Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘Genentech’

Update on RAF resistance in metastatic melanoma

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

Solit and Rosen (2014)

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

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

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

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

to name a few examples.

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

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

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

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

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

Their main assertion is interesting, namely:

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

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

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

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

They went to note:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References:

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

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

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

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

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

Making a difference in NHL and CLL: an interview with Dr Carol Gallagher

For as long as anyone can remember, humanity has wondered, “Why do we do things even when we know we should not?”

James Shelley, Caesura Letters

Akrasia is a rather common affliction in Pharma and Biotech.  After all, why do so many companies fall into the deathly trap of running generic catch-all studies in heterogeneous cancers without an oncogenic target or validated biomarker? Or even specific, well defined subsets to improve the homogeneity ratio?  Or perhaps they knowingly underpower a randomized trial for overall survival?

The list goes on…

Later, senior executives predictably scratch their heads bemusedly when the results come in — and they’re not what they hoped for, or were expecting. No one stopped to ask the obvious question – how can you hit a target you don’t have?

A head-desk kind of moment to be sure.

Hope is not a viable strategy in this business. It’s simply too expensive to shackle the odds against you in the face of intelligent analysis or solid evidence.

That said, rather than rant about this (again), I wanted to take a look and explore R&D and oncology drug development in a more positive light. There are plenty of succeses that have either made it to market or are very close in phae III development in oncology and hematology. It’s always a pleasure to find enlightened and intelligent souls in this realm, people with clarity of vision and a driving passion to get things done right.

I was really thrilled to meet one such person at the American Society of Hematology (ASH) meeting in New Orleans recently in person.

gallagher_bioDr Carol Gallagher, the former CEO of Calistoga and now VC Partner at Frazier Healthcare was truly a delight to chat with. Many of you will recall the stunning early data for what was then CAL-101 (now idelalisib), a PI3K-delta inhibitor in hematologic malignancies such as B cell lymphomas and leukemias (indolent NHL and CLL). They were the first to demonstrate the proof-of-concept for the target and published early clinical results that got people’s attention.

Rather than describe an interview – it was more like a fireside chat between two people with a similar vision – I wanted to share some of the ideas we discussed in New Orleans. The parallels between our experiences with idelalisib and imatinib were quite striking to me… From the central focus on the science and the patients, to the carefully thought out clinical program development etc… only to end up with a sudden realisation that you’ve both gone through similar experiences, with an identical philsophy; “what you too?!” is both pleasant and unnerving at the same time!

Pharma Strategy Blog: One of the things that I was interested to learn is what is your general philosophy with R&D? Strategically, what are you trying to accomplish?

Dr. Gallagher: I think we are at a moment in time that I feel fortunate to be part of where the last 20 to 30 years, we’ve had a much better molecular understanding of what drives the cancer cell. What I’m particularly fascinated with is I think we’re getting even more of an understanding of how that cancer cell is interacting with its environment and the immune system and, of course, as evidenced by PD-1 and the PD-L1, it’s fascinating to now think about that interaction. This has given us a lot of opportunities to think about specific molecular targets that could be drugable, and that could be either a small molecule or antibody, depending on, of course, where the target is, and how we’re thinking about drugging it. That (concept) has changed everything, because we can be more specific in our targeting versus giving people poison.

I think that it’s certainly an efficacy story, but it’s actually a quality of life story. I don’t mean by that registrationable endpoint of quality of life, but I do mean it in the sense of when you’re diagnosed with cancer, don’t you want to try to find a way to manage that disease, but in a way where you could still see your grandchildren or make your daughter’s high school graduation? Certainly, chemotherapy agents have been quite effective. In breast cancer, where it’s a very chemo-responsive disease, it’s hard to imagine that it’s completely going away, but can we find opportunities to give patients therapies that might be more consistent with a good life experience as well as treating their disease?

I was fortunate, for a brief amount of time in my career at Agouron to actually work in the HIV space in those early days of HIV treatment and the protease inhibitors. That was what enabled new products to come very quickly and take over space was that the opportunity to improve the adverse event profile was significant, even though, of course, just even getting the disease treated initially was a major step, but then we were able to actually rapidly, through the industry, improve upon the overall experience for those patients. I think we’re still trying to do that because when you’re living with the disease in a more chronic way, you want to be able to have better therapies.

I have to say the important thing is to focus in on each cancer type because they are all different. I think that the Gleevec example was something we majorly needed for those patients. Now, actually, interestingly, we’re having to manage that, wow, they’re actually living long enough of a time to now have mutations emerge where before, we were just focused on giving them some additional time, and so it’s really great that we’re transitioning.

I saw that too. I worked on Rituxan for a few years at Idec managing that relationship with Genentech, and this was in the early 2000s. What I started to appreciate – that I think has played out in CLL and indolent NHL – is these patients actually do live a fairly long time from the time of diagnosis. It really does matter how much the adverse event profile plays into your life, which is why lots of people would end up choosing single agent Rituxan even though we knew that Rituxan plus chemo would give you more efficacy, but they were choosing no chemo for the quality of life types of aspects of it; again, not meant as a registration endpoint but more of just how you feel every day.

I think that’s where today in R&D, we have to think about the targets but also the patient and their specific disease, and how do we give them true clinical benefit, which is not just efficacy, it’s how do we make their life experience with this disease hopefully better or not so interrupted by having cancer?

Pharma Strategy Blog: I learned that a lot from the Gleevec patients who had advanced. Some of them had six months, if that; maybe some of them had a year. I would go to visit the investigators, and sit in the clinic, and talk to the patients first, and see the PIs at the end. One didn’t want to see them in the middle and get preferential treatment over the patients, but it was a wonderful experience to talk to them, to learn about what is it really like to live with CML or whatever.

Some of them would open up—one lady, she told me she had already booked her funeral! I didn’t know what to say to that and she said, “I want to live long enough to make my daughter’s wedding.” It was six months hence. I found out afterwards from the doctor, “If she gets in the trial, she might live six months. It will be touch and go.” She’s still alive today, and that was 2000, probably 1999/2000, and you start to think about that. Wow, she’s living ten, 11, 12 years for a disease that previously, you had maybe, at the outset, a year.

The other side of this, you don’t necessarily think about at the time, is exactly what you’re saying, is if you turn an acute disease into a chronic one, they have to live with those side effects. We all know the TKIs and antibodies, if you take them for a long period of time, you’re going to have side effects. Some of that aspect of it, and you can see it in CLL with the FCR vs FC or BR in the German trials, where they can argue as long as they like that one is better than the other. But when you look at the side effects and how long patients are getting the side effects, often months afterwards, you can see why patients would choose to take single agent rituximab and feel okay. They might feel a little tired, but they’re not going to get horrible side effects, and I think that’s one of the things that we’re seeing more of in CLL. You can almost imagine with the new CLL11 study that many of these patients with co-morbidities will choose obinutuzunab alone over the combination with chlorambucil, irrespective of the label.

This morning, I went to the ASH press briefing and they had – I still think of it as CAL-101 – they had the idelalisib data, and it looked pretty impressive, but the side effect profile was also, I thought, quite impressive. Patients weren’t having a lot of the dreaded GI effects like nausea, vomiting, diarrhea etc, you could imagine that they’re not distressed and chained to the bathroom. It’s a huge difference.

Dr. Gallagher: Particularly, with that being a patient population where the average age at diagnosis is, I think, 75, and so we’re not talking about a 40-year-old person. We’re talking about a person who likely has other co-morbidities that are challenging for their daily life and to be able to do that.

It was interesting, when we first started thinking about that combination, having worked on Rituxan, I was interested to think about would there be—could idelalisib have enough activity in CLL to be close to a combination that would be R-chemo? That was really our hope, in the sense that then people would have an option—at least earlier in the progression of their disease—that might not be so toxic or causing just daily living skills to not be as easy to do. Is that an opportunity that we actually could see? Of course, the nature of the leukocytosis that is caused where we’re pushing those cells into the blood, we saw early on in the combination work, exploratory work that we did that when you put that with Rituxan, it just cleared everything rapidly. Of course, Rituxan is known that it doesn’t work that well in the lymph nodes in CLL. It is a more peripheral active drug, so it just seemed like an interesting combination to put together.

I have to say my own personal hope was this idea that maybe we could give people a pretty still efficacious option that would then say, “Well, maybe we could wait to do the more toxic things like FCR or even BR.” Bendamustine has its own set of challenges, given that these patients do unfortunately relapse over and over, that could we give them an option? I have to say I was thrilled that the outcome of that trial does actually have a survival benefit even. That makes me believe that we really are going to change the opportunity for those patients to have effective therapy that also allows them to hopefully have a little bit more normal life, not that there aren’t adverse events with these drugs, there certainly are, but I think in comparison, they’re manageable.

Pharma Strategy Blog: I think that one thing that comes down to this meeting, talking to thought leaders and also community oncologists in the poster session, sometimes, we forget that the academic physicians see a lot of younger, fitter, healthier patients because they’ll probably be a little bit more aggressive and educated. They want to live longer, and they’re looking for trials; whereas, in the community setting, they are the 75, 80-year-old patients that you’re talking about.

I’ve heard it so many times from these docs that, “I need something better for my patients. I can’t give them FCR or whatever, they just can’t tolerate it.” Some of them can’t even tolerate bendamustine. They care about their 75 to 80 year old patients, “It’s a big deal, Sally.” We talk about indolent disease, but for them, it’s a different goal of therapy. I do think one of the things that you really start to realize at this meeting is how a whole series of different combinations could evolve, not just idelalisib/Rituxan, but other things in combination.

Dr. Gallagher: Ibrutinib, I think we have a number of very exciting drugs, and I couldn’t be happier that we’ve really started to make some progress, and it is molecularly oriented. It’s really saying these are interesting targets around the B-cell receptor; the AbbVie compound is also very interesting. I feel so excited to be part of what I see is a new era of the dreams that we had over the last ten years are coming to fruition.

Again, it’s not perfect, and we have to keep continuing to strive to do better, but I do hope that these different agents will now offer physicians a whole new tool kit that will let chemo or FC go later into the process, if at all. As you say, 75 to 80, or 75 to 84, there may be other issues that then cause those patients to expire, but in the meantime, they get to their granddaughter’s wedding or things that are real to people.

I have to say, as I have lost my father and have an aging mother, you start to appreciate, I think—and I’m sure physicians, of course, see that with their patients every day—but to appreciate that there are balances of it’s not always just about life extension at any cost because if you’re sick in the hospital with neutropenia (laughter), that’s not actually a very good experience while your family is at home celebrating the holidays.

Pharma Strategy Blog: One of the things a Community oncologist was saying to me yesterday during a session lull was rather interesting. He turned to me and said, “We get obsessed with complete responses and remission!” Then he went on, “I’m thinking about not just the elderly patient, but younger patients. If they get these PRs, and they’re sustained, and they’re durable, and the overall responses are good, and the progression-free survival is good, does it really matter if we don’t achieve a CR?” Now we don’t know the answer yet, but I thought that was a very good question and how the durability plays out will be interesting.

Dr. Gallagher: It’s funny because Langdon Miller, who came and joined us at Calistoga, and was at CTEP earlier in his career, and then at Pharmacia Upjohn, and developed a number of cancer drugs, that was something he talked a lot about when he first came to work with us; that he really thought durable PRs and particularly in these CLL and NHL where to talk about true cure as in most cancers. To talk about true cure, where it’s going away and it’s gone forever, is a difficult thing to achieve. If you’re getting a very durable response where people can live, basically, a fairly normal life for quite a long time, isn’t that like a CR? CRs aren’t always—unfortunately, these patients do relapse, and so it’s not as if we’re talking about a true cure when even we describe CRs in these types of leukemias and lymphomas.

Pharma Strategy Blog: Even if these patients have two to three years on either a single agent or a doublet, and they have a better of quality of life than if they’d had the side effects of FCR, they can still go on to another one with so many choices that we have now.

Dr. Gallagher: Yep, exactly, exactly.

Pharma Strategy Blog: It was interesting that another oncologist in the audience turned to the doc and I and joined in; he chimed in, “Well, you know, I give FCR first line. I give BR second line, and the third line, hmm I put them on a trial for something, or they have pentostatin or whatever they haven’t had.”  He felt strongly at the end of it all though, they were really wiped out, and the patients were like, “I don’t think I can take anymore, I’ve had enough. I’d like something just to keep me happy, like a happy pill.”  He observed, rather astutely, “We need to think about this differently.”

For the Community oncologists, this is a really critical juncture now. With all these new drugs coming along, in the next probably 12 months, where they have several of new ones available and others coming along in trials, I think it will change the way we monitor these patients and how we look at the disease.

You look at the hematology extremes and you have myeloma at one end, where you have the almost nihilistic Total Therapy, and stem cell transplants and the like, yet 20% of them died from the procedure!  Okay, you might have X percent got a cure, but what’s the quality of life after that? Thankfully, in NHL and CLL at the other extreme, we’re moving into an era where there’ll be so many options to hopefully avoid drastic side effects, and it will be really interesting to see where it goes.

Dr. Gallagher: Yeah, I totally agree. I have to say, again, back to my experience of working on Rituxan, is because right before that, as I was talking about it, I was working at Agouron, which became Parke-Davis, Pfizer, and we were working a lot more on the targeted EGFR and then on antiangiogenesis agents. I’d been working more in disease settings like non-small cell lung cancer, where you’re just trying to give them a couple of more months of life.

When I moved over into these indolent diseases and started to really think about, wow, this patient has a number of years, let’s think about how their quality of life matters, it was interesting to me that the physicians themselves, again, back to the single agent Rituxan use, they were, or their patients, someone was recognizing this and making this choice, which from my very academic hat of, well, but we know FCR has a better efficacy percentage, at that time, that data hadn’t been developed. We were still working on it but R-CHOP versus R; we know that that is going to give you a higher response rate of the overall patient population. Why would you ever choose R alone and yet, people were choosing that.

It was such an education where, as you were talking about, you talk to patients, listen to the physicians that are in the Community on the ground outside of Academia, because that balance is very important. I do think that’s one of the things in the United States that’s so interesting is the way that we deliver cancer care is predominantly through the Community and the Academics are certainly very important for advancing research initiatives, but we’re very close to the patient in the United States in the way that we deliver that care. I think we have to keep that balance of listening to what they’re telling us and understanding where there may be opportunities to fill an unmet medical need that might not be quite as Academic as a response rate.

Pharma Strategy Blog: It’s a great time to be in CLL and indolent NHL. I think you’ve been very much a part of that, so I’m really delighted to meet you and hear about the context of what you were trying to do in those early days. It’s certainly coming to fruition now, and that’s really exciting.

Dr. Gallagher: I couldn’t be happier, and it was an amazing team that worked on it. I think the Gilead team has done a great job and will continue with that. There’s some of our Calistoga folks that are part of that Gilead team still, but my hat is off to all the people, all the investigators, the patients. It’s such a great community, and we have to all find a way to work together to advance this, so I really appreciate the time.

FDA approves Roche hedgehog inhibitor vismodegib/Erivedge in basal cell carcinoma

By on January 30, 2012

It’s been quite a roller coaster ride for Hedgehog inhibitors of late.

Infinity Pharmaceuticals Last week, brought negative data as Infinity announced that their phase II trial with saridegib (IPI-926) had been stopped for futility in pancreatic cancer.  This trial sought to determine the impact of the hedgehog in combination with gemcitabine over gemcitabine alone in advanced pancreatic cancer.  Unfortunately, the trial was stopped for futility, meaning the control arm was doing better than the treatment arm.

All is not lost for pancreatic patients though, as Roche/Genentech have a phase II trial currently recruiting patients with the triple combination of gemcitabine, nab-paclitaxel and vismodegib.  Previously, we have discussed the impact of Abraxane on removing the stromal layer in pancreatic cancer in animal models using nanotechnology to enable therapy to work and I think this may be a more promising approach in the long run.

In contrast, there was good news this morning as the FDA approved Roche/Genentech’s vismodegib, now known as Erivedge, in advanced basal cell carcinoma (BCC) who are not candidates for surgery or radiation and for patients with metastatic disease.

The original PDUFA date was scheduled for March 8th, so this is an early approval, but one that is not entirely unexpected given the promising results previously presented at medical conferences over the last 12-18 months.

The goal of the trial was to measure overall response rate (ORR).  In final analysis, the results showed that 30% of the metastatic patients experienced a partial response (PR), while 43% of patients with locally advanced disease experienced a complete (CR) or partial response.  These results represent a clear advance for patients with this disease and studies are also ongoing looking at new combinations to overcome resistance and hopefully, extend outcomes further.

For those of you interested in pricing, it looks as though Erivedge will be $7500/month so that would be estimated $75,000 for typical 10-month course of treatment (HT Ruth Coxeter, CNBC).

Links:

FDA Press Release

Genentech Press Release 

 

A new opportunity for vemurafenib in BRAFV600E colon cancer

By on January 26, 2012

There’s been quite a flurry of commercial news on the Pharma front this morning, with Amgen buying Micromet (whose leading product is blinatumumab in ALL) and Celgene announcing their acquisition of Avila Therapeutics who have a Bruton Kinase Inhibitor (BTK) AVL-292 in phase IB development for lymphomas, which was all the rage at the recent American Society of Hematology (ASH) meeting last month.

The big news for me today, though, wasn’t the commercial acquisitions but a gem of a paper relating to science and its significance for future cancer treatment.

One of the unsolved scientific conundrums that arose in my interview with Dr Gordon Mills (MDACC) at the European Multidisciplinary Cancer Congress (EMCC) meeting in Stockholm last September centred around the RAS pathway, and the BRAFV600E mutation, in particular.

Dr Mills astutely noted that while vemurafenib (Zelboraf) has shown activity in patients with advanced melanoma with the BRAFV600E mutation, he raised the important question why did we not see similar activity in mutated colon cancer?  Of course, one obvious conclusion might be that the target isn’t critical to the tumour’s survival… or is it?  The challenge though, is that these patients do particularly poorly, and usually that is a sign that the mutation is actively driving aberrant activity. Therein lies the quandary, leaving many researchers such as Dr Mills puzzled at the discrepancy and asking why?

This week I’ve been doing a series on colorectal cancer and it is quite by coincidence that today we learn more about the science of colon cancer and BRAFV600E mutations since Pralahad et al., (2012) have just published a Letter in Nature explaining that their research actually suggests that resistance mechanisms might be one of the culprits:

“We performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition.”

This finding surprised me because melanoma typically has low levels of EGFR expression, unlike more epithelial cancers:

“We compared EGFR expression in a panel of BRAF(V600E) mutant melanoma, colon cancer and thyroid cancer cells. Melanoma cell lines indeed express low levels of EGFR.

So what actually happens in melanoma?

“Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition.”

Ah, our old friend, feedback loops!  These have an uncanny knack of popping up in advanced cancers, as the cancer attempts to ensure it’s survival and overcome the targeted therapy, causing adaptive resistance to treatment in their wake.

You may be wondering how common is this mutation in colon cancer then? Well, Pralahad et al., (2012) observed:

“Our data suggest that BRAF(V600E) mutant colon cancers (occur in) approximately 8–10% of all colon cancers.

Note: bracketed bold addition mine.

What does this data tell us?

In short, a combination of vemurafenib and an EGFR inhibitor, such as erlotinib, cetuximab or gefitinib, might be a useful clinical approach to try therapeutically in patients with colon cancer harbouring the BRAFV600E mutation.  Of course, Roche/Genentech have both vemurafenib and erlotinib (Tarceva) in their portfolio, so it would be interesting to see whether proof of clinical concept could be established quickly in a phase I clinical trial.  EGFR inhibitors tend to be rather quirky though, and it remains to be seen whether a small molecule (erlotinib, gefitinib, afatinib) or a monoclonal antibody (cetuximab, pantitumumab) would be the ideal partner for vemurafenib in this setting.

While there is much yet to be done in R&D to advance the scientific research, this important finding teaches us that there is hope for this subset with a generally poorer prognosis yet.

I look forward to following the future clinical progress to see if a viable new combination treatment emerges in BRAF V600E mutated colon cancer – watch this space!

References:

ResearchBlogging.orgPrahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R., Bardelli, A., & Bernards, R. (2012). Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR Nature DOI: 10.1038/nature10868

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Roche files vismodegib for basal cell carcinoma with FDA

By on September 12, 2011

Good news this morning as Roche announced that their Hedgehog (Hh) inhibitor licensed from Curis, GDC-0449 (now known as vismodegib), has been submitted to the FDA for the treatment of advanced basal cell carcinoma (BCC) in patients for whom surgery is not appropriate.

The filing is based on phase II data from the ERIVANCE (BCC/SHH4476g) phase II trial that was reported earlier this year at the American Association of Cancer Research (AACR) meeting. The pivotal trial was a single arm study with the design based on discussions with the FDA, since there are no approved therapies for this setting. In other words, these are refractory patients with advanced disease.

For those interested in the previous data and history, the AACR plenary presentation was previously reviewed and discussed here on PSB, as was the phase I vismodegib data and the evolving Hedgehog market segment.

I first came across this compound several years ago at the Rodman And Renshaw conference in 2009, when Curis presented the initial data and concept – very promising even then – although the CEO was a bit clueless on the market size and opportunity in the Q+A at that time, so it’s been an interesting ride to watch.

The submitted data is based on overall response rate (ORR), the primary endpoint of the trial, which is typical with accelerated review filings based on phase II data in patients who have no other treatment options.  Certainly, the interim data presented at AACR by Dr Ervin Epstein showed some truly stunning responses in some patients that caused some gasps in the audience around me.

The final ORR announced by Roche was 43% patients with locally advanced BCC (laBCC) and 30% in patients with metastatic BCC (mBCC).  At the AACR meeting, I don’t recall the PFS being reached at that time, but Roche/Genentech noted in their press release that:

“The median duration of progression-free survival (PFS) by independent review for both metastatic and locally advanced BCC patients was 9.5 months.“

That’s pretty good news for patients, methinks!  The side effect profile was similar to that presented at AACR (ie no new surprises) and characteristic of Hh inhibitors:

“The most common drug-related adverse events were muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhea. Serious adverse events (SAEs) were observed in 26 patients (25 percent).”

The Roche press release also went on to describe the SAEs more more detail:

“Four patients (4 percent) had SAEs that were considered to be related to vismodegib, including one case each of: blocked bile flow from the liver (cholestasis), dehydration with loss of consciousness (syncope), pneumonia accompanied by an inability of the heart to pump enough blood (cardiac failure) and a sudden arterial blockage in the lung (pulmonary embolism).  Fatal events were reported in seven patients (7 percent).”

Overall, with these kind of side effects, the drug is more suitable for advanced patients as tolerability (including dysgeusia) will be an issue for patients diagnosed earlier, so vismodegib is unlikely to replace surgery in the long run. That said, it does represent an advance for patients in whom surgery is no longer an option.

The early data suggested that resistance to vismodegib might become an issue after 6 months in some patients, but other patients clearly did better than that, which is reflected in the updated PFS data of 9.5 months.  No doubt researchers are already working on the understanding the mechanisms of resistance as exemplified by de Sauvage’s group at Genentech see Metcalfe and de Sauvage (2011) and Dijkgraaf et al., (2011) for examples, which will hopefully lead us to new trials with logical combinations in the near future.

Conclusions:

The big question on everyone’s mind is probably will the FDA accept the filing after summarily sending back the T-DM1 submission with a refusal to file letter?

My educated guess is yes, based on the fact that these patients are clearly refractory to surgery, AND no treatment options exist or are currently approved. That’s a rather different situation from advanced breast cancer, where many many treatment options exist and we don’t know how many of the patients in the T-DM1 trial were truly receiving the drug as salvage therapy.

Based on the clear cut data I saw presented at AACR, I’m expecting that the vismodegib filing will be accepted by FDA and receive a fairly rapid approval.  If approved, vismodegib will offer the first proof of concept for the role of Hedgehog and Smoothened inhibition in the treatment of cancer.

References:

ResearchBlogging.orgMetcalfe, C., & de Sauvage, F. (2011). Hedgehog Fights Back: Mechanisms of Acquired Resistance against Smoothened Antagonists Cancer Research, 71 (15), 5057-5061 DOI: 10.1158/0008-5472.CAN-11-0923

Dijkgraaf GJ, Alicke B, Weinmann L, Januario T, West K, Modrusan Z, Burdick D, Goldsmith R, Robarge K, Sutherlin D, Scales SJ, Gould SE, Yauch RL, & de Sauvage FJ (2011). Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer research, 71 (2), 435-44 PMID: 21123452

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ODAC votes unanimously against Genentech and Avastin in metastatic breast cancer

By on June 29, 2011

Finally, we have a result from the public hearing in Washington DC on whether Avastin is a safe and effective drug in first line treatment of metastatic breast cancer after the Oncology Drugs Advisory Committee (ODAC) voted 6-0 against on all three questions (was Avastin effective, safe and should the indication continue to be upheld).

An overwhelming victory for CDER’s case rather than Genentech/Roche’s.

For those of you wondering whether there was any wriggle room for manoeuvre, take a look at the data for yourselves from the original ODAC meeting last year when the FDA reviewed it.  I put together the response rates and survival curves from the RIBBON1 and AVADO trials at the time, based on the publicly available data on the FDA site for all to see.

Essentially, the 5.5 month survival advantage seen in the original trial (E2100) that garnered approval was not confirmed, with the PFS in the follow up trials virtually disappearing.  The systemic side effects of the drug were however, repeated.  It should be noted that none of the three trials showed any improvement in overall survival, so patients sadly did not in fact, live longer on Avastin than with chemotherapy alone.

Like many people, I ardently wish the results were more positive and significantly so – we would at least have better options for women with breast cancer.  Sadly, they are not and the data wasn’t even close.  Had the two additional trials showed a 5 month benefit per the original E2100 trial that was used to support the initial approval, then I don’t think we would have seen the FDA move to suggest withdrawal of Avastin in December.  In fact, it would have been a clear slam dunk the other way.

It’s easy to say that some women benefited (they clearly did) and that some were harmed by the toxicities or did worse (that is equally clear), but as Francis Collins of the NIH recently said, “anecdote is not the plural of data.”

In the absence of any biomarker to help predict response or suggest who is most likely to benefit from treatment with Avastin, we are left with the totality of the aggregated data. This showed no overall benefit from the addition of Avastin to chemotherapy, even though we may sense that there must be something there to indicate who are the responders from the shape of the curve.  Indeed, after two years, the chemotherapy arm actually did better overall in the AVADO trial, as the arms crossed over.

Dr Len

If anyone wants to read the live public Twitter commentary, I highly suggest you check out Dr Len Lichtenfeld’s (American Cancer Society) tweets from the public hearing – a modicum of thoughtful sensitivity and accuracy in his reporting and colour commentary. He also writes a blog that is well worth reading.  Well done, Dr Len!

Finally, rather than suggest yet another confirmatory trial in metastatic breast cancer at the hearing today, I only wish Genentech had made this offer to the FDA last year when there was more flexibility – a public hearing at your request is hardly the best time for negotiation, but rather a review of the existing evidence.

It isn’t often I agree with the FDA 100%, but in the final analysis they called it correctly on this one.  It’s not over yet though, as FDA Commissioner Margaret Hamburg is expected to make the final decision soon.

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Crossing the blood brain barrier with drug development

By on May 26, 2011

The beauty of social media is that sometimes someone shares something monumental before you even pick it up yourself in a journal you’re subscribed to. I love that – it’s a great way to see how others find things with what I call ‘interestingness’.  This morning, John Carroll of Fierce Biotech tweeted something that gave me goosebumps.

What was hot this morning you may all be wondering?

Crossing the blood-brain barrier (BBB)?

Wow, now that is something that really grabs my attention!  Normally, when you try to target drugs to the brain, you find that the endothelium acts as an impenetrable and largely impervious layer that forces you to keep adding more and more drug in an effort to get a small amount through.  This approach obviously increases side effects and the reality is so little drug actually gets through that efficacy is severely limited.

It also explains why we haven’t made much progress with brain related diseases such as Alzheimer’s, Parkinson’s and Glioblastoma (a malignant brain cancer).

We’ve talked a bit about nanotechnology on this blog and it’s companion, Biotech Strategy Blog, as a way to make things small enough to potentially cross the BBB, but I was keen to see what this was all about.  Enthusiastically, I checked out the original article in Science and Translational Medicine myself (see references below).  The editorial commentary associated with it began:

“As impenetrable as the walls of ancient Troy, the tight endothelial cell layer of the blood-brain barrier (BBB) allows only a few select molecules to enter the brain. Unfortunately, this highly effective fortress blocks passage of therapeutic antibodies, limiting their usefulness for treating diseases of the brain and central nervous system.”

Oof, a tad dramatic perhaps, but what did the Genentech scientists do that was different?

Well, the research team were looking at using a BACE-1 antibody to block the enzyme involved in amyloid production, but the BBB prevented little drug from getting through, despite higher doses.

The engineers then developed a new antibody to take advantage of the fact that cells need iron by creating an antibody with two arms:

  • One arm held anti-BACE1 drug
  • The other arm hosted a receptor called transferrin that carries iron to brain cells, providing a ferry across the barrier

In other words, they made use of the body’s natural transport system in much the same way the Trojan horse carried men.  Perhaps the analogy wasn’t so dramatic after all…

This novel approach allowed the scientists to use lower concentrations of the new drug to get the active therapy through.  This should limit side effects and hopefully, increase efficacy.  According to the authors:

“BACE1 can be targeted in a highly selective manner through passive immunization with anti-BACE1, providing a potential approach for treating Alzheimer’s disease. Nevertheless, therapeutic success with anti-BACE1 will depend on improving antibody uptake into the brain.”

Note my emphasis… I can just see the anti-immunisation crowd up in arms before we even get started on this.

Implications of this research

The obvious potential benefits from this novel approach are in Alzheimer’s Disease research, although I caution that we still need to see results from human trials.

However, what piques my interest is how the technological approach of the iron receptor could be used for other brain diseases such as Parkinson’s Disease and brain tumours such as glioblastoma (GBM), which is a nasty malignant cancer limited by how much drug we can get inside the tumour cells. It crossed my mind that it might not take long for Genentech scientists and engineers to use the iron transport concept to bolt together a new monoclonal antibody combining the transferrin receptor and bevacizumab (Avastin), which is already approved as a treatment for GBM. Who knows how that might pan out, but the idea is very appealing indeed.

It is the development and spreading of novel and creative ideas like these that really excites me as a scientist and reminds me what I loved about it as kid.

Crazy Deranged Fools

This idea is so creative, so simple, so brilliant that I’m giving the Genentech scientists my Crazy Deranged Fool (CDF) award of the month for having the temerity to try something so boldly different – check out Hugh’s cartoon at Gaping Void to find out what that is!

References:

ResearchBlogging.orgAtwal, J., Chen, Y., Chiu, C., Mortensen, D., Meilandt, W., Liu, Y., Heise, C., Hoyte, K., Luk, W., Lu, Y., Peng, K., Wu, P., Rouge, L., Zhang, Y., Lazarus, R., Scearce-Levie, K., Wang, W., Wu, Y., Tessier-Lavigne, M., & Watts, R. (2011). A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-  Production in Vivo Science Translational Medicine, 3 (84), 84-84 DOI: 10.1126/scitranslmed.3002254

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Antibody Drug Conjugates (ADCs) in cancer research: what are they?

By on May 25, 2011

Quite a few questions have hit my inbox recently from people wanting to know more about Antibody Drug Conjugates (ADCs) and how they work.

They basically consist of three things:

  1. Monoclonal antibody
  2. Linker
  3. Cytotoxic agent

Antibody Drug Conjugate (ADC)

Source: Roche

The goal is to create a new molecule that essentially is greater than the sum of its parts by making it more targeted, like a guided missile against the cancer cells.

With normal monoclonal antibodies, they bind to atarget antigen that is a tumor-specific antigen on the surface of a tumour cell. With an ADC, the monoclonal antibody part of the molecule still latches onto the target antigen in the same way, but in this case it now has a powerful cytotoxic attached to potentiate the effect.

As Emeril would say, “Bam!”

You can see a video of how the ADC technology works HERE.

Unfortunately, the site only allows you to watch it there or download the video; it’s not easily sharable with others, short of emailing it.  Sadly, I couldn’t embed it here on the blog post for easy consumption either.

A nicer way would have been to put the educational videos on a company YouTube channel and allow it to be shared through social media via Facebook, Twitter etc. Imagine clicking on a link in Twitter and being taken to YouTube on your iPad, iPhone or Android smartphone?  Or watching an embedded video on someone’s blog post?

That’s a much more fun and immediate way to communicate ideas and technology from a medical or scientific learning perspective than a old fashioned static website.

It is good to see Pharma and Biotech companies active on social media, but they have a long way to go yet in terms of how they can help improve learning about the science behind new cancer research and development in an integrated way that helps the end users, ie the scientists, healthcare professionals, patients in clinical trials and analysts who might be interested.

We really do need to get away from the old web 1.0 world into the 21st century of sharing ideas, tools and medical or scientific information using social media in the web 2.0 era.

That said, there are some advanced ADC’s in clinical development at the moment.  The three leading compounds I’ve come across so far are:

  • Brentuximab vedotin (Seattle Genetics) in Hodgkin Lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL) targets CD30 and now has a brand name, Adcetris.
  • T-DM1 (Roche/Genentech) in HER2+ breast cancer
  • SGN-75 (Seattle Genetics) in RCC and NHL

Overall though, Roche/Genentech probably have the largest active research in this area, with a large portfolio of agents in development across a multitude of different tumour types.  You can check out this full ADC pipeline here.

Seattle Genetics have a couple of abstracts on their ADCs at ASCO this year and Roche have an abstract on the phase III EMILIA trial comparing T-DM1 with lapatinib plus capecitabine in metastatic breast cancer, all on Monday 6th that I hope to check out, that is if the sessions don’t clash!

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Roche files vemurafenib for metastatic melanoma in Europe and US

By on May 12, 2011

Yesterday, Roche/Genentech announced that they have submitted the New Drug Application (NDA) filing for PLX4032 (vemurafenib) in BRAF V600E mutation-positive metastatic melanoma, based on BRIM2 and BRIM3 trials to both the FDA and EMA.

I’ve posted quite a bit on BRAF inhibitors such as vemurafenib on this blog – check out the related posts feature at the bottom if you want to learn more about the history of this class of drugs.

Interestingly, Roche have also submitted the companion diagnostic, cobas 4800 BRAF V600 Mutation Test, which means that oncologists in the community will be able to more easily test patients for the mutation, since these patients are more likely to respond to therapy with BRAF inhibitors such as vemurafenib.

Source: wikipedia

Although melanoma is treatable in the early stages, unfortunately once it becomes metastatic, it becomes more difficult to contain.

Roche have conducted two large-scale clinical trials (BRIM3 and BRIM2) to evaluate the safety and effectiveness of vemurafenib in mestatatic melanoma patients who have the V600E mutation. According to the Company:

“BRIM3 is a global, randomised, open-label, controlled, multicentre, Phase III study that compared vemurafenib to dacarbazine chemotherapy, a current standard of care, in 675 patients with previously untreated BRAF V600 mutation-positive, unresected or locally advanced metastatic melanoma.

The study met its two co-primary endpoints and showed that participants who received vemurafenib lived longer (overall survival) and also lived longer without their disease getting worse (progression-free survival) compared to those who received dacarbazine chemotherapy.

The safety profile was consistent with previous vemurafenib studies.”

The BRIM2 study also formed part of the global filing:

“BRIM2 is a global, single-arm, multicentre, open-label Phase II study that enrolled 132 patients with previously treated BRAF V600 mutation-positive metastatic melanoma. The primary endpoint of the study was overall response rate as assessed by an independent review committee.

The study showed that vemurafenib shrank tumours in 52 percent of trial participants. People who participated in the trial lived a median of 6.2 months without their disease getting worse (median PFS).”

Like many of us, I’ve known family and friends or friends of friends who have been lost to this devastating disease.  Six months doesn’t sound very long, but when you look at many of the oncologic filings over the last decade, very few have actually shown six months improvement in overall survival.  In that context, this represents a dramatic advance for patients.

Of course, we can still do better, and as we learn more about the biology of the disease, so we can develop smarter therapeutic strategies for overcoming malignant melanoma.  This could take the form of new combinations or other BRAF inhibitors that do not target CRAF as well as BRAF, for example:

“The most frequent Grade 3 adverse event observed in clinical trials of vemurafenib was cutaneous squamous cell carcinoma, a common skin cancer treated by local excision (minor surgery done in a physician’s office).

The most common adverse events were rash, photosensitivity, joint pain, hair loss and fatigue.”

It has been shown that activating CRAF, for example, is most likely responsible for the squamous cell proliferation on the skin in some patients.  It appears to be reversible once treatment is stopped.  However, that said, this is still a huge advance and should be applauded as such.

More BRAF and RAF inhibitors are on the way

BRAF inhibitors

Interestingly, Bayer also announced yesterday that their multi-kinase RAF/VEGF/Tie2/RET/KIT inhibitor, regorafenib, was granted Fast Track designation by the FDA for the treatment of patients with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite at least imatinib and sunitinib as prior treatments.  This is an incredibly small population so I don’t expect the trial to accrue speedily.  GIST is largely KIT or PDGF rather than RAF driven.  The trial began enrolling in January this year and accrual is still open – in all, Bayer plan to enroll 170 patients.

I will be interested to see whether regorafenib also activates CRAF as well as RAF – if so, we can expect some squamous cell proliferation in the adverse events – while multi-kinase inhibitors can be effective, we also have seen some off-kinase side effects, as shown with sorafenib and sunitinib.

What does this data mean?

The vemurafenib filing is excellent news for patients based on the data and pictures I have seen of responses in various conference presentations to date.  It’s a great success story of finding an aberrant mutation, developing a diagnostic to enable widespread testing for it and matching the patient to the treatment.

What I also like is the fervour with which the melanoma scientist-physician community is researching the methods of resistance and looking at new combinations with BRAF inhibitors almost as soon as they detect them – a great showcase for what to do.

We can also expect update on the BRIM2 and 3 trials at the forthcoming annual meeting at ASCO next month – I can’t wait to see how the data is maturing!

Assuming that vemurafenib is approved, it will also be interesting to see what happens post-approval, since Daiichi Sankyo bought Plexikkon, complicating the potential marketing and sales roll-out considerably.  One can wonder at the old adage that two’s company, but three becomes a crowd to manage.

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FDA moves to withdraw Avastin in breast cancer

By on December 16, 2010

Well, the long awaited decision by the FDA on bevacizumab (Avastin) in breast cancer has finally been published and is probably the least surprising decision by the agency in 2010:

“The Office of New Drugs (OND) recommends withdrawing approval of the breast cancer indication for bevacizumab (Avastin).  This indication was approved on February 22, 2008, under accelerated approval provisions for use in combination with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.

As a condition of the accelerated approval, Genentech was required to submit data from two ongoing trials (AVADO and RIBBON1) to provide verification of the treatment effect on progression free survival (PFS) and to provide additional information on the effects on overall survival (OS).  These two trials failed to confirm the magnitude of benefit originally observed in the E2100 study on which accelerated approval was based.  In addition, there was an overall increase in serious adverse events related to bevacizumab.

The modest benefit observed with Avastin together with the substantial adverse reactions observed in breast cancer trials to date fail to provide a favorable risk-benefit profile to support continued marketing of Avastin for a first-line metastatic breast cancer indication.  It is the conclusion of OND that the breast cancer indication for Avastin be withdrawn.”

Source: FDA

This is not a surprising decision following the recent ODAC vote of 12-1 to withdraw the drug for the treatment of breast cancer based on the AVADO and RIBBON1 trial results, which was discussed in detail previously on this blog.  The overall survival data actually showed a slight benefit in favour of the chemotherapy (docetaxel) only arm in AVADO, for example, (31.9 vs. 30.2 months).

Also of interest to many is the more results from the neoadjuvant trial with bevacizumab prior to surgery.   Negative trial results were announced at the San Antonio Breast Cancer Symposium last week, essentially adding another nail in the coffin for a solid rationale for earlier use in breast cancer.

For now, the drug will remain on the market and available in this indication, but the clear intent by the FDA is that they plan on withdrawal following the lack of confirmation for full approval.  The company, Roche/Genentech, have 15 days to request a hearing and judging by the press releases so far, this will be sought.  No doubt significant patient advocacy will also be mobilised in support.

There is no question that some women with breast cancer have benefitted from treatment with bevacizumab, but without a biomarker to determine who is most likely to respond to the therapy, it is difficult to see how it can remain on the market given three overwhelming negative trials demonstrating little overall benefit and some not insignificant risk of systemic side effects.

For me, though, what this body of data consistently shows is that, combined with the negative bevacizumab in adjuvant colorectal cancer, VEGF plays a much clearer role in metastatic disease such as colorectal cancer where the tumours are more vascular and often larger.  In breast cancer, the tumours are typically much smaller by comparison.  It may well be that we learn more about the process of angiogenesis from negative data and how tumours grow.  Angiogenesis is a highly complex process and we still need to learn how other growth factors such as PDGF, angiopoeitins, Tie-2 etc, may play a role in tumour growth.  This has yet to be elucidated but research is ongoing.  The recent post discussing cancer cell seeding teaches us that we have much to learn about the whole process of angiogenesis from early growth to metastasis.  VEGF is clearly not the only target involved.

Meanwhile, this developing story will clearly continue to unfold in 2011.  The New York Times has a different angle on this story, so check it out for yourselves.

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