MaverickNY | Pharma Strategy Blog

Developing a predictive biomarker for PARP inhibition

Today’s Science Friday post looks at the identification of a potential new biomarker and possible strategies for expanding use of PARP inhibitors in patients most likely to respond to them as a way to validate the the approach prospectively. This has important implications for future clinical trial designs with this class of drugs.

Photo Credit: Ben Sutherland via flickr

Regular readers will be very familiar at my rants against broad catch-all studies and phase III trials with targeted agents that do not have a biomarker or even a logical well defined subset of patients because it’s akin to blindfolding an archer, turning him around 360 degrees and then asking him to hit a bullseye 50 or 100 yards hence.

How can you hit a target you can’t see?

PARP inhibitors have had a bit of a chequered history after the initial excitement was later followed by a series of rather disappointing clinical trial results, which occurred for a multitude of reasons. Several of the approaches sadly fell into the category of ‘Five things not to do in R&D’ as delineated in my recent tongue-firmly-in-cheek post on the topic. I’ll leave interested and curious readers to ponder at length exactly which of the no-nos they managed to break!

That said, we do know a few things of relevance:

PARP1/2 inhibitors have produced sustained anti-tumor responses in patients with germ-line BRCA gene mutations
Biomarkers other than BRCA1 and BRCA2 are clearly needed to predict responses to PARP inhibitors
Catch-all trials without segmenting for BRCA mutations and biomarkers are highly unlikely to be successful (recall the spectacular phase III failure in triple negative breast cancer with iniparib, for example)
Next generation PARP inhibitors have focused on more clearly defined subset populations with greater success (and potency).

Chris Lord and Alan Ashworth’s lab have recently published some nice work (open access, see Refs below) that is worthy of discussion. Bajrami et al., (2013) decided to dive a little deeper and look at what genes and mutations might affect the responses to PARP inhibition:

“In hypothesizing that additional genetic determinants might direct use of these drugs, we conducted a genome-wide synthetic lethal screen for candidate olaparib sensitivity genes. In support of this hypothesis, the set of identified genes included known determinants of olaparib sensitivity, such as BRCA1, RAD51 and Fanconi’s anemia susceptibility genes.”

The main reason behind this approach quickly becomes apparent – there is a huge need for it:

“One of the major issues in the clinical development of PARP1/2 inhibitors is the identification of biomarkers other than BRCA1 and BRCA2 gene mutations that predict a favourable response to therapy.”

While patients with germline BRCA mutations have a greater tendency to respond, they don’t account for all the responses that have been seen in the clinic. What else is involved?

What did they find?

“Integration of the list of candidate sensitivity genes with data from tumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity.”

In other words, when CDK12 was low, PARP sensitivity was high, making it a potential predictive biomarker for response to therapy with a PARP inhibitor.

What does this mean?

“The appearance of CDK12 in our olaparib sensitization gene list, alongside the CDK12 mutational data, suggested the possibility that loss of CDK12 function could sensitize tumor cells to PARP1/2 inhibitors and that loss of CDK12 function in HGSOVCa could be a predictive biomarker for response to this developmental class of agents.”

In other words, it would be useful to evaluate loss of CDK12 as a biomarker of response for PARP inhibitors in prospective clinical trials in breast and ovarian cancers, with and without germ-line BRCA mutations.

CDK12 is only one of nine genes known to be mutated in high grade serous ovarian cancer (HGS-OVCa), for example, so should patients be identified upfront who have loss of CDK12, then it may be enough to ensure response to a PARP inhibitor, irrespective of BRCA status. Clearly this work is still very early, but it creates a smart and well argued rationale that can be tested in clinical trials.

Should the approach be validated, then it could well expand the utility of PARP inhibitors in the clinic based on a predictive biomarker. I would be interested to see what happens not only with olaparib, but also the new generation of PARP inhibitors from Abbott (veliparib), Biomarin (BMN 673) and Clovis (rucaparib), to name a few who are conducting trials in breast or ovarian cancers.

If this works, it will be a thing of beauty.

References:

Bajrami I, Frankum JR, Konde A, Miller RE, Rehman FL, Brough R, Campbell J, Sims D, Rafiq R, Hooper S, Chen L, Kozarewa I, Assiotis I, Fenwick K, Natrajan R, Lord CJ, & Ashworth A (2014). Genome-wide Profiling of Genetic Synthetic Lethality Identifies CDK12 as a Novel Determinant of PARP1/2 Inhibitor Sensitivity. Cancer research, 74 (1), 287–97 PMID: 24240700

Photo Credit: Ben Sutherland

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:

RAF + MEK inhibitors (downstream resistance)
RAF + PI3K-AKT-mTOR inhibitors (cross resistance)
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:

Solit 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 MaverickNY 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

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Will intermittent dosing transform TKI therapy in cancer research?

By MaverickNY 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.

Neal 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:

RAS-ERK pathway is a key downstream effector pathway of oncogenic PI3K
ERK inhibition is required for apoptosis (cell death) to occur with a PI3K inhibitor
It is important to coordinate downregulation of AKT and ERK since both are necessary for induction of apoptosis and antitumor activity
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:

Marie 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.

Dr 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.

Medivation announce interim results of PREVAIL in pre-chemotherapy CRPC

By MaverickNY on October 22, 2013

This morning Medivation and Astellas announced the interim results of the PREVAIL trial in the pre-chemotherapy castrate resistant prostate cancer (CRPC) setting.

The independent data monitoring committee (IDMC) recommended stopping the trial early due to significant efficacy and unblinding the data.

Accordingly, the press release headline stated that:

“Study Will Be Stopped Early and Enzalutamide Will Be Offered to All Qualified Study Participants; 30% Reduction in the Risk of Death, Hazard Ratio=0.70 (p < 0.0001); 81% Reduction in the Risk of Radiographic Progression or Death, Hazard Ratio=0.19 (p < 0.0001.”

Now, I don’t know about you, but it’s quite a while since I saw a cancer trial with such an impressive hazard ratio (HR) for overall survival (OS) as well as being highly significant. Essentially, there is a 30% reduction in the risk of death compared with placebo even at this early point.

It was interesting though, that initial sentiments on Twitter suggested that some analysts were bothered by the absolute numbers when comparing the PREVAIL and AA-302 trials in the same setting. Enzalutamide achieved a 2.2 month improvement over placebo whereas abiraterone recorded a 5.2 month advantage, although in their case, the curve was only trending towards survival and did not cross the significance line.

Since the drugs were not compared in a head to head study, you can’t really compare apples with oranges even though the placebo arms were similar, at around 30 months each. The important point here is that one trial achieved statistical significance and the other did not. The clue is in the trial design and relative size of the respective studies.

Curious to see what urologist reactions were to the announcement, I checked out sentiments on Twitter, including Dr Benjamin Davies (Univ. of Pittsburgh) and Prof Bertrand Tombal (Leuven):

@dsobek also easier to use. No steroids. Urologists will love it. It’s like casodex which we use in spades

— daviesbj (@daviesbj) October 22, 2013

PREVAIL (enzalutamide pre-chemo) positive..Great news for doctor and patients. http://t.co/RUirE6Tx0D

— Bertrand TOMBAL (@BertrandTOMBAL) October 22, 2013

The other side of the coin, though, is some scepticism and nihilism from the analyst corner:

Sell-Side: I’m really concerned that 3/4 of Xtandi patients in PREVAIL study are still alive. #DERP $MDVN

— Adam Feuerstein (@adamfeuerstein) October 22, 2013

I’m kind of shocked that anyone would even think that, never mind say it. To be clear, those are not Adam’s words, but rather he’s summarising analyst chatter on the conference call (not verbatims), albeit in his own inimitable fashion. Obviously the point of new therapies is that you want patients to live longer, surely?! Their obvious disappointment, however, can be put into a context of sorts:

my guess is $MDVN sell-side analysts would’ve rather seen better mOS and weaker HR vs zytiga…which is why they’re analysts and not doctors.

— zach (@zbiotech) October 22, 2013

Sometimes I despair of people in the industry’s inability to understand basic statistics. What we have is snapshot, not the full data, that will come at a conference presentation when the full analysis is conducted post unblinding. Personally, I think these interim results, based on the HR and P value are encouraging, but what we really need to see are the survival curves because they tell a much more complete picture.

It should be noted that what many of the Wall Street analysts appear to have missed is that what we have is an early slice of the data – median overall survival (MOS) has obviously not yet been reached!

It is also unfortunate that Medivation only used a small sample of at risk patients (n=59) at 30 months to estimate the survival since the rest were censored or dead as David Miller keenly observed:

@zbiotech Found out: 59 is the total “at risk” at 30 mo. Everyone else in the trial is censored (69%) or dead (31%) on the KM curve.

— David Miller (@AlpineBV_Miller) October 22, 2013

This is a great way to create confusion unless you are expressly clear in the press release.

That said, if the trial is unblinded and placebo patients still alive are allowed to switch over, then we may only see the MOS for the enzalutamide arm in the future and not the comparator since the data will be confounded by switching.

For a different perspective, I also reached out to Prof Bertrand Tombal (Leuven), one of the lead European investigators in the trial, for his measured and considered thoughts on some of the key issues arising from this news:

1) What are your top line impressions of the PREVAIL data?

“I am a Urologist and every minutes patients are dying from prostate cancer, despite the last-years logarithmic infatuation in drugs. On top of that, recent data from Sweden that the proportion of patients dying from PCa without having received docetaxel is much larger than anticipated. So having more drug in the pre-docetaxel setting is critical, either to delay its use or treat patients that are and will remain unfit for it.”

“As a urologist, I am absolutely impressed by the delay in PFS and the unprecedented HR of 0.19 in radiographic progression-free survival. That speak to me….In addition, it does it without compromise and discussion on the impact on survival 0,70 and a 30% reduction in the risk of death..What more toxicity, especially when you know the limited toxicity of the drug.”

“It is funny to see how people have a different look of the 2 face of the co-primary endpoint coin…I look at PFS because it speaks to my patients.”

2) Many people in the US appear to be concerned that the absolute magnitude of the enzalutamide benefit is lower than that for abiraterone in the pre-chemotherapy setting (2.2 vs 5.2 months), what are your thoughts on this?

“I still have trouble understanding the meaning of a difference in median survival when the median are not reached ??? That’s computed median, arithmetic medicine if you wish. I want to see the curve…There is not mystery that regulators approve drugs based upon hazard ratios and not medians. They are much better representation of the benefit. In addition, due to the availability during the trial of approved drugs known to improve overall survival, placebo patients would be expected to have taken other drugs to increase survival.”

3) Not many countries in Europe have reimbursed abiraterone in the pre-chemo setting, is it likely that enzalutamide will be treated differently based on the fact it shows a significant OS?

“I don’t know, but in Europe most countries values Qualys and ICER, and for qualys you need to extent survival…It is more complex that a simple HR and we will need more results.”

4) Presuming enzalutamide is approved pre-chemo, which drug should urologists give first: abiraterone or enzalutamide?

“That a tricky one…Let’s say that the most popular drug so far is still bicalutamide 50 mg, and in absence of direct comparison between drug, convenience for the patient and the urologist is very often a very discriminating choice…”

5) The cumulative cost of prostate cancer care is increasing as new drugs are approved, is it going to be cost effective to treat for 32 months with an expensive new drug for only a 2 month survival benefit or do we need more effective treatment options?

“That is the real challenge, especially with the European Perspective. In Europe, where the access to treatment is mostly based on solidarity rather than private insurance, it means political choices, ethical choices and a lot of thinking on new model…based on performance, sure.”

Well said, sir!

Ultimately, we need to wait to see the full presentation and look at the survival curves before making a more informed decision. Hopefully, this data will be presented at the ASCO GU meeting in January, making a very interesting start to the 2014 cancer conference calendar.

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Can Merck make an impact in pancreatic cancer?

There were a number of interesting posters at the AACR-NCI-EORTC Molecular Targets meeting today. Specifically, two on metastatic pancreatic cancer caught my eye. You can read about the other one on Millennium/Takeda’s ADC MLN0264 here.

This is an area of high unmet medical need with the fourth highest number of cancer deaths in the US and a median survival of 10 months or less. Even with improvements in the standard of care, it still remains a miserable cancer to get.

Many of you will be aware that KRAS is mutated in 90% of pancreatic cancer cases. As Dr Barry Nelkin (Johns Hopkins) noted today,

“The good news is that we know the target, the bad news is that we haven’t been able to hit it… Yet.”

We do know that KRAS activates three major signaling pathways, namely:
1. RAF/MEK/ERK
2. PI3K/AKT/mTOR
3. RAL.

Oddly, we have a plethora of inhibitors for the first two, but not for RAL. Unfortunately, RAL signaling is critically important in pancreatic cancer.

Dr Nelkin observed that it has been shown that inhibition with CDK5 resulted in the loss of RAL activity in pancreatic cancer cells, as well as reduction in their ability to form tumours and metastasize in vivo. Interestingly, addition of PI3K or MEK inhibitors further decreased the cells transformation.

Dinaciclib (Merck), an inhibitor of CDK1,2,5 and 9 was shown to block RAL activity in pancreatic cancer cells as well as inhibiting xenograft growth and metastasis. In other words, RAL is now druggable!

The researchers at Johns Hopkins showed some nice preclinical evidence that tumour size was reduced in pancreatic cell lines when dinaciclib was combined with either an Akt inhibitor (MK-2206) or an ERK inhibitor (SCH772984).

These results therefore provided a solid rationale for combining a CDK5 inhibitor with one from the PI3K/Akt/mTOR or RAF/MEK/ERK pathways in the clinic. A phase I combination trial of dinaciclib plus MK-2206 is currently enrolling at four centres, including three in the US.

Overall:

I think this is a most interesting trial with a solid rationale that is well worth evaluating in advanced pancreatic cancer. The story though, gets a little interesting. I tweeted to Dr Nelkin’s colleague, Dr Anirban Mitra, who is now Professor of pancreatic cancer research at MD Anderson and learned something rather surprising:

@MaverickNY thanks! Need a company that will push this to clinic, now that MK2206 is dead. We are seeing cytocidal not cytostatic effects.

— Anirban Maitra (@Aiims1742) October 21, 2013

Cytocidal for the uninitiated means they are seeing pancreatic cancer cells being killed. It’s a short word but it means a lot.

At the poster today, Dr Nelkin confirmed that he had heard rumours to this effect, but stated Merck had at least committed to finishing the phase I trial. It’s not immediately obvious why MK-2206 might be discontinued or on the chopping block, but who knows what will happen if the phase I data turns out to be stunning. I for one, sincerely hope that they are.

Other companies with a CDK5 and a PI3K/AKT/mTOR inhibitor in their pipeline would do well to watch out for the readout of these results – they could be very interesting indeed.

Removing the PD-1 brake enhances the effect on adoptive CAR T cells

Someone in my Twitter stream kindly shared a link to an article this morning on how removing the PD-1 brake enhances the effect of chimeric antigen receptor (CAR) T cells in solid tumour models.

Whoa! Read that again and digest the implications.

We already know that the current leading immunotherapies, blocking PD-1/PD-L1 and adoptive therapy with CART, are rather effective in some cancers, but I’m willing to bet that few would have expected this effect, even though it makes a lot of sense when you actually sit down and think about it.

Certainly it gave me goosebumps reading the articles.

What do the papers show?

Morales-Kastresana et al., (2013) offer a nice review of the state of play with immunotherapies that is well worth reading. They explain that,

“It is conceivable that PD-1 limits the signal transduction capabilities of the artificial chimeric receptors at the immune synapses between CAR-transduced cells and tumor cells. The tumor cell lines in culture constitutively expressed PD-L1 and presumably keep expressing this molecule in the tumor microenvironment.”

Much of the work with CART to date has been reported in CLL and ALL from Carl June’s lab at U. Penn, but what about the potential in solid tumours? Ovarian and breast cancers have been mentioned as possibilities from thought leaders I’ve spoken to at recent conferences, although we’ve been waiting to see some solid preclinical data that might help understand the best options with this approach.

Morales-Kastresana and colleagues describe the important work of John et al., (2013) as:

“A combination of T cells with a CAR recognizing HER-2 on the surface of tumor cells and a mouse anti-PD-1 mAb in the treatment of HER-2 breast carcinoma–transplanted tumors. The CAR chosen includes the signaling domains of CD28 and CD3z. Each of the elements in the two-pronged combination shows signs of monotherapy efficacy, but there are very interesting signs of synergistic, rather than additive, effects on the HER-2–transfected mouse models.”

Although this is preclinical work, the Australian group have demonstrated something very simple and elegant – namely, uncoupling the PD-1 brake can make CART more effective in two solid tumour HER2 breast cancer models:

“This combination therapy was shown to significantly inhibit tumor growth in two different mouse models leading to eradication of disease in a proportion of mice. Both of these approaches have been used singly in the clinic showing good safety profiles where objective and complete responses have been reported against various cancer types.”

They also went on to observe that:

“However, many patients do not respond to either treatment alone. The current study shows that combining these two modalities can dramatically increase antitumor effects against established disease. Furthermore, we show that the increased effects from combination therapy did not cause pathology in mice and that therapeutic responses strongly correlated with a decrease in MDSCs.”

Where MDSCs are myeloid-derived suppressor cells.

Myeloid cells, for the uninitiated, are often associated with inflammation. Reducing them is a very good thing in cancer therapeutics.

Oddly by coincidence, I was reading an excellent article on combining anti-PD-1 and CTLA-4 in PNAS from James Allison’s lab yesterday (see References below) where they also demonstrated that a reduction of myeloid cells in tumours following anti-PD-1 therapy.

What does this research mean?

This is the first time I’ve seen evidence that blocking PD-1 can potently enhance CAR T-cell therapy. It clearly has significant scientific and clinical implications for potentially improving therapeutic outcomes of this approach in patients with cancer, including solid tumours.

These are promising preclinical results in mouse models but we should be very careful making any leap or extrapolation to clinical trials or outcomes in humans at this stage.

There are also many potential challenges ahead. Not least is the complication of cross company R&D.

Novartis and Celgene are the leaders in developing CART therapies, while several companies including BMS, Merck, Roche, AstraZeneca and others are advancing anti-PD1 or PD-L1 immunotherapies in their R&D pipelines. As far as I know, no one company has both approaches in house, so this will mean alliances would need to be developed in order to progress the exciting concept. I really hope it happens, but commercially, two company combination trials and alliances are still very challenging for the Pharma industry on many levels.

It is sometimes easier to license in an additional compound than it is to try and work out a two company clinical trial, strange though that may seem to industry outsiders.

Update: (17 February 2014)

This morning Novartis announced that they had acquired Co-Stim Pharmaceuticals, a Cambridge, MA based antibody company that develops immune stimulants and checkpoint inhibitors, including anti-PD-1. Although the compounds are currently in Discovery phase, we can expect Novartis and NIBR to be focusing significant effort on moving some of these agents through preclinical then to the clinic reasonably speedily. The potential for combining a PD-1, not only with the CAR- T cell construct, but also with existing TKIs in various solid tumours offers a wonderful opportunity to explore the broader environs of cancer immunotherapy.

Nice job!

References:

John LB, Devaud C, Duong CP, Yong CS, Beavis PA, Haynes NM, Chow MT, Smyth MJ, Kershaw MH, & Darcy PK (2013). Anti-PD-1 Antibody Therapy Potently Enhances the Eradication of Established Tumors By Gene-Modified T Cells. Clinical cancer research: PMID: 23873688

Morales-Kastresana A, Labiano S, Quetglas JI, & Melero I (2013). Better performance of CARs deprived of the PD-1 brake. Clinical cancer research: 19 (20), 5546-8 PMID: 24004672

Curran MA, Montalvo W, Yagita H, & Allison JP (2010). PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proceedings of the National Academy of Sciences of the United States of America, 107 (9), 4275-80 PMID: 20160101

The CLL Landscape is rapidly a’changing…

By MaverickNY on October 10, 2013

Yesterday evening, Gilead announced that the Data Monitoring Committee (DMC) had recommended early stoppage of the 116 trial, which looks at idelalisib in relapsed/refractory disease in patients who are not eligible for chemotherapy. These patients usually have comorbidities or are elderly and frail, and often receive chlorambucil or rituximab alone. The study compared the combination of idelalisib plus rituximab versus rituximab alone.

Fortunately, the early stoppage was for a good reason – the interim analysis demonstrated a statistically significant improvement in PFS in favour of the combination over rituximab alone. Adverse events were consistent with previous experience of the drug.

I would imagine that Gilead will seek a filing this year in the near future (presumably once the Government shutdown is over) and we can possibly expect a late breaker at ASH. This is good news for CLL patients and at least six months earlier than expected.

Based on this information, I would also expect approval for idelalisib in relapsed/refractory CLL by ASCO next year, a year ahead of schedule. The company have already filed in relapsed/refractory NHL, so the FDA will have a solid safety database from which to make an informed decision.

The frontline CLL trial, presented by Dr Susan O’Brien at ASCO, compared the combination of rituximab plus idelalisib to rituximab alone and is still ongoing. I’m hoping we will have an update on this at ASH in December.

Gilead have undertaken a smart strategy to date with most of their trials in combinations with approved therapies such as rituximab and bendamustine, which will make it easier for community oncologists, who treat the majority of CLL patients, to integrate a new therapy in their existing treatment options. Sometimes, getting these physicians to switch to a new single agent drug from long established practices is harder and slower than people realise.

Adding something to the existing standard of care is a much easier sell to community doctors, who usually have have older, less fit patients than the Academic physicians, who put their younger, good performance patients into clinical trials where possible.

In the runup to ASH, the CLL market is now getting very interesting – and crowded.

Recall that Roche announced their phase III results for GA-101 (obinutuzumab) in the frontline setting for the same patient segment at ASCO. They are expected to gain approval soon, probably before ASH and have breakthrough status in this indication.

Pharmacyclics and J&J previously filed ibrutinib in 3 indications and have breakthrough therapy designation in CLL, NHL and mantle cell lymphoma (MCL) as single agent therapy. Approval is also expected this year. There is no doubt that they have a potent and effective single agent in these diseases.

Obviously, a lot of people have wondered whether a combination of ibrutinib plus idelalisib will lead to better overall response rates than either alone. I actually asked this question of the companies presenting at a NYAS meeting a year or two ago, and predictably, they weren’t too enthusiastic.

Why?

Well, it’s much harder for two companies to collaborate on joint trials than it is for a company to manage two agents of their own. To this end, I’m always arguing that companies with a broad and deep pipeline are more likely to win out in the long run if they have the components for logical combinations in the disease being evaluated in house.

What does all this mean?

Source: Gilead

What this means is that Gilead and Roche are well placed in CLL and indolent NHL, since Gilead can combine idelalisib (PI3K) with their SYK inhibitor (upstream in the pathway like BTK), GS-993, and Roche can potentially combine GA-101 (anti-CD20) with their Bcl2 inhibitor, ABT-199/GDC-0199.

Many of you will recall the preclinical data at AACR earlier this year looking at Gilead’s two agents and demonstrating some synergies worthy of testing in the clinic. This combination is already in the clinic with two phase II studies currently enrolling in refractory CLL, iNHL and other lymphoid malignancies.

What we should look for is not just the initial response rates and PFS from individual trials, but what the impact of inhibiting two or more pathways will have on survival with subsequent therapies over time. Resistance in leukemias and lymphomas can sometimes take a while to take effect and there are multiple targets to aim at, so cycling different novel combinations by line over time will be interesting to watch.

Strategically, it’s not just about the isolated data with one drug in one line of therapy – we may well see a large improvement in 5 and 10 year survival rates for CLL and iNHL in the long term, with a better quality of life for patients – that’s what oncologists really want to see in the future.

These new developments will undoubtedly put pressure on Infinity, since their PI3K delta/gamma inhibitor is much further behind and will need to define a clear and compelling proposition to differentiate IPI-145 from not only idelalisib (PI3K delta), but also obinutuzumab and ibrutinib.

One thing is clear – such a fertile seam of new therapies – ibrutinib, obinutuzumab and idelalisib in the near term, followed by ABT-199 and IPI-145 in the medium term, is going to change the CLL and iNHL landscapes forever. That’s a good thing for patients, caregivers and oncologists.

ASH is going to be the meeting of the year at this rate… for those of you needing an overview of the leading agents in the CLL/iNHL landscape, check out this pre-ASCO overview here.

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Update on KRAS and NRAS mutations in colorectal cancer

By MaverickNY on September 19, 2013

A new NEJM article on KRAS and metastatic colorectal cancer (CRC) caught my eye last week. One of the challenges with this disease is the limited effectiveness of EGFR monoclonal antibodies such as cetuximab (Erbitux) and panitumumab (Vectibix).

However, science is very instructive sometimes, as Dr Berlin noted in his NEJM editorial last week:

“After the determination that activating mutations in exon 2 of the gene KRAS predicted the inefficacy of anti-EGFR antibodies, reanalyses of multiple trials suggested that these agents could be more effective when administered to a more limited cohort of patients.”

The KRAS exon 2 finding essentially became the first biomarker of response for these drugs, although it should be noted that it is not perfect because even after screening for it, not all patients respond, so other factors are also involved.

The big question is what are they?

The new analysis by Douillard et al., (2013) attempted to address this issue further. They delved deeper by doing a pre-planned retrospective analysis of the phase III Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) study. Specifically, they looked at rarer KRAS mutations and also NRAS mutations to see if they had any impact.

RAS mutation status was determined for 90% of the patients who were randomised in the trial, giving a solid body of data from which to draw some meaningful conclusions.

What does the data show?

The PRIME study results demonstrated that in patients without RAS mutations (n=512), progression-free survival (PFS) was 10.1 months with panitumumab–FOLFOX4 versus 7.9 months with FOLFOX4 alone. Overall survival (OS) was 26.0 months in the panitumumab–FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group.

These results showed a clear benefit in favor of adding panitumumab to standard chemotherapy in patients without RAS mutations.

What was interesting, however, was that not all patients in this subset responded well. In total, there were 108 patients (17%) who had nonmutated KRAS exon 2, but had other RAS mutations instead. These mutations were associated with inferior PFS and OS with panitumumab–FOLFOX4 treatment. In other words, it was more consistent with the findings in patients with KRAS mutations in exon 2. Additionally, BRAF mutations were a negative prognostic factor.

What does the data mean?

This was the key question I asked Dr Douillard, since understanding the impact of the findings is usually important to how oncologists will select and treat patients when considering panitumumab therapy:

“The data mean that we need to better select patients in 1st line treatment of metastatic colorectal cancer to be treated by FOLFOX-panitumumab to improve the risk/benefit ratio. This analysis extended to other exons of Kras and the 3 exons of Nras, identified the proper targeted population to deliver appropriate personalized medicine and avoid using this combination in any RAS mutant patients who will not benefit from it and potentially experience a detrimental effect.”

Where are we going next?

Science never stands still and our learnings are necessarily incremental. This data, while important, isn’t the final answer, as Dr Douillard observed:

“First, the full mutational status analysis of Kras exons 2, 3 and 4 as well as Nras exons 2, 3 and 4 should be rapidly implemented. However this does not fulfill all the unmet needs, and further research is needed to understand the mechanism(s) of resistance that will develop later under treatment.”

In other words, we still need to continue to understand the science of resistance better, so that we can develop new improved therapeutic strategies to overcome it.

ECCO 2013 trial updates

A couple of trial updates in the ECCO program for next week caught my eye and if there’s anything of interest, then a fresh update will follow:

Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. Speaker: V. Heinemann (Germany)

ASPECCT: a randomized, multicenter, open-label, phase 3 study of panitumumab (pmab) vs cetuximab (cmab) for previously treated wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Speaker: T. Price (Australia)

Some thoughts…

In Europe, where people with cancer are diagnosed and treated in Academic cancer centers, doing routine detailed mutation analysis as part of the work-up in order to make definitive therapy decisions isn’t an issue. In the US, though, not all patients are seen in Academic or tertiary hospital centres, so I’m not sure how many oncologists in the Community setting will consider this in advanced colorectal cancer patients.

The good news is that research such as this will help us not only better select select patients for targeted therapy but also avoid harm, as Berlin noted in his editorial:

“Although the benefit of excluding patients with RAS mutations from receiving anti-EGFR antibody therapy is logical and expected, it was not anticipated that anti-EGFR antibodies might harm patients who have tumors expressing nonmutated KRAS in exon 2 and other RAS mutations.”

This speaks eloquently to the first rule of medicine – first do no harm. Selecting out patients with KRAS and NRAS exon mutations will clearly lead to better outcomes on EGFR therapy such as panitumumab in colorectal cancer.

I look forward to seeing KRAS research evolve further as we continue to improve our knowledge and understanding going forwards. One thing that may be of interest is where we are with MEK inhibitors and KRAS mutations in CRC in different mutational subsets.

References

Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, & Patterson SD (2013). Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. The New England journal of medicine, 369 (11), 1023-34 PMID: 24024839

Berlin J (2013). Beyond exon 2–the developing story of RAS mutations in colorectal cancer. The New England journal of medicine, 369 (11), 1059-60 PMID: 24024844

Posts by MaverickNY

What did they find?

What does this mean?

References:

1. Is the target oncogenic?

2. Is the science solid?

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

4) Is it a good company?

5) Does the company/drug offer value?

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

Resources:

What does all this mean?

Reference:

1) What are your top line impressions of the PREVAIL data?

2) Many people in the US appear to be concerned that the absolute magnitude of the enzalutamide benefit is lower than that for abiraterone in the pre-chemotherapy setting (2.2 vs 5.2 months), what are your thoughts on this?

3) Not many countries in Europe have reimbursed abiraterone in the pre-chemo setting, is it likely that enzalutamide will be treated differently based on the fact it shows a significant OS?

4) Presuming enzalutamide is approved pre-chemo, which drug should urologists give first: abiraterone or enzalutamide?

5) The cumulative cost of prostate cancer care is increasing as new drugs are approved, is it going to be cost effective to treat for 32 months with an expensive new drug for only a 2 month survival benefit or do we need more effective treatment options?

Overall:

What do the papers show?

What does this research mean?

Update: (17 February 2014)

References:

In the runup to ASH, the CLL market is now getting very interesting – and crowded.

What does all this mean?

The big question is what are they?

What does the data show?

What does the data mean?

Where are we going next?

ECCO 2013 trial updates

Some thoughts…

References