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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

Red and Green Flags in cancer research and development

By on January 24, 2014

Recently, there was a red flags meme going around the biosphere started by Xconomy’s Luke Timmerman on 21 Red Flags in Biotechs to Ignore at your Peril. This inspired excellent contributions from David Sable on the buy side with his red and green flags, as well as Katrine Bosley from the Biotech CEO’s perspective and Andrew Goodwin on the research and investor side. They are all excellent reads so if you missed this wonderful collection, please do check them all out.  If anyone wants to add new ones, please highlight them in the Comments below.

My perspective is a little different, coming from multiple angles of science and academia, industry, consulting, and as blogger on cancer research and development both here and on our sister site, Biotech Strategy Blog.

A few people asked me what my thoughts on biotechs were and what my 5 red flags might be, but back then we were in the middle of the launch of our new conference coverage service and planning for the last round of medical meetings on the oncology circuit.

My side comes from an oncology/hematology/immunology background and may not be broadly applicable outside those specialist fields. Without further ado, here are things I tend to consider when evaluating companies in this space, whether that be as an analyst, consultant, investor, blogger or whatever hat is on that day:

1. Is the target oncogenic?

This sounds obvious, after all, how can you hit a target you don’t have or know about? As Dr Len Saltz lucidly explained it well here – companies who ignore the basics are doomed to failure.  In the world of targeted therapies, this is probably key. If it doesn’t matter to the survival of the tumour, then the chances are efficacy will be poor and all you add are unwanted side effects.

There are numerous examples from the difference in targeting BRAF vs. BRAFV600E in metastatic melanoma to pan PI3K vs. PI3K delta in CLL and NHL, and many many others.

Basically, a mutated target is more likely to matter than mere overexpression or amplification of target, nebulous targets are much harder to pin down and increase the chances of failure.

Another related red flag is completely misunderstanding the disease being studied.  You can tell when companies make this mistake easily, because they tend to lump multiple different subtypes into one trial.  Not only do various tumour types behave differently, but various subsets can also behave in different ways – some are chemosensitive, others not, some respond to targeted agents, some don’t.  An excellent example is soft tissue sarcomas (STS), where each subset can be treated as individual diseases; doing a catch-all trial here is a huge red flag as it is usually doomed to failure. A much smarter approach is isolate key oncogenic targets and select patients or subsets most likely to respond to the targeted therapy being investigated.

Solution: Validate the specific target early, before you run large phase III trials.

2. Is the science solid?

We’ve all sat through small cap biotech presentations that bamboozles with fancy science and dare I say it – fervour. Except that the subsets the agent appears to work in appear to be odd, at best. Lack of a validated biomarker or target is another red flag, as are catch-all studies. After all, why would you want to treat a so-called targeted drug in an untargeted fashion? Often, these approaches portend negative overall trial responses and retrospective frantic data mining for a subset that explains the few responders.

Related to the ‘right target’ is something called therapeutic index – that is, are we shutting down other relevant pathways to reduce resistance? All too often, a small company has only one drug and no broad pipeline to add and combine modalities to achieve this. That makes it harder to compete unless they license the agent or get bought out by a bigger company with another drug to partner with it. The solid science argument might therefore apply to a logical combination rather than monotherapy – the company that refuses to see this is likely to experience a few challenges along the way.

Another red flag is the use of old fashioned preclinical models that have no relevance to modern research. It happens more often than many realise. Even worse is the paucity of relevant preclinical research and then having to do the work after a spectacular phase 3 trial failure, when thoroughness of the research before the trials would have saved a lot of pain, angst and even embarrassment.

Solution: Best to do the biomarker and validation work in preclinical and phase I/II, then run prospective trials based on more stringent patient selection criteria to improve your chances of success.  You are often better off running multiple phase II trials to keep refining and honing the approach and combinations with greater degrees of certainty than rush into expensive randomized studies and failing badly.  Companies that do these two things well offer clear green flags to biotech watchers.

3. Does the phase I and II investigator pool include relevant researchers e.g. translational scientists or immunologists?

Many will be surprised how many ‘targeted’ agents involve clinical trials with clinicians who are not scientists, or worse, come from the chemotherapy world.  Dovetail this with the catch-all approach from #2 and you have a recipe for disaster before you begin.  Even big pharma can fall into this trap.

These seemingly random approaches tend to met with vague quotes from thought leaders, “It’s well worth trying” or “I think it’s a good idea” without any precise rationale for why the concept will work.  These doctors are easy to spot in press briefings – they look like a deer in the headlights when pressed with detailed scientific questions and run a mile from being interviewed afterwards, unless it’s for the kind of benign potted quotes mentioned above.  Not a good sign.

4) Is it a good company?

There are some biotech and pharma companies who unfortunately have a string of failures behind them.  The uninitiated often dismiss this, citing the Thomas Edison example of many tries before finally achieving success.  You could also argue that maybe, just perhaps, they keep making the same fundamental mistakes outlined above and haven’t learned to adapt.

Other flags here are openness and transparency, or rather the lack of it.  This includes selective disclosure and hyping of efficacy claims while understating the adverse event profile. Research and being on top of the data will stand many in good stead here, whether from a licensing, competitive analysis or investment standpoint.

Just as David Sable mentioned one of his red flags was being disrespected, for example by the company person who sits in his seat at the head of the table, there are similar parallels on the other side:

Good companies tend to be open, accessible and transparent, in my experience. They routinely offer or provide access to their scientists, researchers and thought leaders doing the work when asked.  They don’t exclude you from briefings: “No, because you’re merely a science blogger.”  Ouch yes, been there done that!

5) Does the company/drug offer value?

There is no doubt that being first to market offers a competitive advantage and later drugs may need to provide superior efficacy or tolerability, but if you are looking at 5/6/7th to market, you have to question what is the real value add going to be?

Companies who just happen to have a me-too and no clue how or where their drug will add value over the ones before them are notable red flags.  Incremental improvement in outcomes is one thing, same old, same old is quite another.  Future revenue success is driven by having a clear path to market and a good value proposition that is compelling. Without these, any clinical R&D is largely wasted time and effort, not to mention a significant expense.  Being aware of changes in the competitive landscape as well as flexible in adjusting to them is also critical.  Look at how many companies have been caught surprised and flat footed by the rise of immuno-oncology, for example.

On the other side are those companies who are smart and innovative; they position the product creatively, whether it be in the form of a combination with another agent that overcomes resistance or delays the resistance thus improving survival for patients add clear value.  Another way to create more value is that the drug can work in a slightly different way from what went before e.g. it hits a more relevant oncogenic target creating a well defined patient segment and path to market (see #1) or has fewer off-target effects, thereby improving tolerability.

It’s not all bad news and red flags in oncology R&D

Green flags include innovative, successful companies with a demonstrable track record of launches and drugs that make a difference to patients lives.  There’s no mystery why Roche/Genentech and Novartis consistently stand out from the pack in oncology/hematology – they have a relentless mentality to innovation and value creation as well designed, scientific based trials.  BMS have done very well transforming their oncology franchise from chemotherapies that hit the patent cliff to being a leader in immune-oncology with their acquisition of Medarex and partnerships with biotech companies such as Innate Pharma for licensing deals.

It’s up to the rest of the pack to innovate better and faster if they want to catch them up.

Resources:

Luke Timmerman’s 21 Red flags for biotechs

David Sable’s Red Flags and Green Flags

Katrine Bosley’s Red and Green Flags

Andrew Goodwin’s Red and Green Flags

2 Comments

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

Effectively targeting KRAS in lung cancer with a MEK inhibitor

Today is the 1000th blog post here on PSB, a milestone I never imagined actually reaching while writing the inaugural and rather boring post way back in 2006. At that time, 10 posts seemed a lot, never mind 100 or 1000! Anyway here we are, thus the facing the new dilemma of what to write about to celebrate the event.

The nice thing about having a following on Twitter is a ready supply of suggestions and papers from readers. Today’s suggestion comes from Angela Alexander (@thecancergeek), a Post Doc in breast cancer research at MD Anderson who asked if I had seen the exciting new phase II data on MEK inhibition in lung cancer from Pasi Janne’s lab. I’ve long been an admirer of his work, so it is fitting the data has just been published in Lancet Oncology this week (reference below).

Background on KRAS in lung cancer:

KRAS is a particularly tricky gene target because some tumours are seriously addicted to this oncogene, making it tough to completely shutdown from a pathway perspective. Part of the reason is that few drugs possess sufficient therapeutic index and thus resistance can occur fairly early. Recently, though, a number of companies have been exploring targeting downstream of KRAS to see if that approach could attentuate the driver activity in some way. One of these targets is MEK, which many of you will be familiar with in metastatic melanoma, where MEK inhibitors have been shown to be an effective strategy in combination with BRAF inhibitors to produce improved outcomes.

KRAS has been found to be abnormal, or mutated, in approx. 20-25 percent of patients with non-small cell lung cancer (NSCLC), making it the most frequent of the mutations seen in this disease.  We also know that KRAS mutations predict a poor response to EGFR inhibitors and are a negative prognostic indicator.  Finding therapeuetic strategies to overcome KRAS are therefore a high priority in clinical research.

What is the latest study about?

Janne et al., (2012) performed a simple but elegant phase II study looking at the impact of adding a MEK inhibitor, selumetinib (AZD6244/ARRY-142886) from AstraZeneca and Array to standard chemotherapy, docetaxel (Taxotere) to determine whether targeting KRAS indirectly would impact overall survival (OS) and allow patients to live longer. Selumetinib targets both MEK1 and MEK2 and previous phase I trials suggested a promising safety and efficacy profile to warrant further investigation.

To get an idea of the complex logistics involved in the study, 422 patients were screened from 67 sites in 12 countries, of whom 87 whom previously received initial chemotherapy and had both NSCLC AND the KRAS mutation were selected to participate in the trial, indicating an incidence of 20.1% for KRAS-positivity in this sample:

Source: Jänne et al., (2012)

Half the sample (n=44) were randomised to receive standard docetaxel chemotherapy (75 mg/m2 q3w) plus selumetinib capsules (75 mg BD) and the other half (n=43) received docetaxel plus placebo. Both groups were treated until progression or toxicities were unacceptable. Subsequent therapies were allowed, but not crossover.

The primary endpoint for this study was OS and secondary endpoints included PFS, objective response and others such as safety.

What did they find?

Now, first up I would expect the docetaxel alone group to have an overall survival in the second-line setting of around 5-6 months. In this trial the MOS for the placebo group was 5.2 months, which is in line with expectations. However, the selumetinib arm had a near doubling in MOS to 9.4 months, which I think is quite impressive in a very difficult to treat subgroup. PFS also saw a doubling from 2.1 months in the docetaxel alone group to 5.3 months in the docetaxel plus selumetinib group.

Toxicities appeared to be in line with previous trials – selumetinib tends to increase grade 3/4 events when combined with docetaxel i.e. neutropenia (67%) compared to the docetaxel alone group (55%), febrile neutropenia (18% vs. 0%) and asthenia (9% vs. 0%).

What can we conclude from this study?

I thought these results were very promising, although of course, the caveat is that it’s early days yet and a larger phase III multi-center trial is needed as a confirmatory study – not all phase II trials will yield positive data once they complete phase III so we cannot project that far yet. The main added toxicity, myelosuppresion, is to be expected given that it is likely additive to the existing effect seen with docetaxel alone.

This is, however, the first time I can recall seeing very solid evidence that adding a MEK inhibitor to standard chemotherapy in second-line NSCLC significantly improved overall survival in patients with KRAS mutations.

Overall, these results are encouraging and definitely warrant a phase III confirmatory trial with docetaxel and selumetinib in the second-line setting for NSCLC patients with the KRAS mutation.

References:

ResearchBlogging.orgJänne, P., Shaw, A., Pereira, J., Jeannin, G., Vansteenkiste, J., Barrios, C., Franke, F., Grinsted, L., Zazulina, V., Smith, P., Smith, I., & Crinò, L. (2012). Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study The Lancet Oncology DOI: 10.1016/S1470-2045(12)70489-8

Time to rethink cancer clinical trials strategy?

By on November 27, 2012

Recently, I’ve been pondering clinical trial design and wondering whether there is better way to do things, since much of the current concepts were based on cytotoxics that often had a very narrow therapeutic window.  With the advent of oral tyrosine kinase inhibitors (TKIs), the model seems, well, a bit old and tired and doesn’t always help us develop the optimum outcome.

In phase I oncology clinical trials, for example, we seek to find the MTD, as explained by Drs Rubenstein and Simon (PDF download) at the NCI:

“The phase I trial is designed as a dose-escalation study to determine the maximum tolerable dosage (MTD), that is, the maximum dose associated with an acceptable level of dose-limiting toxicity (DLT – usually defined to be grade 3 or above toxicity, excepting grade 3 neutropenia unaccompanied by either fever or infection.”

What usually happens afterwards in cancer research is that the RP2D or Recommended Phase II Dose is suggested, often just a bit under the MTD.

The idea behind this is to maximise the efficacy, since after all, that’s what we’re aiming to achieve in the large scale phase III trials viz improved survival, whether it be progression-free survival (PFS) or overall survival (OS).  PFS defines the time elapsed before symptoms worsen, while OS tells us whether people are living longer or not based on the therapeutic intervention.

But recently over the Thanksgiving Holiday I was reading Tim Ferriss’s “The 4 Hour Workbook” where he discussed the concept of ‘minimally effective dose’ or MED in the context of exercise and workouts.  This lead me to wonder if this is something we should consider in oncology clinical trials – would the Pareto 80:20 principle work here too?

In other words, instead of seeking the MTD should we actually test for the MED and have less toxic side effects in the process?  This potentially would also lead to better adherence and may even improve overall survival.

You probably think I’m nuts at this point, but hear me out.

Physicians and Pharma companies often forget that in the real world, patients fail to comply with oral cancer medications due to intolerable side effects that make their lives miserable.  Not everyone is young, fit and healthy with an excellent performance status – multiple regimens and prior chemotherapy can really take it out of you, leaving you wiped out to face the next round.  Even tyrosine kinase inhibitors (TKIs) are not always a piece of cake to take.  The constant niggly, but low volume side effects, can wear anyone down.

In support of this argument, let’s look at the impact of adherence on survival.  I remember listening to David Marin from the Hammersmith present their findings on CML and compliance at EHA last summer.  They observed that if adherence was less that 90%, then survival was dramatically impacted.  You can see the difference in the curves on Biotech Strategy Blog. It still vividly sticks in my mind 18 months on!

What’s also fascinating, is that in Rubinstein and Simon’s document, they also discuss the idea of “Finding the Minimum Active Dose” as shown in the table below, although I have never seen anyone discuss this in all the cancer conferences I have been to over the last 20 years!

Should we use minimally effective dose in cancer research

Thus, if we were to reconsider the whole concept of higher dosing in favour of minimally effective dosing, then we might actually see better adherence and compliance on a broad scale and therefore, better outcomes for more people.

If we then add in the growing trend to combine two TKIs or a TKI and monoclonal, whether approved or as a novel-novel combination, a fresh approach to testing drug combinations rather than different MTDs starts to look more appealing.

Just a thought.

 

 

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ASCO 2012 Update 2: Overcoming resistance in metastatic melanoma

By on June 29, 2012

Photo Credit: Sally Church Pharma Strategy BlogFollowing on from my preview of the 2012 American Society of Clinical Oncology (ASCO) meeting, I am now working through updates on some of the hot topics.

I’m delighted to announce The Chemical & Engineering News blog ‘The Haystack’, have published my second guest post on advances in metastatic melanoma.

This is a devastating disease that has seen very few advances over the last decade since the approval of dacarbazine (DTIC) until last year when the FDA approved two new therapies in vemurafenib (Zelboraf) for patients with the BRAFV600E mutation and ipilumumab (Yervoy), an immunotherapy that targets CTLA4.

Since then, we’ve realised that the inevitable happens – patients tumours become resistant to single agent TKI therapy because adaptive resistance pathways are activated and cross-talk with the MAPK kinase pathway often occurs.  The question of how we can improve on the encouraging results seen so far was explored in new trials in Chicago?

For those of you interested, you read my summary on The Haystack about the new developments in metastatic melanoma from ASCO, which includes dabrafenib, trametinib, anti-PD-1 and others.

For those who missed it, I also wrote a guest post about the ASCO 2012 data on overcoming resistance in non-small cell lung cancer.

May I take this opportunity to wish all my American readers a very enjoyable July 4th Independence Day weekend!

 

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Aggregating the 2012 ASCO tweets

By on June 1, 2012

It’s that time of the year – the annual American Society of Clinical Oncology (ASCO) conference in Chicago begins in earnest with Friday being the main travel day for many people before they hit the ground running for the poster sessions this afternoon.

This year, in addition to insights and analysis here on PSB, I’m delighted to announce that I’ll be writing some posts for the Chemical and Engineering News (C&EN) blog, The Haystack after the meeting (links to follow).

For me, one of the key themes emerging from the abstracts is overcoming drug resistance – we know that single agent targeted therapies are not enough, the question is what are the logical combinations needed to shutdown the pathways more comprehensively to improve outcomes.  Stay tuned for more on this important topic!

For those of you in town for ASCO, there’s an unofficial Tweetup this evening organized by Adam Feuerstein of The Street and others for anyone interested in joining a mix of people to natter about the hot topics over a beer – check out the details here.

As usual, the aggregated tweets from the event under the #ASCO12 hashtag are posted in the widget below for those who are interested in following along remotely. If you have any questions, please feel free to post them in the Comments below the post and I’ll do my best to answer them:

Stunning data with dabrafenib (BRAFV600E) in metastatic melanoma and brain metastases

By on May 22, 2012

Sometimes following the progress of cancer drugs can be very depressing given the failure rate, but every now and then something comes along that really brightens the landscape considerably. This week was one of those times.

Eighteen months ago, I posted a note from the 2010 ESMO meeting regarding GSK’s GSK208436 (now known as dabrafenib) in an early phase I/II trial in brain metastases associated with melanoma that was presented by Dr Georgina Long on behalf of an Australian group.

Do check out that original post – it’s well worth reading for some background context in the light of the new data.

At that time, the data and brain scans were quite simply stunning, but the big unanswered question was how durable would the responses be?  After all, many of you will know that people with metastatic melanoma generally have a poor prognosis, with a median overall survival of approximately 9–11 months (see Balch et al., 2009).

Originally, the finding that the drug crossed the blood brain barrier was a surprise, as this MD Anderson press release notes:

“The drug’s activity against brain metastases was initially a serendipitous finding at one study site.  In one patient, a research PET scan performed just before starting dabrafenib revealed a brain metastasis, but this result was not available until after treatment began.

The institution’s ethics board approved the patient to continue treatment because a follow-up PET scan two weeks later showed decreased metabolic activity in the brain metastasis and subsequent MRIs showed a reduction in its size.”

This week we learned more about the progress of dabrafenib in brain metastases associated with melanoma from a new publication in The Lancet by the same group, in conjunction with researchers from MD Anderson’s Department of Investigational Cancer Therapeutics group (see Falchook et al., 2012). This time, the phase I/II data was reported in incurable patients with brain metastases (n=184, 156 of whom also had metastatic melanoma).

The goals of this study were to determine the safety and tolerability, as well as establish a recommended phase II dose in patients.

The most common side effects were in line which those previously reported for BRAFV600 mutant inhibitors:

“The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%).”

For those of you interested in the recommended phase II dose, the group found that 150mg twice daily was the optimal dose for dabrafenib.

At the initial ESMO presentation in 2010, 9 out of 10 of the patients saw reductions in the overall size of their tumours, so I was most interested to see the latest progress with efficacy in a larger cohort of patients. In this study, the shrinkage continued apace:

“Brain metastases in most patients given dabrafenib reduced in size, with four patients’ metastases completely resolving.”

Emphasis mine.  Overall, the phase II portion of the trial demonstrated that the responses continue to look rather encouraging:

“At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%) and confirmed responses in 18 (50%). 21 (78%) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%) had a confirmed response.

In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months.”

I highly encourage reading of the paper for the waterfall plots alone – they are pretty impressive!  Overall, nine out of ten patients with brain metastases saw their tumour shrink, as noted in MD Anderson’s press release.

What about the survival curves? So far, the authors have reported the following in the current study:

  • Non-brain metastases (n=36): median PFS 5·5 months
  • Brain metastases (n=10): median PFS 4·2 months

The authors speculated the reason for the variability in responses may be due to severity of the disease:

“Differences in progression-free survival in patients with varying lactate dehydrogenase concentrations or ECOG performance status suggest that burden of disease could affect response durability.”

Overall survival data was not provided, presumably because they were not yet met, but these early data are very encouraging signs given that few drugs cross the blood brain barrier, leading the authors to conclude:

“Dabrafenib is the first drug of its class to show activity in treatment of melanoma brain metastases. Clinical trials of melanoma usually exclude patients with brain metastases because of preclinical predictions about drug distribution into the CNS.

We hope that the introduction of drugs that are effective in Val600 BRAF-mutant melanoma metastasised to the brain will result in new trial designs that allow such patients to be included.”

Inevitably, with combination data for BRAF + MEK being presented at this year’s ASCO meeting as highlighted in my preview video, I don’t think it will be long before we see a new trial looking at dabrafenib plus trametinib in this patient population to see whether dual inhibition can overcome the inevitable acquired resistance that develops.

References:

ResearchBlogging.orgFalchook, G., Long, G., Kurzrock, R., Kim, K., Arkenau, T., Brown, M., Hamid, O., Infante, J., Millward, M., Pavlick, A., O’Day, S., Blackman, S., Curtis, C., Lebowitz, P., Ma, B., Ouellet, D., & Kefford, R. (2012). Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial The Lancet, 379 (9829), 1893–1901 DOI: 10.1016/S0140–6736(12)60398–5

Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ, & Sondak VK (2009). Final version of 2009 AJCC melanoma staging and classification. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 (36), 6199–206 PMID: 19917835

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Highlights of AACR 2012 – Part 1

By on April 17, 2012

The 2012 American Association for Cancer Research (AACR) meeting in Chicago was interesting for several reasons.  While there were no truly ground breaking data such as in previous years as with, for example:

  • vemurafenib in BRAFV600E melanoma
  • vismodegib in basal cell carcinoma (BCC)
  • crizotinib in ALK+ lung cancer

there were a lot of encouraging signs for the future.

What made the meeting exciting for me was the sheer number of new compounds emerging from late preclinical to early phase I – clearly companies are looking to restock their pipelines with the threat of major patent cliffs imminent.  Not everyone is chasing new compounds to license in!  The sheer breadth and depth of the pathways targeted by the new compounds took me a little by surprise.

It was clear from discussions with numerous new product people that while pipeline boards are starting to look a little healthier than of late, many of the new compounds are not yet public, but effort are being made to expedite these into the clinic too. Roche and Novartis have dominated the oncology landscape of the last few years but there were signs of resurgence from old stalwarts such as GSK, Lilly, Pfizer, Amgen and Merck. Such fierce competition is good to see.

Posters from Day 2 at AACR...

The small biotechs were also showcasing some interesting data and over the rest of this week, I’ll be highlighting some of the ones I liked and also explaining some of the new targets and biomarkers that caught my eye.

There was, however, a noticeable dearth of handouts and QR codes (for the PDFs) in the poster sessions this year, necessitating more requests for copies by email, hence the delay in covering the highlights post conference.

I’m pleased to say, however, that many presenters generously shared their poster offline and some of these will be discussed later this week.

Here are some of the topics I’m going to be covering in more detail:

  • Update on the PI3K-AKT-mTOR and RAS-RAF-MEK pathways
  • New targeted agents in late preclinical and phase I development
  • Review of the Science Policy session on regulatory and clinical challenges in new drug approvals
  • Update on new approaches in colorectal, prostate and lung cancers

Check back PSB daily this week for more detailed analyses and insights…

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J&J unblind Zytiga phase 3 trial in pre-chemotherapy castrate-resistant prostate cancer

By on March 8, 2012

The big cancer news that hit the news wires this morning was not entirely surprising:

“Janssen Research & Development, LLC today announced that it has unblinded the Phase 3 study of ZYTIGA (abiraterone acetate) plus prednisone for the treatment of asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer (CRPC) who have not received chemotherapy.”

Source: Press Release

Given the accelerated approval of abiraterone in the post-chemotherapy setting last year, the results in the pre-chemotherapy setting were widely expected to:

  1. Be even better in earlier stage than the 3.9 months OS advantage already seen
  2. Likely to have an early study halt

Zytiga already has Compendia listing through mention in the NCCN Guidelines with level 2a evidence in the pre-chemotherapy setting, essentially listed with ketoconazole.  Several industry friends with access to market data have mentioned that the pre-chemotherapy share for abiraterone is already around 20-25%, not bad at all given it doesn’t have full approval prior to docetaxel use and has been on the US market less than a year.

No clinical details were provided by the Data Science Monitoring Committee (DSMC), but the data are expected to be presented at a clinical meeting later this year (Adam Feuerstein of The Street speculated that ASCO was a likely target).  I do hope so, but that would suppose an abstract was sent in with no data by the late breaking deadline of Feb 1st.

The company did state that:

“The company plans to submit for regulatory approval in the United States and around the world beginning in the second half of 2012.”

At this rate, J&J should receive the new indication in the first half of 2013, based on the 302 trial data, depending on whether the filing is accepted as an accelerated, priority or regular review.  No doubt this information will be apparent after filing has taken place.

One challenge with early stoppage of trials based on progression-free survival (PFS) is that determining whether patients truly live longer, as judge by overall survival (OS), becomes much more difficult, if not impossible.  Once patients on placebo are offered the active drug, there is a crossover effect confounding any subsequent data analysis.

The news today will impact several other companies in the advanced prostate cancer landscape

Medivation and Astellas are expected to file MDV3100 in the post chemotherapy setting soon based on the phase 3 AFFIRM study.  This agent has several attractive advantages over abiraterone in that:

  • no concomitant prednisone or steroid administration is required (hence less puffiness and related side effects) and
  • it targets splice variants as well as the AR, which may lead to less drug resistance.

Based on the post-chemotherapy data we’ve seen so far (MDV3100 saw a slightly longer improvement in OS, which may be related to the above), we can expect that the phase III PREVAIL trial prior to docetaxel to also show a similar trend to the Zytiga study.  It won’t surprise me at all if the interim analysis also leads to the DSMC recommending early unblinding.  Based on the Zytiga data, it wouldn’t surprise me if the interim analysis for MDV3100 came up as early as mid next year, which would be earlier than expected.

Two drugs that will be impacted by these developments with hormonal agents are Dendreon’s Provenge, which is approved prior to docetaxel and Sanofi’s Jevtana (cabazitaxel), which is approved after docetaxel.

The immunotherapy sipuleucel-T (Provenge) is an unlikely partner for combination with abiraterone given that steroids suppress the immune system, while many older men with metastatic would much rather take a pill than undergo the debilitating side effects of myelosuppressive cytotoxics such as the taxanes.  Certainly my Dad was in that category, as are many men in their 70’s.  Once approved, Alpharadin (radium-223) may well offer a useful option for that subset of patients, especially of they have already tried ADT and seen biochemical relapse with rapidly rising PSA levels.  Provenge is likely to be negatively impacted by Zytiga approval pre-chemotherapy.

Approval of Zytiga in the pre-chemotherapy setting will likely increase its share there, since many oncologists are somewhat sceptical about Provenge in terms of how it works, how effective it is, how to monitor patient progress on it (it doesn’t seem to affect pain, PSA or any of the usual markers of disease) and the hefty price tag ($93K for 3 infusions) doesn’t help either.  MDV3100 would likely have an even stronger impact, since urologists dislike using steroids and managing the complications, plus Astellas have a solid franchise in urology already.

At this rate, Jevtana will be pushed further out down the treatment paradigm and reserved for salvage therapy in the younger, fitter patients.  Its biggest challenge is competing with it’s fellow taxane, docetaxel, since many oncologists will re-challenge with the generic if the patient previously did well on it.  Any delay (through improved survival with newer, earlier treatments) will delay time to cabazitaxel uptake.  This will likely get worse once MDV3100 is approved, and oncologists can sequence them.

At what point will we see placebo trials go away?

I’m not a big fan of placebo-controlled trials, except where there are no standard of care or alternative clinical options for patients.  Until recently, the advanced prostate cancer market was relatively immature with few approved therapies, so placebo trials were de rigeur.  Going forward though, new entrants to the market will face the ethical dilemma of how can placebo-controlled trials be justified in a market where drugs such as abiraterone (or MDV3100 and Alpharadin, if approved) have a proven survival advantage?  It will push the bar for new market entries higher (and more costly).  Millennium’s TAK-700 (orteronel), which is similar to abiraterone but may or may not need steroids, may well have just made it into clinical trials in time before that window shuts off.

And finally…

The good thing is that after a decade of not much happening in the advanced prostate cancer market, we are seeing a lot if new therapies, often with different mechanisms of action, being developed for this disease.  There are others I haven’t mentioned here, including custirsen (Oncogenex) and cabozantinib (Exelixis) which are also undergoing clinical trials and we await those results too.

As more drugs for castrate-resistant prostate cancer (CRPC) are approved, sequencing and combinations will also come to the fore to determine optimal strategies for improving outcomes for men with prostate cancer.  It’s an exciting market to be following given the rapid progress over the last year or so, but hopefully, this is just the beginning and there will be much more yet to come.

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