Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts from the ‘New products’ category

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

Will intermittent dosing transform TKI therapy in cancer research?

By on January 17, 2014

At AACR last year, one of the most revealing presentations was on metastatic melanoma, specifically, some elegant research by Meghna Das Thakur (NIBR) demonstrating that intermittent pulsing of vemurafenib (a BRAF V600E inhibitor) led to less resistance than inhibiting the target 24/7.

Many of us wondered whether such a pulsing approach would be useful for other tyrosine kinase inhibitors (TKIs).

Fast forward to this week.

CD current Jan 2014Neal Rosen’s lab at MSKCC has an interesting new paper out looking at the effects of pulse dosing with PI3K and ERK inhibition, since targeting both has long been suspected to be key in overcoming cross-resistance.

Recall that despite promising preclinical research, most of the early patient trials looking at targeting the PI3K-Akt-mTOR and RAS-RAF-MEK-ERK pathways in combination were, however, disappointing to say the least, both in terms of the side effect profile, and also with respect to clinical efficacy.

These results also applied to combinations with chemotherapy, which were added to either agent to try and induce cell death via apoptosis.

We know that the PI3K pathway is dysregulated in many cancers, so why have the combinations tried to date produced less than optimal results?

Well, Will et al., (2014) showed that:

  1. RAS-ERK pathway is a key downstream effector pathway of oncogenic PI3K
  2. ERK inhibition is required for apoptosis (cell death) to occur with a PI3K inhibitor
  3. It is important to coordinate downregulation of AKT and ERK since both are necessary for induction of apoptosis and antitumor activity
  4. Such an effect can be achieved with intermittent dosing, which will also likely decrease toxicity and allow administration of therapeutic doses

Ah so the same concept that Das explored in metastatic melanoma could also have potential with PI3K and MEK inhibition!

I find this approach fascinating because in the past, when I queried whether we needed to hit two targets maximally and continuously, rather than look at intermittent or minimally effective dosing (MED), industry people were up in arms and sent me more heated emails on this topic than anything else we’ve ever blogged about!

Meanwhile, Rosen himself hinted at this solution in a talk at the AACR Molecular Targets meeting in Boston last year and said a publication was underway to explain their findings. Generally, I don’t report on unpublished findings out of respect to the scientists and thus didn’t mention it in our extensive AACR Targets Coverage, but am delighted this is now a topic for more public discussion.

Part of the conundrum was articulated by Will et al., (2014) in their author manauscript (see below for the link under the Cancer Discovery Online First Section this month):

“Since mTOR and AKT inhibitors reactivate PI3K signaling, we asked whether PI3K inhibitors have more significant antitumor activity, perhaps by inhibiting other PI3K targets in addition to AKT/mTOR.

Selective PI3K and AKT inhibitors were compared in tumors with activation of PI3K pathway signaling in order to assess differences in the biochemical and biologic consequences of their inhibition. Both inhibitors effectively inhibited downstream targets of AKT, relieved feedback inhibition of growth factor receptors, and inhibited cell growth. However, in HER2-dependent breast cancers, PI3K inhibitors, but not AKT inhibitors, caused the rapid induction of a significant degree of apoptosis.

We find that, whereas AKT inhibitors inhibit AKT/mTOR and activate ERK signaling, PI3K inhibitors inhibit both. They cause durable inhibition of AKT signaling but also transient inhibition of RAS activation and ERK signaling, both of which are required for induction of apoptosis. Moreover, induction of apoptosis by an AKT inhibitor is significantly enhanced when combined with a MEK inhibitor.

Our results show that PI3K is upstream of wild type RAS as well as AKT/mTOR, and this causes the therapeutic consequences of PI3K inhibition to be significantly greater than those of AKT inhibition.”

A number of different inhibitors of PI3K, AKT, mTOR and MEK were explored in this research, so the results are not limited to one or two.

One important question that the group sought to address the inhibition issue:

“PI3K inhibitors cause rapid inhibition of ERK in breast cancer cells with HER2 amplification, but P-ERK levels rebound fairly quickly. Even so, this transient inhibition is required for significant induction of apoptosis by these drugs. We asked whether more complete and sustained inhibition of ERK might enhance induction of cell death by the PI3K inhibitor.”

They found that:

“These results suggest that, in some cells, inhibition of other non-AKT targets of PI3K contribute to induction of apoptosis, or that stronger MEK inhibition is required to fully activate apoptosis. Combined inhibition of MEK and PI3K caused more apoptosis than any of the other treatments in all three models.”

This lead to further work and the finding that:

“Pulsatile PI3K inhibition caused initial tumor regression and significantly suppressed tumor growth. The effectiveness of intermittent administration of the PI3K inhibitor and its superior antitumor activity compared to AKT inhibition were confirmed in another HER2 amplified, PI3K mutant breast cancer model, MDA-MB–361.”

The reason for this?

“We hypothesized that the effectiveness of PI3K inhibition was due in part to its combined inhibition of ERK and AKT.”

The Will et al., (2014) article is available online and open access (see here for direct link) – I highly recommend those interested in this field checking it out and reading the nuggets for yourself, it’s well written and easy to follow.

What does all this mean?

It would be hard for me to improve on Will et al., (2014) conclusion that:

“Recently, treatment with more selective PI3K inhibitors has led to greater therapeutic efficacy in lymphomas and in breast cancer with PI3K mutation or HER2 amplification. The ability of any PI3K inhibitor to inhibit signaling adequately is limited by physiologic toxicity. Moreover, attempts to combine MEK inhibitors with `dual specificity’ PI3K or AKT inhibitors have been complicated by severe toxicity at modest doses of these drugs.

The idea that the pathway must be inhibited continuously dominates the clinical development of these drugs.

Our finding that transient inhibition of PI3K is effective in in vivo models suggests that periodic rather than continuous target inhibition is an alternative strategy that would allow adequate pathway inhibition without causing inordinate toxicity or chronic feedback reactivation of receptors.

Thus, combining PI3K inhibitors, MEK inhibitors and, perhaps, inhibitors of key reactivated RTKs, and administering them at high dose on intermittent schedules may be a more effective therapeutic strategy for these tumors.”

Overall, don’t be surprised to suddenly see new clinical trials emerge evaluating intermittent dosing with PI3K and MEK inhibitors. The only questions in my mind is who will be the first to go this route and who will be able demonstrate superior efficacy and tolerability in patients?

The scientific rationale is very solid for intermittent dosing with BRAF V600E inhibitors and now with the combination with a PI3K plus a MEK inhibitor; it will be really interesting to see if such an approach will translate successfully in the clinic.  I hope it does because improving outcomes is ultimately what we are all here for.

Reference:

ResearchBlogging.orgMarie Will, Alice Can Ran Qin, Weiyi Toy, Zhan Yao, Vanessa Rodrik-Outmezguine, Claudia Schneider, Xiaodong Huang, Prashant Monian, Xuejun Jiang, Elisa de Stanchina, Jose Baselga, Ningshu Liu, Sarat Chandarlapaty, & Neal Rosen (2014). Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of
RAS-ERK signaling Cancer Discovery : 10.1158/2159–8290.CD–13–0611

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.

Transformative antibody technology in cancer research

By on July 30, 2013

Recently, I came across an exciting new development in a Nature publication and couldn’t resist teasing my Twitter followers with this terse statement:

Naturally, this mischievous tweet set off a lot of folks frantically trying to guess what I was referring to and the @replies came in thick and fast.

The National Science Foundation defines transformative as:

“Transformative research involves ideas, discoveries, or tools that radically change our understanding of an important existing scientific or engineering concept or educational practice or leads to the creation of a new paradigm or field of science, engineering, or education.  Such research challenges current understanding or provides pathways to new frontiers.”

Many suggestions came hurtling in, most related to a drug or company, but actually what I was referring to was a transformative technology – the biggest clue was in the question 🙂

Bispecific antibodies, to be more precise.

I was completely inspired by an article by a group of scientists in Nature Biotechnology by Speiss et al., (2013) – the link is included in the references below and is well with reading. It’s one of those things you read and think, “Wow, wish I had thought of that!”

Genentech kindly gave me access to one of their scientists involved, Dr Justin Scheer (gRED), who explained the rationale behind their approach and what they hope to do with this technology.  More on that in a moment, but first it’s a good idea to understand where I’m coming from.

Let’s take a look at both the potential and limitations of the various types being developed as cancer therapeutics, and the basics underpinning monoclonal and bispecific antibodies in more detail.

What are monoclonal antibodies?

Essentially, a monoclonal antibody is a manufactured molecule that’s engineered to attach to specific defects in cancer cells. They mimic antibodies the body naturally produces as part of the immune system’s response to invaders.

The immune system is trained to attack foreign invaders in the body, but it doesn’t always recognize cancer cells as enemies because they are formed from massive proliferation of the body’s own cells i.e. not foreign, unlike bacteria and viruses.

Monoclonal antibodies are usually directed to attach to certain parts of a cancer cell. An easy way to think of it is that the antibody ‘marks’ the cancer cell and makes it easier for the immune system to find and destroy.

How do monoclonal antibodies work?

The majority of currently available monoclonal antibodies are monospecific, i.e. having a single specific target e.g. CD20 or CD19, for example. The classic example in oncology is rituximab. Rituximab attaches to the CD20 protein found on B cells, which is associated with some types of lymphomas. When rituximab attaches to CD20, it makes the lymphoma cells more visible to the immune system, enabling them to be attacked and destroyed.

Treatment with rituximab lowers the number of B cells, including healthy B cells. The body will produce new healthy B cells to replace them and ensures that the cancerous B cells are less likely to recur.

While results with this approach have been impressive in some cases, there are limitations because cancer is highly complex and more than one target may be need to be addressed. This means that drug combinations are needed, increasing the complexity of clinical trial design especially in dose finding and MTD studies, risk of added or overlapping toxicities, increased costs etc.

Monoclonal antibodies such as rituximab have some other limiting factors though, as Speiss et al., (2013) observed:

“They lack natural Fc regions, they cannot bind to the neonatal FcRn receptor; binding to FcRn delays antibody clearance and improves pharmacokinetic (PK) properties.”

The lack of an Fc region also means that monoclonal antibodies typically cannot activate T-lymphocytes – because this type of cell does not possess Fc receptors – so the Fc region cannot bind to them.

A new potential solution exists

Antibodies that target two antigens are known as bispecific antibodies. Only one is currently available commercially (catumaxomab, Removab) and binds to CD3 and EpCam, although there are several in late stage development, including blinatumomab (Amgen) in ALL. The latter is interesting because it is part of the new generation of antibodies known as bi-specific T-cell engagers (BiTEs).

A bispecific monoclonal antibody (BsAb) is a manufactured protein that is composed of fragments of two different monoclonal antibodies and consequently binds to two different types of antigen.

Manufacturing a monoclonal antibody, while more complex than an oral tyrosine kinase inhibitor (TKI), is easier than a bispecific antibody. Much of the limitations seen so far with bispecific antibodies have been technological rather than clinical. What the Genentech scientists set out to do is succinctly described by Dr Scheer in the short Soundcloud below:

What are the advantages of bispecific antibodies?

The main advantage of bispecific antibodies is the ability to combine a cytotoxic cell (e.g. CD3) or ADC with a tumour specific protein target (e.g. CD19 or CD20) although a number of different combinations could be considered. In other words, you would get the ability to home in on the specific tumour target together with enhanced cell killing.

This could be a potent combination, except that technology-wise, they are difficult to engineer as Speiss and colleagues noted:

“… bispecific-antibody design and production remain challenging, owing to the need to incorporate two distinct heavy and light chain pairs while maintaining natural nonimmunogenic antibody architecture.”

There are some technological difficulties in engineering bispecific antibodies, though.  Blinatumomab was mentioned as one example by Speiss et al., (2013) because:

“… some bispecific antibody fragments (e.g., the anti-CD19-CD3 single-chain fragment blinatumomab) are expressed as a single polypeptide chain they include potentially immunogenic linkers.”

What was fascinating about the Nature Biotech paper was that they reported on a new process they had developed to manufacture bispecific antibodies:

“We present a bispecific-antibody production strategy that relies on co-culture of two bacterial strains, each expressing a half-antibody.  Using this approach, we produce 28 unique bispecific antibodies.”

One thing I thought was particularly cool about this novel approach is that bacteria are easier to manipulate and having a foreign component in the antibody will potentially mean that the human body’s immune system will hopefully pick it up more easily. Essentially, these new chemical structures could act as a powerful cancer homing device against specifically chosen targets.

The example used in the paper was a new bispecific antibody they engineered from co-cultures of EGFR and MET. Remember that Genentech/Roche already has a TKI against EGFR (erlotinib) on the market and a MET antibody (onartuzumab) in development. Neither of these drugs hit both targets and yet as Speiss and colleagues noted:

“MET and EGFR drive the growth of a marked proportion of non-small cell lung cancer tumors. MET and EGFR are often co-expressed and co-activated, and MET signaling can compensate for loss of EGFR signaling and vice versa.”

Image Courtesy of Roche's gRED unit: Bispecific antibody with two distinct binding arms that inhibits both MET (orange) and EGFR (green). The bispecific antibody, shown here in red and blue, has a natural antibody architecture

Image Courtesy of Roche’s gRED unit: Bispecific antibody with two distinct binding arms that inhibits both MET (orange) and EGFR (green). The bispecific antibody, shown here in red and blue, has a natural antibody architecture

As Dr Scheer observed, we don’t know yet is where the company will go with this exciting technology, but if the approach shows promising efficacy in future clinical trials, then it’s easy to see how multiple new bispecific antibodies could be easily developed for different tumour types, with far more potency and utility than single targeted therapies alone.

Stop and think about that possibility for a moment.

Transformative science isn’t always about finding a new target, sometimes the breakthrough is in removing the technological limitations to create a much more robust platform with enormous therapeutic potential.  At that point, the biology, targets and imagination become the limitations, not the technology itself.

I have a feeling that this platform is a much more exciting breakthrough than many realise – it’s the sort of approach where you can see, to paraphrase a famous watch company’s ad – some day all antibodies will be made this way.

References:

ResearchBlogging.orgSpiess C, Merchant M, Huang A, Zheng Z, Yang NY, Peng J, Ellerman D, Shatz W, Reilly D, Yansura DG, & Scheer JM (2013). Bispecific antibodies with natural architecture produced by co-culture of bacteria expressing two distinct half-antibodies. Nature biotechnology PMID: 23831709

ASCO 2013 Highlights Part 2

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

Immunotherapy

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

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

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

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

CLL

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

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

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

Breast and Lung Cancers

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

Pancreatic Cancer

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

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

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

ASCO 2013 Preview Video

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

 

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ASCO 2013 Highlights PD-1 and PD-L1 immunotherapy

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

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

Source: Roche

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

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

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

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

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

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

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

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

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

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

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

Overall:

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

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Overcoming drug resistance in lung cancer

On the final day of the annual 2013 meeting of the American Association for Cancer Research (AACR) in Washington DC, Jeffrey Engelman (MGH) hosted an excellent plenary session on “Cancer Evolution and Resistance” with a series of superb talks not only from himself, but also Neal Rosen (MSKCC), Todd Golub (Broad Institute) and René Bernards (Netherlands CI).

If this session is included in the webcast, I would highly recommend watching the whole thing several times, as it was one of the meeting highlights for me. Despite being on the very last day, the large hall was pretty packed and well worth waiting for. You can check availability of the AACR 2013 webcast talks here.

I’m going to focus on some of the specifics in NSCLC from Engelman’s talk for this update.

Where are we in the quest to improve outcomes in lung cancer?

Jeff Engelman, courtesy of MGH

Jeff Engelman, courtesy of MGH

Engelman discussed the basics of what we know about adaptive resistance to TKI therapy in solid tumours – most of them (EGFR and ELM4-ALK in lung, BRAF in melanomas, HER2 in breast, and cKIT in GIST) typically being in the range of 8-11 months, with only GIST seeing an impact for nearly 2 years (20 months).

Thus we can see that the resistance develops over time as mutations and amplifications in the tumour evolve in adaptation to the initial efforts to inhibit the target. Indeed, approx. 50% of EGFR lung cancers develop the T790M mutation, while ~33% of resistant ELM4-ALK cancers show new mutations (e.g. L1196M, G1269A and others).

The development of these changes essentially serves as a way to bypass tracks and and continue to allow downstream signalling of PI3K and MEK to occur, thereby driving growth and cell survival. What then happens is a myriad of other pathways become activated to help drive signalling, for example MET, HER2/HER3, IGF1R etc in EGFR driven cancers and EGFR and cKIT amplification in ALK lung cancers.

As an analogy, think of this process like a road traffic system – if the route into New York from New Jersey was cut off at the Holland Tunnel, so traffic would increase to the Lincoln Tunnel or Verrazano Bridge and if those were cut off, traffic would then flow onto the George Washington Bridge, as it adapts and seeks new escape routes from the original destination.

Eventually, the cancer evolves further with defects in growth arrest and apoptosis, as seen with transformation from NSCLC to SCLC in some patients with EGFR cancers, and even changes in the microenvironment through epithelial mesenchymal transition (EMT) and loss of BIM.

The key question is what can we do about overcoming or delaying resistance?

One strategy would be to evaluate more potent inhibitors e.g. LDK378 instead of crizotinib in ELM4-ALK cancers. Another might be to explore logical combinations to address shutting down the bypass tracks. A third might be to add in a new inhibitor to target the specific mutations that evolve e.g. T790M inhibitor in the case of EGFR driven cancers when it appears.

Some of these trials are already underway and we should have more data soon.

Another way, as we saw with the last post on metastatic melanoma, is to identify mechanisms of resistance using laboratory models and lab specimens. This approach can potentially lead to more rational drug development in the clinic. Traditionally, scientists have induced resistance in mice, looked for the mechanisms (a process that can take 1-2 years), validated them in lab samples of patients, and then treated with a new treatment strategy.

This process is obviously time consuming though and not every patient can wait that long for the answer. Engelman then explained how they are looking at ways to streamline the process in Boston. After the mouse resistance experiments are completed, they have added in a drug combination screen to look for logical treatment strategies i.e. what can be added to the original drug to overcome resistance?

A very elegant example was given for EGFR lung cancer where they evaluated 78 test drugs in a screen with and without gefitinib to determine those which led to cell death. Other examples were given for ELM4-ALK cancers.

The screen results suggested that most of the resistant models produced 3-6 hits. These might include adding a MET inhibitor to an EGFR inhibitor in EGFR mutant cancer, an EGFR inhibitor in MET amplified cancers and a SFK inhibitor in the case of ELM4-ALK cancers, for example.

These results are still early, but they do look very promising. Validation studies are still needed, but early studies they performed suggested that the hits are indeed showing efficacy in vivo.  A preclinical example for this concept was shown in vivo by adding ABT-263 (Bcl2 inhibitor) to gefitinib and seeing first a rise in tumour growth with the EGFRi and then a large drop in volume when either ABT-263 or AZD6244 (MEK) was added.

Based on the exciting initial concepts in animals, they are now moving to patient derived models since next generation sequencing (NGS) can help identify the mechanisms of resistance and combined with the drug combination screens, we may see more individual level treatments for patients on a case by case basis.  These might be based on large scale (over 100 cell lines) testing derived from resistant biopsies to identify effective combinations and match them to the relevant biomarkers.  It sounds easy and obvious, but few centres are doing this in practice.

This is true personalised medicine in action.

It is also pretty exciting to me as we know that cancer, even in different patient tumours, is very heterogeneous and requires a more personalised rather than a one size fits all approach. As Engelman observed,

“Heterogeneity of resistant clones within individual patients may pose additional challenges to overcome resistance.”

The second half of his really excellent talk focused on the use of sequential biopsies in patients to explain the heterogeneity and how it can lead to transformation from NSCLC to SCLC and back again in response to treatment with an EGFR inhibitor. That’s an in-depth discussion for another day though, but suffice to say it was a fascinating topic.

And finally…

I can see these novel and applied techniques eventually moving very fast and adopted in top level Academic centres where they have the resources and knowledge to marry basic and translational research with clinical practice in early stage trials, but for many Community or even regional Academic physicians, this will be virtually impossible without referral of patients to clinical trials in the Academic centres, at least for now.

Ultimately, we will see more improvements in treatment for lung cancer when we figure out not only the targets, but also how to overcome adaptive resistance, add logical new combinations, and select future treatment based on biopsies as the tumour evolves its response to each line of therapy. Treatment will essentially need to be chosen on an individual patient basis in the long run by evaluating adaptive resistance to each new combination over time.

The idea that we can use mouse models and drug combination screens with sequential patient biopsies to better understand the adaptive response to therapy over time is not new but few have managed to put processes and strategies in place to make this happen in real time. Patients often can’t wait 2 years or more for a new combination trial to open, but the Boston approach is very promising and I’d like to applaud all those at the Boston group (MGH, Dana-Farber, MIT/Broad etc) for their groundbreaking work in this field. Keep your eyes peeled for more updates in this exciting area of research!

Bromodomain Inhibitors – an exciting new target in cancer research?

One of the interesting things about basic cancer research is that new targets emerge all the time, offering fresh opportunities for developing novel therapeutics in the quest for clinical improvement. While you see many companies chasing the same well established targets, often generating me-toos, sometimes serendipity favours the bold and the brave, as we recently saw with Pfizer’s development of crizotinib for ALK+ lung cancer.

So what’s new on the R&D front?

Bromodomain inhibition is a novel cancer target and one that I am looking forward to learning more about at forthcoming annual meeting of the American Association for Cancer Research (AACR) in Washington DC.

The plenary session on Monday April 8 on Epigenetic Targets in Cancer includes a presentation by James Bradner (Dana-Farber Cancer Institute) on Bromodomain Inhibition in Cancer.

What are BET bromodomains?

Although there are 47 bromodomain proteins, a subset of four proteins are associated specifically with the BET bromodomain, including a terminal (T) node:

  1. BRD2
  2. BRD3
  3. BRD4
  4. BRDT

These bromodomains are acetyl-lysine binding pockets that target bromodomain-containing proteins to histones and thereby affect chromatin structure and function. The binding of BET protein bromodomains to chromatin regulates gene expression. Whenever histones are involved, epigenetics are never far behind.

Thus in simple terms, it is now believed that targeting the binding of bromodomain and extra-terminal [BET] proteins to chromatin, it may be possible to regulate gene expression, and in particular, the transcription of key oncogenes such as MYC, which can lead to arresting of cell-cycle progression and apoptosis (programmed cell death).  In plain English, this means that cancer cells are selectively killed.

Some of the groups original preclinical work in this area was published in Nature a couple of years ago – it was ground breaking work because generally protein-protein interactions such as MYC are considered very difficult targets to drug, unlike tyrosine protein kinases (TKIs), which are more accessible. More recent work by Lin et al., (2012) in Cell elaborated on the significance of low and high MYC levels.

Since then, the research has moved into the translational and clinical space. Small molecule inhibition of BET is a drug development target of Cambridge, MA based Constellation Pharmaceuticals, who announced last September that they partnered with The Leukemia & Lymphoma Society to develop their novel BET for the treatment of hematologic malignancies.

Highlighting the significance of this work is the announcement in January this year (see Fierce Biotech’s piece for more details) is a $95M deal with Genentech, which includes a buyout option. I thought this was a smart move at the time, given the importance and solidity of the basic research findings. The venture funds invested in privately-held Constellation Pharmaceuticals clearly have an exit strategy in mind.

I am hoping that Dr Bradner’s AACR plenary presentation will discuss Constellation’s drug development pipeline.

What makes BET bromodomain inhibitors of even more interest as a potential target is the possibility that there may be biomarkers that will identify those patients most likely to respond to therapy. For those of you interested in a basic understanding of biomarkers, you can read more on Biotech Strategy Blog for an overview.

Preclinical research published by the group in the March 2013 edition of Cancer Discovery highlights how a genetic biomarker could be used to identify those cancer patients likely to respond to a new class of cancer drugs, BET Bromodomain Inhibitors.

MYC is overexpressed in many cancers but until recently, has largely been ignored as an ‘undruggable target’.  A rare malignant childhood cancer known as neuroblastoma, for example, is associated with the amplification of the MYCN gene and generally considered to be difficult to treat unless it is caught early and surgical resection is feasible. New work published in Cancer Discovery by Puissant et al., gives hope that therapeutic targeting with bromodain inhibitors might be a feasible strategy to pursue.

Recent research published in 2011 in the Proceedings of the National Academy of Science (PNAS) by Jennifer Mertz et al., at Constellation Pharmaceuticals showed that you could target MYC dependence in cancer by inhibiting BET bromodomains. They showed that:

“Small molecule inhibition of BET bromodomains leads to selective killing of tumor cells across a broad range of hematologic malignancies and in subsets of solid tumors.”

Fast forward to the work published in Cancer Discovery. Using high-throughput screening the researchers at Dana Farber found that amplification of the MYCN gene in neuroblastomas was sensitive to BET bromodomain inhibitors. Using cell lines with MYCN amplification and a mouse model of neuroblastoma, they showed that BET bromodomain inhibitors prolonged survival and had anti-tumor effects.

The Cancer Discovery abstract describes the significance of this work:

“Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new com- pound class with promising anticancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, show a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma.”

What does all this data mean?

It has long been known that MYC protein is likely oncogenic in some tumour types, including some hematologic cancers and paediatric neuroblastoma, but the challenge has finding ways to effectively target it at effective therapeutic levels. This new research has now moved forward the field sufficiently, such that not only have potential biomarkers of response been identified, but inhibitors are also in advanced preclinical development. This is an exciting new avenue of research that is well worth watching out for in the future.

References:

ResearchBlogging.orgFilippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W., Fedorov, O., Morse, E., Keates, T., Hickman, T., Felletar, I., Philpott, M., Munro, S., McKeown, M., Wang, Y., Christie, A., West, N., Cameron, M., Schwartz, B., Heightman, T., La Thangue, N., French, C., Wiest, O., Kung, A., Knapp, S., & Bradner, J. (2010). Selective inhibition of BET bromodomains Nature, 468 (7327), 1067–1073 DOI: 10.1038/nature09504

Puissant, A., Frumm, S., Alexe, G., Bassil, C., Qi, J., Chanthery, Y., Nekritz, E., Zeid, R., Gustafson, W., Greninger, P., Garnett, M., McDermott, U., Benes, C., Kung, A., Weiss, W., Bradner, J., & Stegmaier, K. (2013). Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition Cancer Discovery, 3 (3), 308–323 DOI: 10.1158/2159–8290.CD–12–0418

Lin, C., Lovén, J., Rahl, P., Paranal, R., Burge, C., Bradner, J., Lee, T., & Young, R. (2012). Transcriptional Amplification in Tumor Cells with Elevated c-Myc Cell, 151 (1), 56–67 DOI: 10.1016/j.cell.2012.08.026

Mertz, J., Conery, A., Bryant, B., Sandy, P., Balasubramanian, S., Mele, D., Bergeron, L., & Sims, R. (2011). Targeting MYC dependence in cancer by inhibiting BET bromodomains Proceedings of the National Academy of Sciences, 108 (40), 16669–16674 DOI: 10.1073/pnas.1108190108

Schnepp, R., & Maris, J. (2013). Targeting MYCN: A Good BET for Improving Neuroblastoma Therapy? Cancer Discovery, 3 (3), 255–257 DOI: 10.1158/2159–8290.CD–13–0018

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ASH 2012 update on ARRY-520 in multiple myeloma

By on March 1, 2013

After highlighting the interesting biomarker program associated with AVEO’s tivozanib in renal cell and triple negative breast cancers in the last post, several people wrote in asking about other biomarker programs that have piqued my interest. Regular PSB readers will know that I’m not a fan of catch-all trials at all because the population being studied is too heterogeneous – use of biomarkers can help select which patients are more likely to respond to a particular drug and thus produce greater efficacy.

Another small biotech doing some interesting and compelling biomarker work is Array BioPharma, based in Boulder, Colorado.

What’s exciting about the ARRAY pipeline?

They have a nice pipeline of interesting targeted agents that are being developed with several big Pharma partners including AstraZeneca (selumetinib) and Novartis MEK162), both MEK inhibitors. Dennis Slamon’s lab has published some initial data on their work on predictive biomarkers with selumetinib for those interested (see References below).

MEK inhibitors are thought to target KRAS, which causes resistance in lung cancer and melanoma.  Combining MEK with a PI3K inhibitor may reduce the adaptive resistance and prolong survival. I’m expecting to see more on these at the forthcoming AACR and ASCO meetings in April and May. The approach is most likely to be incremental rather than a home run, though.

The ARRAY biomarker program that has intrigued me was presented in multiple myeloma (MM) at ASH in December. They have a novel kinase that targets Kinesin Spindle Protein (KSP) codenamed ARRY-520, which has a novel mechanism of action. For those of you interested in learning more about the basic biology of the KSP concept, I highly recommend checking out the papers in the Reference section below as they explain the targeting of the microtubilin concept well and how KSP inhibition differs from what we know of the taxanes as well as some useful background on the compound itself.

Some of you will remember previous KSPs that failed in the clinic such as ispinesib, for example, but not all compounds are equal or destined to fail. Much of cancer research is iterative – tweaking molecules to improve the conformation (shape), reducing side effects or improving potency. Sometimes a whole program can be canned because the company selected the wrong tumour type or trial design – you don’t always get multiple shots on goal in small biotechs!

What’s interesting to me is the focus of Array in multiple myeloma, a particularly difficult and foxy disease to impact clinically. The basic rationale behind this approach is that KSP is a microtubule protein required for mitosis (cell division); inhibition leads to cell death (apoptosis).

Now, remember the bedrock of therapy in MM has been proteasome inhibitors (bortezomib and now carfilzomib have been approved) and Immune Mediated inflammatory Disease agents or IMiDs (thalidomide, lenalidomide and now pomalidomide are all approved). This means that new agents with a different mechanism of action attract a lot of attention, especially if they can potentially be combined with existing drug classes to prolong survival and push patients into minimal residual disease (MRD) where the myeloma clone is drastically suppressed, much as we see in CML with the BCR-ABL inhibitors.

Inevitably, new drugs in MM are tested in a highly refractive population, either as a single agent or in combination with dexamethasone (dex) to determine if they have any efficacy.

Recall that two new agents approved by the FDA in relapsed/refractory MM had relative low single digit response rates (RR) as single agents i.e. carfilzomib (22.9%) and pomalidomide (7.4%) with improved RR in combination with low dose dex i.e. carfilzomib (34%) and pomalidomide (29.2%)

The two ARRY-520 analyses at ASH looked promising

Dr Satin Shah, ASH 2012

Dr Satin Shah, ASH 2012

The first part of the phase II study from Shah et al., (Abstract #449) looked at patients who were highly refractive to bortezomib and/or lenalidomide.

They observed that ARRY-520 had encouraging efficacy with and without dex. The first cohort (n=32) evaluated single agent therapy with ARRY-520 and saw 19% confirmed responses (CR) and 15% partial responses (PR); the subset who were both bortezomib and lenalidomide refractory had an ORR of 15%.

Meanwhile, the second cohort (n=18) looked at the combination with low-dose dex and demonstrated a PR or better of 22% in a heavily pre-treated population (more than 10 prior regimens). Adverse events included the usual myelosuppression (neutropenia, thrombocytopenia, anemia) seen in myeloma, but importantly, no treatment related neuropathy was observed.

The second element of the analysis looked at the same patients, but described the results from a biomarker, alpha-1-acidic glycoprotein (AAG). AAG is a serum protein that can have elevated levels in MM. As Dr Shah noted, AAG is not known to bind to standard of care agents in MM but is thought to bind to ARRY-520 with a negative impact by reducing the available amount of drug. In other words, they have a sub-therapeutic exposure to ARRY-520.

In the phase II study, they found that the hypothesis was supported: patients with high levels of AAG had poorer responses, while patients without elevated AAG levels had much better responses and the ORR increased to 33%, a dramatic improvement. The pre-dose AAG levels therefore correlated with response.

Obviously, the biomarker will need to be validated in larger, randomized controlled trials, but it would be very useful to be able to select patients upfront who could receive ARRY-520 either in combination with low dose dex or with a proteasome inhibitor or IMiD and see a more pronounced response. An initial trial with carfilzomib suggested an acceptable toxicity profile, while this is an encouraging start, we still need more data on the safety and efficacy of the combinations going forward.

Assuming the ongoing Phase Ib combination trials demonstrate good tolerability and efficacy, ARRY-520 could be potentially be combined with dexamethasone and either carfilzomib or pomalidomide in the relapsed/refractory setting for greater responses than the doublets alone.

Some additional thoughts…

I thought the Array KSP compound looked very encouraging indeed – multiple myeloma is crying out for:

  1. New agents with a different mechanism of action from the existing standards of care that can be combined to give solid results from triple combinations.
  2. More competition in the refractory setting to push out the MOS further and try to achieve minimal residue disease (MRD), which would impact the lives of patients with multiple myeloma significantly.

Beyond Kyprolis and Pomalyst, here are other agents in phase III studies being tested in refractory MM such as the HDACs e.g. panobinostat and vorinostat. The vorinostat data presented at ASH in 2011 was singularly disappointing, but hopefully we will hear about the phase III panobinostat results later this year.

In the meantime, Array have a nice compound in ARRY-520 and a potentially useful biomarker of response to help select patients upfront who are more likely to respond to treatment. As far as I know, they don’t yet have a partner for the program and may well need one for the large phase III trials that will be needed for FDA approval or they may well try to go it alone using the capital raised from the MEK partnerships. MM is certainly a promising avenue worth exploring for ARRY-520 and I look forward to hearing more about its development.

References:

ResearchBlogging.orgGaron, E., Finn, R., Hosmer, W., Dering, J., Ginther, C., Adhami, S., Kamranpour, N., Pitts, S., Desai, A., Elashoff, D., French, T., Smith, P., & Slamon, D. (2010). Identification of Common Predictive Markers of In vitro Response to the Mek Inhibitor Selumetinib (AZD6244; ARRY-142886) in Human Breast Cancer and Non-Small Cell Lung Cancer Cell Lines Molecular Cancer Therapeutics, 9 (7), 1985-1994 DOI: 10.1158/1535-7163.MCT-10-0037

Sarli, V., & Giannis, A. (2008). Targeting the Kinesin Spindle Protein: Basic Principles and Clinical Implications Clinical Cancer Research, 14 (23), 7583-7587 DOI: 10.1158/1078-0432.CCR-08-0120

Tunquist, B., Woessner, R., & Walker, D. (2010). Mcl-1 Stability Determines Mitotic Cell Fate of Human Multiple Myeloma Tumor Cells Treated with the Kinesin Spindle Protein Inhibitor ARRY-520 Molecular Cancer Therapeutics, 9 (7), 2046-2056 DOI: 10.1158/1535-7163.MCT-10-0033

Will biomarkers revolutionalise treatment with tivozanib?

By on February 25, 2013

Following last weeks post on the phase III clinical data for tivozanib in advanced renal cell cancer (RCC), I thought it would be useful to provide an update on AVEO’s biomarker program.

I’m very excited about the work they are doing in this area and have been following them keenly since they first presented their initial work on myeloid cells in RCC at the AACR diagnostic conference back in 2010.  Since then, other companies have also published work in this field, including Regeneron, who also noticed the presence of myeloid cells in their work with aflibercept in glioblastoma.

Biomarkers have been very much a bête noire in angiogenesis research – we know that some patients respond well to therapy, but others do poorly and may actually be worse off.  The challenge has been finding a way to link biology with response in order to improve patient selection.  Genentech/Roche have laudably spent millions in their quest for biomarkers with bevacizumab (Avastin), with researchers clearly very frustrated at the confounding data presented at the 2011 ECCO meeting in Stockholm. Clearly, we have a long way to go in this field.

Murray Robinson, AVEO

Murray Robinson, Courtesy of AVEO

Last week I caught up with AVEO’s Murray Robinson (who is the Special Advisor to the CEO), to discuss the progress they are making on the biomarker front.

The recent ASCO GU meeting in Orlando highlighted very interesting data on a new biomarker they are researching, which involves a hypoxia gene signature in RCC (PDF download).

While this data is still preliminary at the moment, it is being tested prospectively in some ongoing trials in both renal and breast cancers.  Readouts are expected by the end of this year and may reveal some interesting findings.

PSB: Does the hypoxia biomarker in your poster at ASCO GU connect with the myeloid biomarker you presented back in Denver at AACR, or is this completely different?

Murray Robinson: This is one is independent of that, completely different, although as you can imagine we are looking at the myeloid biology in this same dataset. To put that to rest, we ran into some technical details, technical challenges on that. Remember when you are doing these trials, you only get the material you get, and you don’t always get the quality, and can’t go back and recut it.

We are really looking forward for the marker in this paper as well as that that myeloid work, to an ongoing study of a 100 patients mostly in the US, RCC – BATON (Biomarker Assessment of Tivozanib ONcology) study and we will get to take another look at this hypoxia biomarker, the myeloid biomarker and a few others that we are looking at. That study will mature soon, we are expecting probably sometime later this year.

PSB: Are these two biomarkers going to be practical in the future for community oncologists to use or is it going to be something that is a research tool do you think?

All of us are now applying high resolution molecular analysis to all of the tumors, all the TCGA work, whole genome transcriptome on things. As the field has done that, we have all been amazed and enlightened by the complexity within what the field used to call a single genotype.

We are all recognizing there are many molecular subsets. This of course was first elucidated 10 years ago in breast cancer. In breast cancer we are very comfortable with these idea, it’s not breast cancer, it’s ER+, or HER2 amplified or triple negative. And of course treatment assignment can be based on that, and we are even further refining those subsets. We haven’t that kind of resolution until recently with many of the other tumor types.

Let’s turn to renal cell carcinoma, (RCC) which is the subject of this work. We in the field have long considered clear cell renal carcinoma, which is 85% of RCC, to be a tumor type. However, as the field has begun to sequence and do profiling on many of these tumors, we have begun to recognize that it is in fact more complex than that.

In our poster, we first cited some great pioneering work by Dr Kim Rathmell down at UNC Chapel Hill where she really was one of the first to take a look at these subtypes of clear cell, and has reported now, and we excerpted one of her figures from a recent paper of hers on our poster. And she sees three major subtypes of clear cell kidney cancer. Two of those subtypes she has talked about before, and we won’t spend much more time talking today. They don’t seem to differentiate for a number of key biological features. A third type she has identified, and we also independently identified, is the subject of this work.

What we, and others, have recognized is that there are new, previously underappreciated, subtypes of clear cell carcinoma.  We focused on this one novel subtype, which Kim called Cluster 3, and we then applied some of our own bioinformatics platform to this, in which we have comprehensively charaterized tumors for key robust signatures.

We applied those key robust signatures that usually represent biology to this third tumor type.  We saw that there were a number of key features in which these tumors varied, this is about 15% of clear cell RCC, so it is a relatively small subset. We noticed in particular that one of the dominant differentiating features of this tumor was the expression of its hypoxia responsive genes.

We recognize there’s a different tumor type here, and that the tumor type is now low for a large signature that we have had for hypoxia, and we of course are thinking translationally, and in terms of molecular diagnostics as well.  We optimized to reduce that hypoxia gene signature to a nine gene signature and we optimized the ability to measure those genes often using single sections from clinical paraffin embedded material.

We are absolutely thinking about this biology and are looking toward to the development of a simple diagnostic test, if that were warranted.

We looked at that nine gene signature, quantified it then looked at its impact on response to tivozanib as well as sorafenib.

PSB: My understanding from looking at your poster in this particular subset with the hypoxic element is that some patients did better in response to tivozanib than others?

Murray Robinson: That is the observation that we made.

Our interest in looking at hypoxia in tivozanib is that hypoxia as we showed in one of our figures, that signature relates to the over-expresssion of key VEGF ligands, VEGFA, PLGF and VEGFC.

One hypothesis that we generated from these observations is that when the VEGF pathway is deregulated or overactive as it is in most of clear cell, then you are more likely to respond to a selective, potent VEGF pathway inhibitor like tivozanib. Conversely, then if you find a subtype that is not, the hypothesis is that it would not respond well.

We tested that in the study, and with the important caveat that we had 69 samples out of the total trial of 517 patients, then we looked at this subtype. Well, we predicted the subtype would represent about 15% of the total, so we went form 69 down to about 30 samples, then 15% of those I think we ended up with 4 of the low subtype in both [arms]. We all recognize those are pretty small numbers. We are really looking forward to the second study I mentioned to you.

PSB: You will still have to validate the results in a larger sample?

Murray Robinson: We think that would be prudent. We think it is difficult to make much out of 4 samples, however that is the amount that would be predicted. It is consistent with all the work that we have done previously. We are also certainly pleased that those 4 patients did not perform well on tivozanib, whereas in the remaining 85% of those patients, those patients did very well.

In fact median PFS of the high patients, representing 85% of the study population, was 18.3 months, which is very respectable progression free survival.

PSB: In other words you have a very good way upfront to potentially predict up front which patients might do well on tivozanib?

Murray Robinson: That was the hypothesis going into this, this was a prospectively designed hypothesis that we wrote up. It was not exploratory.

There is another point here that we’re pretty excited about. One thing we know about the field, that we didn’t 10 years ago, is that despite the original enthusiasm around the VEGF pathway as being a key angiogenesis inhibitor pathway, we all know the large amount of clinical data over the last 10 years with different VEGF pathway inhibitors has been disappointing.

I think there has been a lot of disappointment about the expectations about the VEGF inhibitors versus their performance. The VEGF pathway inhibitors are working, there are a number of indications there, but it certainly hasn’t been that universal broad-acting, cytotoxic agent that we all thought it was, would have been back in 1999.

The bigger question is can we use an understanding of the biology, an understanding of gene signatures, to better select patients in other indications? What we showed in this paper is that 85% of these patients have this VEGF deregulation signature and that is consistent with the fact that clear cell carcinoma actually exhibits robust single agent response to tivozanib and activity with other VEGF type agents.

We really are interested with the signature in expanding and using this as a biomarker outside of clear cell carcinoma, and we have now have done that. Those studies are in progress.

We did a survey of this hypoxia signature across multiple tumor types and made an observation that we are pretty excited about. That is, we found that the hypoxic signature is not as prevalent in those tumor types as it is in clear cell.

We did find that it was present in subsets of tumor types, and we particularly noted that in triple negative breast cancer (TNBC), the hypoxia gene signature is high in a high proportion of triple negative breast cancer.

That is interesting because there is some anecdotal or retrospective clinical data that suggests that VEGF pathway inhibitor agents may work a little bit better in triple negative breast cancer, a challenging tumor type with high unmet medical need.

That observation led to us starting a new phase 2 trial in breast cancer, the BATON-breast study that we started a few months ago. In that study, we will be looking at triple negative breast cancer and we are looking at a randomized phase 2, and we are looking at paclitaxel versus paclitaxel plus tivozanib. In that study we will be measuring the hypoxia biomarker signature.

We have started that and are planning on using a specific assay to look at those patients.

PSB: And finally, for the prospective renal trial with biomarkers when do you expect that to read out, is it anytime soon?

Murray Robinson: I would expect to look for that around the end of the year, recognizing that we don’t know when that’s going to mature, but second half of the year that is when we are expecting. We are looking forward to those results.

We think that there is a strong hypothesis for this and we are pleased in the TIV0-1 study that we saw data consistent with the hypothesis.

Some personal thoughts and additional insights… 

Before anyone gets in too much of a tizzy, note that the data reported at ASCO GU are preliminary findings in a small sample size with only a few (n=4) hypoxia low patients, as Dr Robinson fairly pointed out.  They need to be validated prospectively in a randomised controlled study to ensure that the initial findings are real and not a fluke. The good news, however, is that the consistent lack of response in these patients enabled the hypothesis to be tested further in new trials. It’s certainly a concept that worth testing.

We have known, or suspect, that VEGF inhibitors work in conditions of tumour hypoxia, but this is the first time I can recall anyone connecting the hypothesis to clinical response.  Assuming that the findings can be validated in the prospective trials – and a commercial assay developed in the future – then the ability to select patients with RCC who are more likely to respond to a VEGF inhibitor such as tivozanib would be most welcome.

Would other VEGF inhibitors need to show the same effect or would a class effect be assumed?  In my book, you can’t always assume that one biomarker for one drug will always translate to others without data.  In this study a significant effect was seen for tivozanib but not sorafenib based on the hypoxia biomarker.  We don’t know what the impact is with other VEGF inhibitors such as sunitinib, pazopanib, bevacizumab and axitinib. It will be most interesting to see what happens here, as the hypoxia biomarker made be a differentiating factor for tivozanib in the future.

The upside for a VEGF inhibitor in TNBC is potentially huge, much bigger than RCC.  What would drive this element though is not only positive data but also a way to predict and select which patients are more likely to respond.  Essentially, if the data is positive, it may well redefine a subset of the disease, much in the same way that CD117 (KIT) enabled GIST patients to be differentiated from other types of soft tissue sarcomas.  When you can do that, it makes matching treatment to patients a whole lot easier for clinicians and pathologists.

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