward results.

Ovarian cancer data was a mixed bag – olaparib continues to look promising in this setting, although the Avastin OCEANS data caught a few people by surprise – yet another PFS endpoint met but no overall benefit in survival and the expected incidence in bowel perforations. I think this will likely be reserved for high risk women, if used.

There was a lot of interesting/promising data in phase II, which are too numerous to mention right now – check back as I will be adding some notes on some of the emerging compounds that I liked.

Meanwhile, I’m aggregating the tweets from the hematology meeting using the #EHA11 hashtag – you can track them in the widget below if interested in following along remotely. Most of the tweets from me will likely be on leukemias, lymphomas and multiple myeloma.

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BMS and Roche join forces in metastatic melanoma

By 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.

How vemurafenib works in BRAF V600E metastatic melanoma

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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What's hot at ASCO 2011?

By on May 31, 2011

This weekend I’m heading off to Chicago for the annual meeting of the American Society of Clinical Oncology (ASCO).  I’ll be writing some in depth pieces and daily highlights from the conference, but in the meantime, many of you will be wondering what might be interesting amongst the 5,000 or so abstracts.

Here’s a quick snapshot of some data I’m looking forward to catching up on – there’s no clapperboard or guy with a teleprompter behind the camera, just a few ideas and some things to watch out for:

http://youtu.be/TNwQvV4aYl8

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Six feet under – snowpocalypse 2010

By on December 27, 2010

Maybe two feet under snow really, judging by my back yard, which is largely sheltered and not prone to drifts. It looks like a pristine Winter Wonderland.

For once, the weathermen were right when they said a blizzard was coming.  Twitter and Foursquare are abuzz with people signing in or tweeting about #snowpocalypse2010, #snomageddon or #snomg in jest, but really it’s just a lot of noise about the first snowfall of the season.

The result out front on the street is a big mess though, as the howling wind, drifting snow and snow ploughs have created huge 6ft ridges behind which are parked cars in igloo like humps.  Glad I parked on the left hand side to avoid that conundrum 😉

Still, there is a good two feet plus on the path and pavement, so shovelling it all will be the highest priority today.

Wherever you all are in the world, stay warm and dry.  I’ll leave you with an old post on the ipilimumab data to contemplate some thoughts, since this will be a hot topic of discussion in January with the FDA ODAC meeting scheduled for the beginning of Feb.

It will also soon be time for the annual year in review for 2010 and predictions for 2011 posts coming up.  What were your big events in cancer this year?  Do let me know if you have any predictions for next year in the comments below.

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Metastatic melanoma – what’s new on the horizon?

By 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:

  1. The responses are not durable as resistance (eg associated with MEK or AKT amplification) sets in.
  2. 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.

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:

ResearchBlogging.org 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 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.

 

ResearchBlogging.org 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 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}

 

ResearchBlogging.org 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 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.

 

ResearchBlogging.org 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

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