malignant melanoma | Pharma Strategy Blog

#ESMO 2010 round-up #3

By MaverickNY on October 14, 2010

Back from Milan and ESMO 2010, I thought it would be a good idea to quick a final quick overview of some of the early data from phase II trials that look interesting and might be worth watching as the research evolves (in no particular order).

1. Addition of cetuximab to cisplatin increased survival in triple negative breast cancer

Jose Baselga presented the results of a multi-centre randomised trial (from Spain, Belgium, Austria, Portugal, the UK and Israel) that compared the combination of cetuximab (Erbitux) with cisplatin versus cisplatin alone in 173 women with triple negative breast cancer (TNBC).

Although the overall response rate (ORR) trended in favour of the combination (20.0 vs 10.3%), the result did not meet the pre-specified assumptions. Interestingly though, the progression-free survival (PFS) showed a significant improvement with the addition of cetuximab (3.7 vs 1.5 months, P<0.03). Two months doesn't seem much, but in an advanced, highly aggressive disease, it may represent a disproportionally large improvement.

I'm not sure why cisplatin was chosen as a comparator, especially as TNBC is a particularly hard subset to treat, but the trial is ongoing to determine overall survival and a phase III study will likely evolve to determine if the results are repeatable in a larger population.

2. GSK2118436 in advanced melanoma with brain mets looks promising in a phase I/II study

By promising, I mean this was a very small cohort of patients who saw some early and unexpected evidence of tumour shrinkage in brain mets that had evolved from primary melanoma. The scans shown by the presenter, Georgina Long, from the Melanoma Institute Australia and Westmead Hospital in Sydney actually gave me goosebumps and it wasn't the chill in the room. You just don't expect to see such noticeable shrinkage with a single agent in this setting because this is a horrid, aggressive disease that has a nasty tendency to metastasize easily.

What was interesting about this study is that GSK2118436 is a BRAF inhibitor that also specifically targets V600E, similarly to Plexxikon/Roche's PLX4032. In both cases, they bind to the protein and shut down signaling activity. Although the trial is very early, since it looked at 3 different cohorts, the small subset with brain mets (n=10) were what caught everyone in the audience's attention, although good responses were also seen in the advanced melanoma group without brain mets.

To put the results in context, all 10 patients experienced some control of their brain mets, with 9 of the 10 patients having reductions in the overall size of their tumours. The overall reductions ranged from 20-100% of brain metastases that were 3mm or larger in diameter before treatment.

That just doesn't happen with advanced melanoma with brain mets… at least, I've never seen such dramatic responses before.

The big questions for me are how long will the responses be durable before resistance sets in and how soon is a larger scale trial going to get up and running? This is a very promising and most unexpected development that is worth following.

Dr Long summed it up very nicely:

“The ability to inhibit oncogenic BRAF is the most important development in the history of drug treatment of melanoma.”

3. ARQ-197 continues to show positive results in NSCLC

In this presentation, the final results of the phase II trial in non-small cell lung cancer (NSCLC) were discussed. We've covered this promising agent, ARQ-197 (ArQule/Daiichi Sankyo), a small molecule c-MET inhibitor, before on this blog.

A final analysis looked at the complete results in more depth. Patients treated with ARQ 197 plus erlotinib (Tarceva) developed new metastases in a median time of 7.3 months compared with 3.6 months for patients treated with erlotinib plus placebo.

What I found interesting in this study was that this effect was more pronounced among patients with non-squamous (NS) histology, since the median time to develop new metastases was 11.0 months in the ARQ 197 plus erlotinib arm compared to 3.6 months for those treated with the control arm (erlotinib plus placebo). I'm not sure why the NS over squamous histology should matter, but they clearly benefitted more.

The sponsors, ArQule and Daiichi Sankyo, have announced that they plan to pursue a phase III trial in this setting. It would, however, be nice to see an analysis of any lung biopsies collected to see if there are any relevant biomarkers that would explain the differences in histology and responders, otherwise many physicians may see this as an incremental improvement, if confirmed in a larger trial. Were thre any differences in people who were EGFR mutation or MET positive, for example?

There was certainly some energetic discussion in the Q&A, with tough questions asked of the speaker regarding why go ahead with a phase III study given a small benefit and why use OS when PFS is small and complicated by crossover, all very fair questions. Like many, I'd really like to see more granular analysis of who is responding to this agent and why before rushing into a phase III trial that may see a disappearing of any positive signal when investigator bias is eliminated in a larger randomised trial.

4. METMAB showed promising results in a subset of lung cancer patients

In the same session, David Spiegel presented the data from a phase II study with a different c-MET inhibitor. Here, patients with advanced NSCLC (n=128) were randomly assigned to receive either erlotinib plus METMAb (Roche/Genentech), a monoclonal antibody that binds specifically to the MET receptor on cancer cells or a control arm (erlotinib plus placebo).

The reason for the interest in c-MET inhibitors is that MET activation has been implicated in the resistance of lung cancers to EGFR inhibitors such as erlotinib. The big question is therefore whether a combination of the two would overcome resistance or not, thereby prolonging life.

In this study, participants were tested for mutations in the EGFR gene and also for expression of MET in tumour samples.

The results were interesting – 51% of patients whose tumours expressed MET and those who received METMAb plus erlotinib had better OS and longer PFS than those who received erlotinib plus placebo.

Furthermore, in the subset of MET+ patients, adding METMAb to erlotinib nearly halved the risk of disease progression or death during the study compared to those treated with erlotinib plus placebo. In addition, patients whose tumours did not express MET protein appeared to do worse when treated with the METMAb/erlotinib combination, suggesting that the biomarker may be able to determine who is more likely to respond to therapy.

This is good news if it is repeatable in a phase III trial and show durable efficacy with good tolerability, because then potentially, oncologists would be able to screen and preselect patients for treatment with METMab rather than expose all patients to the systemic side effects without hope of it working.

Last but not least, there was some updated information on the novel trastuzumab-DM1 (T-DM1) combination therapy (Roche/Genentech).

4. T-DM1 continues to show solid results in metastatic breast cancer

Edith Perez presented the results of a phase II study looking at first line treatment with a new combination agent, trastuzumab-DM1 or T-DM1, in metastatic breast cancer.

As far as I know, T-DM1 is the first of a new type of cancer therapy known as an antibody-drug conjugate. Basically, it binds together two existing cancer drugs with the aim of delivering both drugs specifically to cancer cells, ie trastuzumab (Herceptin), an approved monoclonal antibody that targets the protein HER2 and DM1, a chemotherapy agent that targets microtubules. The goal of the new combination is too see if cardiotoxicity, a common problem associated with standard anthracycline therapy, is reduced and if efficacy is subsequently improved.

Women with breast cancer were randomised to treatment with either trastuzumab plus the chemotherapy drug docetaxel, or T-DM1. All 137 participants had HER2-positive metastatic cancer, with no prior chemotherapy for their metastatic disease.

The good news is that the early results demonstrated that T-DM1 has good anti-tumour activity as well as much lower toxicity when evaluated side by side to standard therapy.

After a median of approx 6 months of follow up, the overall response rate of in women who received T-DM1 was 48% compared with 41% in the control arm (trastuzumab plus docetaxel). The rates of clinically relevant adverse events were also significantly lower in the T-DM1 arm (37%) compared to the rate in women given traztuzumab plus docetaxel (75%).

Overall, I think the slight improvement in ORR was more than compensated by the dramatic improvement in side effects, which ultimately affect a patient's quality of life when undergoing cancer treatment. According to my chicken scratch notes from the session, cardiotoxicity and myelosuppression were both much improved in the T-DM1 arm over standard therapy.

Perez noted that the final analysis of the PFS data is expected in 2Q 2011, which I'm sure will be eagerly awaited based on the encouraging early data, although feeling better is one thing, but ultimately the sine qua non is will the women live longer?

All in all, I'm glad I trekked all the way to Milan for ESMO. There was more positive and promising early data than expected and aside from the repetitive blister walks, it was an enjoyable event. It was also nice to catch up with some friends in person and meet several readers of this blog who kindly came up and introduced themselves – I hope you all enjoyed the conference as much as I did!

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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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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

ASCO 2010 Preview #1

By MaverickNY on May 11, 2010

It's only 3 weeks to go to the Annual ASCO meeting in Chicago so I thought it would be a good time to kick off the annual preview of key data. One of the things that sets the tone of the meeting is which abstracts are in the plenary session. Sometimes I don't attend the session if it looks arcane, but this year looks really interesting and worthwhile attending.

The selected abstracts comprise the following:

#LBA1: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or Fallopian tube cancer (FTC): A Gynecologic Oncology Group study.

#2: Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: IFCT-0501 randomized phase III study in advanced non-small cell lung cancer (NSCLC).

#3: Clinical activity of the oral ALK inhibitor, PF-02341066, in ALK-positive patients with non-small cell lung cancer (NSCLC).

#4: A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma.

Now, three of these trials promise some excitement. The one I'm surprised about is the French Intergroup study looking at a taxane plus platinum in lung cancer. In case anyone is wondering, the trial (link) states that:

"It thus seemed to us justified to compare a standard arm, the vinorelbine or the gemcitabine (with the choice of the center) in monotherapy with an experimental arm, association carboplatine + paclitaxel."

Carboplatin plus paclitaxel (with or without bevacizumab) is pretty much standard as first-line treatment for non-small cell lung cancer (NSCLC), so now we know that the doublet is likely more effective than single agent gemcitabine or navelbine in the elderly too, but for me all four are old drugs, likely available as generics and it's all an iteration of what we mostly know already. I'm particularly interested in new and exciting agents that are coming through or new indications or more recent drugs as we see them expand their utility.

The results are no doubt important, but plenary important? It could
have well led off an oral lung cancer session and received attention at
Best of ASCO perhaps, but for me, the plenary sessions should be
about groundbreaking new therapies or indications, which the other three
clearly are.

Still, the Korean study in ALK-positive people with NSCLC really gets my attention because we've only heard about a US study in the past, so seeing how this evolves Globally is vitally important. Pfizer have done a nice job speeding this agent, PF-02341066 (crizotinib), through development having recognised the significance of the rearrangements and then invested significant resources to moving it forward. They should be commended for that and I sincerely hope the results continue to be positive.

What is also nice is that I've come across a few new ALK inhibitors at AACR and elsewhere that may work in patients where crivotinib stopped working, perhaps as a reult of new mutations. This is an exciting area of research, even if it just affects a small subset of patients. Cancer is a heterogeneous disease so researching and identifying different subtypes that can be then targeted with new therapeutics is critical.

After excitedly listening to the BMS R&D Day, I was expecting that ipilimumab might have a chance of a plenary with the melanoma data because the example they gave just took your breath away – this is what we all live for in cancer research – something that really makes a difference to the disease and makes you go, "oh wow!" You can read more about that commentary here. Roche and Plexxikon also have a promising compound in development (PLX4032) that targets BRAF. At Roche's R&D Day, they noted that they planned to present the phase II data later this year at a melanoma meeting. That's how the timing rolls sometimes.

The bevacizumab (Avastin) data in ovarian cancer was previously announced by Roche earlier this year to be positive, so this is excellent news for women with ovarian cancer. I really look forward to seeing the results in full. What's particularly important about this trial is that it is the first positive phase III study of an anti-angiogenic therapy in advanced ovarian cancer. I think Judah Folkman would be mightily pleased with the progress of angiogenesis inhibitors such as Avastin so far, if he could see them. It's all too easy to forget the visionaries in research and focus on the results.

For some reason, ovarian cancer always seems to be the poor cousin to breast and lung cancers and regimens that work in either tend to dribble down to ovarian cancer years later, but all three share many similar regimens.

From tomorrow, I'll start an ASCO series taking a look at some of the bionic biotechs with interesting data and a review of some of the big cancers and the potentially interesting data that may be worth highlighting and checking out.

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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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Ipilimumab from BMS looks like an interesting new melanoma drug

By MaverickNY on March 5, 2010

It's been a frantic week on the work front and today was no different, but I wanted to highlight a really interesting slide from the BMS pipeline presentation yesterday afternoon.

Here's one of the slides Elliot Sigal, President of R&D, showed from one of the ipilimumab trials. More data may be available at ASCO if the submitted abstract is accepted, but for now, even though it's only an n of 1, a picture tells a thousand words:

Source: BMS

After all the recent good news about malignant melanoma, hopefully at least one of these promising agents will make it to market in the not too distant future, offering people suffering with the condition a glimmer of hope. I sincerely hope the CTLA4 results turn out to be durable.

In the meantime, we can all wonder until June, when the annual ASCO meeting will held.

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Update on malignant melanoma therapies

By MaverickNY on February 23, 2010

After yesterday's post about the NY Times article on Roche/Plexxikon's PLX4032, a few people wrote and asked about other therapies in development for the treatment of malignant melanoma.

Melanoma is the deadliest form of skin cancer and occurs in about 69,000 patients in the United States each year, resulting in approximately 9,000 deaths. Sadly, the number of melanoma cases worldwide is increasing faster than any other cancer.

One of the most promising agents in development is Pfizer's tremelimumab (CP-675,206), a humanised IgG2 monoclonal antibody targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA4), a natural brake on the immune system that has been implicated in melanoma. The basic idea is that tremelimumab inhibits CTLA4, thereby stimulating or enhancing the body's immune response to tumours and fight the cancer.

Tremulimumab has had a bit of a chequered history though. Pfizer discontinued a phase III study of the drug in patients with advanced melanoma after an interim review showed tremelimumab would not be superior to standard chemotherapy.

What's particularly interesting is that last month Pfizer announced another phase III trial of tremelimumab, declaring that analysis of the data from the discontinued study had identified the biomarker that will be used to select patients for the upcoming study completed in conjunction with Debiopharm, although details on what the biomarker actually was were not given.

Meanwhile, earlier this month, a new article appeared in Cancer Clinical Research, describing the data in a phase II study in people with relapsed melanoma, where the drug had already failed to work.

This trial, a single-arm phase II study, showed that 16 of the 241 evaluable patients had partial responses, ranging in duration from 8.9 to 29.8 months. Median time to response was 7.0 months. Eleven of the 16 patients (69%) had ongoing responses at their last assessment.
The clinical benefit rate was 21%, based on 16 partial responses and 35 people with stable disease.

One patient with a response, who had a family history of sudden death, died of an apparent cardiac event 321 days after enrolling in the study. The other 15 responders were alive when the researchers wrote the paper, with survival ranging from 20 to 34 months. Median overall survival for the entire cohort was 10.0 months.

The researchers noted that response rates with single-agent chemotherapy usually range from less than 8% to 15%, with limited durability. Immunotherapy with high-dose interleukin-2 produces similar response rates, with better durability but with more severe toxicities. The results with tremelimumab are therefore very encouraging and having a biomarker associated with it can only help screen out those patients who are more likely to respond to therapy.

Medarex and BMS are developing a similar anti-CTLA4 agent, ipilimumab (MDX-010), in melanoma and prostate cancer. This agent has received more attention in prostate cancer of late, but the phase II data in melanoma was presented at ASCO last year.
The updated survival results from follow-up extensions of three Phase II ipilimumab studies of patients with advanced metastatic melanoma (Stage III or IV) showed that the two-year survival rate ranged from 29.8 to 41.8 percent in patients who received ipilimumab.

Looking at the data in more detail, we can see that the results are based on follow-up of up to 37.5 months (median follow-up ranged from 10.1 to 16.3 months) of the patient population from studies 008, 022 and 007 treated with 10 mg/kg of ipilimumab during induction and maintenance therapy and showed:

Two-year survival rate of 32.8 percent in patients who had progressed while on or after receiving standard treatment (Study 008)
Two-year survival rate of 29.8 percent in patients who were previously treated, relapsed or failed to respond to experimental treatment or were unable to tolerate currently approved therapies (Study 022)
Two-year survival rate of 40.6 percent and 41.8 percent in patients receiving ipilimumab plus budesonide or ipilimumab plus placebo, respectively, which included treatment-naïve patients and patients previously treated with therapy other than ipilimumab (Study 007).

Novartis also have a RAF inhibitor similar to Roche's PLX4032, called RAF265, which is currently in phase I development. It differs in that it also inhibits VEGFR-2, which is associated with angiogenesis. Another TKI in development, TKI258 (formerly CHIR2558), is a fibroblast growth-factor receptor (FGFR) inhibitor, as well as targeting VEGF and PDGFR.

This raises an interesting idea – in some patients, inhibiting several pathways such as RAF, CTLA4 and FGFR or VEGF may be the ultimate answer to prolonging survival, although we don't know if that approach would work yet.

Coordinating studies across several companies, each with drugs not yet approved, is also fraught with difficulties. This is where patient advocacy groups such as the Melanoma Research Foundation and ACOR have most power in conjunction with the physicians to compel Pharma companies to:

a) consider combination trials earlier in collaborative efforts

b) speed up development of new and promising agents

Overall, the results from the anti-CTLA4 antibodies and RAF inhibitors look promising and it will be interesting to see what happens at ASCO this year as well as moving forward in the future.

Kirkwood, J., Lorigan, P., Hersey, P., Hauschild, A., Robert, C., McDermott, D., Marshall, M., Gomez-Navarro, J., Liang, J., & Bulanhagui, C. (2010). Phase II Trial of Tremelimumab (CP-675,206) in Patients with Advanced Refractory or Relapsed Melanoma Clinical Cancer Research, 16 (3), 1042-1048 DOI: 10.1158/1078-0432.CCR-09-2033

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Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘malignant melanoma’

#ESMO 2010 round-up #3

What causes resistance to BRAF inhibition in melanoma?

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

ASCO 2010 Preview #1

Malcolm Gladwell on cancer research

Ipilimumab from BMS looks like an interesting new melanoma drug

Update on malignant melanoma therapies