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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:

Jänne, 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 MaverickNY 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!

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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Zaltrap – a simple dosing error or not?

By MaverickNY on November 9, 2012

The recent approval of Sanofi/Regeneron’s VEGF targeted monoclonal antibody, ziv-aflibercept (Zaltrap) in combination with FOLFIRI, for the treatment colorectal cancer (CRC) after failure of prior therapy with the FOLFOX regimen has proven to generate quite a controversy.

The efficacy benefit, although modest at 1.4 months extra survival, is similar to that seen with bevacizumab (Avastin) in the same setting. The pricing, however, was clearly set at a premium at approximately $11,000 a month compared to less than half that for bevacizumab. I never thought I would be blogging about the price of Avastin actually looking very reasonable!

Unsurprisingly, a consensus that this would be hard to justify was met with a firm reaction from academic thought leaders, including a very strongly worded Op Ed in the NY Times from Drs Peter Bach, Leonard Saltz and Robert Wittes at Memorial Sloan-Kettering Cancer Center (MSKCC), who declared that the price differential was too steep and Zaltrap would not be included in the formulary there. Dr Saltz is well known for his opposition to high drug prices and the increasing cumulative cost of treating the disease.

Yesterday afternoon a new twist in the tale appeared with a new story in The Cancer Letter (paid subscription required) that Sanofi had halved the price of Zaltrap only two months after the launch in response to public pressure and criticism. There were several interesting things to note from the article:

The drug’s price was pegged to the 10 mg/kg every two weeks dose of Avastin.
If the company discounts the drug’s price without adjusting the Medicare reimbursement rate, this would create a windfall for prescribing physicians.
Patients’ copayments would continue to be calculated based on the old price.

Based on this, I can’t see MSKCC changing their position, at least until the retail price changes, since there is no benefit to their patients in paying more than they would for Avastin.

Point 2 raised by the Cancer Letter makes me wince slightly. Although it doesn’t affect Academic physicians, since the Institutions purchase drugs from wholesalers or directly from manufacturers (in this case, Sanofi), in the community setting, oncologists purchase drugs from wholesalers, collect the patient co-pays and claim the reimbursement from the CMS or payers. In this case, they would make a bigger margin on prescribing Zaltrap over Avastin until the retail price is adjusted. This would be like going back to the old days of making huge margins on the spread with generics. Essentially, it offers the oncologists in private practice a large reimbursement incentive in the short term to prescribe Zaltrap over Avastin, at least until the price is changed at the CMS. The patient, however, is still forced to pay their copays at the original price and get no break from the Sanofi price reduction.

The dosing issue is slightly pertubing though. It’s well known that the dose of Avastin has usually been 5mg/Kg in colorectal cancer for some years, at least since 2004 from memory, while the dose in other solid tumour was indeed 10mg/Kg. Sometimes a loading dose of 10mg/Kg is used in patients with a high disease burden followed by the 5mg/Kg maintenance dose. The actual Avastin PI is very general since the drug was originally approved back in 2003:

“The recommended doses are 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with intravenous 5-FU-based chemotherapy. Administer 5 mg/kg when used in combination with bolus-IFL. Administer 10 mg/kg when used in combination with FOLFOX4.”

Of course, what happens in practice is that drugs are sometimes approved with two different doses based on the trials at the time and clinical practice evolves with experience and knowledge. In this case, IFL and FOLFOX4 have given way to FOLFIRI and FOLFOX6 as the base regimens to which biologics are added. It didn’t take the CRC community long to realise that a 5mg/Kg dose worked just as efficaciously as the 10mg/Kg infusion when given with FOLFIRI and FOLFOX6, as well as being more cost effective.

The community practice is reflected in the current NCCN Guidelines, which offer oncologists an overview of the standards for different regimens in different tumour types. You can see the recommended regimens and dosing schedules for colon cancer in the snapshot below:

Bevacizumab dosing in colorectal cancer

This confirms my suspicions and intuition having worked in the colorectal cancer field several times and not seeing much change there since 2004. Doctors are creatures of habit and safety, unless you give them a compelling (efficacy or reimbursement) reason otherwise. The NCCN Guidelines are created by a committee of Academic experts based on best practice and are usually followed by oncologists in private practice.

The moral of this story for pharma companies is don’t rely on product prescribing information (PI) for setting your pricing as they are often superceded by clinical practice as referenced in NCCN and ASCO Guidelines!

Update on KRAS in pancreatic cancer

Today, I’m heading off to The New York Academy of Sciences (NYAS) for an afternoon of lectures on pancreatic cancer. It’s free for members and only $40 for non-members. Previous 1-day and half day meetings I’ve attended at NYAS have been packed with information and very enjoyable.

Why am I interested in this meeting?

Well, aside from Icarus Consultants being one of the media partners for this worthy event, we like to support scientific causes that facilitate cancer research and the communication of the data.

We know that the standard of care may possibly be changing soon with the data from the nab-paclitaxel (Abraxane) due before the year end, but even if the median survival is doubled from 5-6 months with gemcitabine to 10-12 months with nab-paclitaxel, we still have a long way to go in overcoming both primary and acquired resistance to treatment. Additional improvements in the future will likely come from targeted agents aimed at different oncogenes. There is a lot of active research going on now to try and figure out what those targets are and how best to attack them effectively.

Scientifically, the event promises to be an interesting one – we know that KRAS plays an important role in resistance to treatment in this disease – so understanding how things work in tumorigenesis is crucial for potential new breakthroughs in this terrible disease. There are two lectures on KRAS and another on autophagy that I am particularly keen on hearing.

David Tuveson (Cold Spring Harbor Laboratory) is also giving an overview of therapies in development based on their mouse model of pancreatic cancer, including a new target they are working on ie Connective Tissue Growth Factor (CTGF), which I confess is a new one for me!

If you’re going to the meeting, do introduce yourself and say hello! It’s also not too late to register if you are in the NY Metro area. An online webinar is available for members who can’t make it to the live event.

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Prospect of Abraxane in Pancreatic Cancer excites ESMO 2012

By MaverickNY on September 30, 2012

One of the most interesting highlights of this ESMO for me has actually not been some new data or science that was presented here, but the sense of anticipation about the forthcoming nab-paclitaxel (Abraxane) data in pancreatic cancer.

The pancreatic cancer KOLs are a relatively dour group, much as melanoma specialists were until the advent of BRAF inhibitors. It’s largely a function of toiling away in a known graveyard zone with few effective therapies to offer patients and their families and then, suddenly, a new breakthrough is borne that re-energises the sub-specialty and propels it forward again.

I was therefore mildly surprised to find that the rare corporate symposia I attended on Friday afternoon was:

a) packed to the gills with standing room only and
b) the KOLs in an excited and feisty mood.

It was clear that something interesting was up.

Whilst it was made abundantly clear by the panel that the final data isn’t yet available, all of the KOLs presenting were at pains to say in their presentations it will be in “a few weeks” or “very soon” so thankfully we won’t have long to wait for the press release.

It is unlikely full details will be available until the data is presented at a major conference though, possibly ASCO GI, but we should at least have some indication whether it is positive or negative. After all, they sometimes do get a sense from their own patients whether one arm is doing better than the other or not, even if they don’t know until unblinding if it is a successful combination or a futile one.

The issue of futility is a real one i.e. did the patients on the treatment arm do worse than than the standard? We were vividly reminded of that today when Dr Dan Petrylak presented the phase III MAINSAIL data in castrate resistance prostate cancer, which demonstrated that patients receiving docetaxel and prednisone plus lenalidomide did worse than docetaxel and prednisone plus placebo. It is a risk and certainly can happen!

My assumption though, is that the nab-paclitaxel data is positive since a first cut of the analysis could be available by now, especially if the data will be announced soon. Why else would there be such warm enthusiasm from a well respected panel? Here are some examples of the sentiments expressed:

Dr Tempero: “We are on the verge of something exciting”

Dr Scheithauer: “The results are really good with nab-paclitaxel!”

Dr Ducreux: “The improvements in treatment of pancreatic cancer will come from new chemotherapies and combos.”

Dr Hidalgo: “The phase III (nab-paclitaxel) data will be available in a few weeks.”

Hidalgo discussed the role of SPARC in tumour growth and metastasis – it increases metastatic cell aggressiveness and is also involved in feedback loops involving angiogenesis see recent post on gemcitabine and nab-paclitaxel. SPARC expression can exist in both the stroma and the tumour. It has also be shown to correlate with improved overall survival and gemcitabine response. Reduction in SPARC by nab-paclitaxel leads to increased uptake by gemcitabine by removing the stromal barrier.

In concluding his presentation on the biology of pancreatic cancer, Dr Hidalgo emphasised the importance of targeting the stromal layer, which acts as a barrier protecting the pancreas and that “nab-paclitaxel appears effective.” Since one follows the other, the clues to what they all clearly knew were there.

You can read the Storify that Pieter Droppert of Biotech Strategy Blog collated from the live tweets of the session.

For those of you interested, I previously wrote about the preclinical evidence for nab-paclitaxel blasting through the stroma back at AACR in 2009. The scans from the animal models pre and post nab-paclitaxel were pretty impressive. You could instantly see the rationale for effectively blasting it out, thereby providing a haven for gemcitabine to work more effectively by increasing apoptosis and increasing tumour regression. It should be noted that while nab-paclitaxel has been shown to affect the stromal layer, whereas gemcitabine does not.

Hidalgo described how the combination of “nab-paclitaxel and gemcitabine shows interesting clinical and tissue effects” while showing some impressive PET scans of response. He went on to say that, “what I hope is the combination will be improved based on a median OS in the 10, 11 month range.”

In summary…

We’ll find out very soon whether the KOL expectations are correct, but if true, the combination of nab-paclitaxel and gemcitabine could potentially lead to a new standard of care. In turn, there are several impacts that will likely result from positive data:

1) It will provide a new chemotherapy doublet for future trials to be compared to. This will raise the bar in pancreatic cancer for new entrants including Threshold’s agent, TH–302, that is also attracting a lot of attention here at ESMO.

2) Positive news regarding doubling of overall survival will be particularly good for patients suffering from this terrible disease.

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Update on bavituximab in non-squamous lung cancer

By MaverickNY on September 11, 2012

Last Friday, Peregrine announced their initial phase IIb results with bavituximab in second line non squamous non-small cell lung cancer (NSCLC). The topline results were most interesting to say the least, since the company suggested that adding bavituximab to docetaxel in second line doubled the rate of survival in these patients. The data was presented by Dr David Gerber (University of Texas, Southwestern in Dallas) at the Chicago meeting of the Multidisciplinary Symposium in Thoracic Oncology in the late breaking session.

What is bavituximab?

Bavituximab is a monoclonal antibody that targets phospholipid phosphatidylsterine (PS), which exists in the membrane of vascular endothelial cells.

In normal conditions, PS is hidden in the inner membrane, but in cancer conditions, the tumour microenvironment can cause the PS cells to also be expressed on the outer membrane. It is thought that chemotherapy can also heighten the PS exposure in the tumour microenvironment, leading to reduced anti-tumour responses.

Bavituximab’s role is to bind to the activated PS on the outer membrane, essentially blocking PD mediated tumour suppression. This is an immune effect, similar to PD–1, whereby it allows the body to recognise the presence of cancer and stimulates it to fight the tumour.

What was the trial design?

The phase II trial randomised patients with non-squamous NSCLC (n=121) to receive one of the following:

1) Docetaxel 75mg/m2 3qw + placebo for up to 6 cycles (n=40)
2) Docetaxel 75mg/m2 3qw + bavituximab 1mg/Kg qw for up to 6 cycles (n=40)
3) Docetaxel 75mg/m2 3qw + bavituximab 3mg/Kg qw for up to 6 cycles (n=41)

Each of the groups then received maintenance therapy ie placebo or bavituximab (1 or 3mg/Kg) until progression.

The primary endpoint of the trial was response rate and the secondary endpoints included PFS, OS, safety and duration of response.

Where were the centres?

Aside from University of Texas Southwestern in Dallas, other US sites included Hershey, several regional cancer centres and a number of community oncology sites, presumably US Oncology. Internationally, the centers included sites in Russia, India and Ukraine.

The trial details can be found in the clinical trials database.

What did the results show?

Based on the company’s press release, the interim data analysis appeared to suggest that adding bavituximab to docetaxel doubled the overall survival from 5.6 months with docetaxel/placebo to 12.1 months in the pooled bavituximab arm. Each active arm was 11.1 and 13.1 months for 1 and 3 mg/Kg respectively. I’m not sure that the individual arms were significantly different from docetaxel alone or just the pooled data, which naturally doubles the N number and hence power in determining the difference. That’s quite a different proposition to start with.

While these results are not unheard of, they require caution for a number of reasons. We need to remember that they are reminsicent of other, similar small company phase II trials in lung cancer such as Antisoma’s ASA–404, where an increase of 8 months or so in the phase II study was not repeated in a large scale randomised phase III trial. I do think there is enough here from the current bavituximab study to warrant testing the immunotherapy in phase III RCT, but I would urge caution in extrapolating the results at this time.

What are the potential issues with this study?

a) Small phase 2 trials in oncology are fraught with bias, which often disappears when tested on a larger scale in reputable US and EU centers.

b) Not all patients in Eastern Europe are aggressively treated to progression upfront in the same way they are in the US, in other words they may be relatively undertreated, which can influence the subsequent outcome.

c) We don’t have a breakdown by country of the results across groups – did the Eastern EU and Indian patients do better than the US ones? How many patients came from each country that participated and in which arm?

d) It is always tricky to extrapolate from small N numbers of this size, especially when no data for how well the groups were matched in terms of prognostic factors is provided beyond age, performance status etc. There was, howver, a noticeable lower number of caucasians and a higher number of asians in the 3mg bavituximab arm, for example. Would this affect the results? Who knows in a small sample!

e) No mutational analysis was made available – this means more patients with a poorer prognosis could confound the data in the 3 groups and we have no idea why some patients did better than others.

f) The amount of prior Avastin varied across the groups – from 20% (placebo) to 18% and 15% in the bavituximab arms and although not significant in a small sample size, the groups should have been better balanced for this. I would be very wary if these numbers were repeated in a much larger scale trial, especially when considering the bleeding events were higher in the bavituximab 1mg group, which also received more prior Avastin than the 3mg group but a lower number overall any adverse events or grade 3+ events.

g) It’s also difficult to interpret these data in a small sample size, especially when you consider that the toxicities in the docetaxel plus bavituximab 1mg group appear to be better than docetaxel alone. This make little sense to me.

When considering the efficacy data, there are also some other noticeable anomalies:

1) The differences in PFS are small (3.0, 4.2 and 4.5 months) between the three groups but the OS curves show a more dramatic difference. This is normally an obvious red flag – you wouldn’t predict this to happen from the marginal PFS data based on central review.

You can see the OS data as shown on Yahoo Finance:

2) The other odd thing about the PFS data is that at around month 7, the curve for the 3mg bavituximab arm suddenly drops below the 1mg arm and parallels the placebo arm, yet the OS is still better in the bavituximab arm compared with docetaxel alone? Crossover does occur in trials, but it does seem an odd drop and leads me to wonder why and what happened at that point? In addition, with immunotherapy there is usually a delayed effect rather than an upfront effect so one would expect the results in the bavituximab arm to prolong over time if the agent is working effectively.

3) While PFS of 3–4 months for a docetaxel combination is normally acceptable in second line, I would have expected the OS to be longer than 5–6 months for docetaxel alone. It is possible, however, that MOS has not yet reached and these data will improve over time since 10–11 months is a realistic target. If median OS has not yet been reached since this is interim data, then we need to wait and see what the final data will be – with and without bavituximab – since any initial benefit seen before MOS can potentially disappear over time.

Overall:

These data are very early and offer both hints of promise and portends to future doom (ie a negative phase III trial). Three things I would like to see:

1) Full data analysis with median rather than interim OS for the phase II trial
2) Subset analysis by country and prognostic factors such as mutational analysis
3) Phase III results from a randomised controlled trial involving US and EU academic centres that eliminates inevitable phase II bias

I would also caution readers to avoid extrapolating too far from interim data from small phase II trials based on the Antisoma experience in NSCLC!

ASCO 2012 Update 2: Overcoming resistance in metastatic melanoma

By MaverickNY on June 29, 2012

Following 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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A surfeit of riches in CLL and NHL: on bruton kinase and PI3K delta inhibitors

By MaverickNY on June 27, 2012

This week I’m attending an interesting 2-day conference on PI3K at the New York Academy of Sciences (NYAS).

It brings together a broad faculty of researchers in the field looking at novel aspects of the PI3K-Akt-mTOR pathway in depth.

One aspect that has become clear with these compounds is that there’s probably more that we don’t know than we do – it’s a highly complex network of nodes and cause-effect that needs to be unravelled.

We do know a few things though, for example, PI3K and mTOR are often activated in advanced disease and can cause resistance to therapy as we have seen with aromatase inhibitors in ER+ disease and trastuzumab in HER2+ breast cancer. We also know that inhibiting PI3K or mTOR can lead to activation of compensatory pathways that serve to drive oncogenic signalling and tumour survival. It’s complicated!

The most advanced agent in the PI3K class is probably Gilead/Calistoga’s GS-1101 (formerly CAL-101), which is a delta isomer inhibitor being evaluated in B-cell hematologic malignancies such as mantle cell lymphomas (MCL), indolent NHL and CLL. After promising phase I and II trials, it has now moved into randomised controlled phase III trials.

Yesterday, Langdon Miller (Gilead) gave a nice overview of the GS-1101 program. One couldn’t help but marvel at the waterfall plots obtained to date, along with the before and after pictures of a women in her 40’s with refractory CLL – a dramatic difference – she looked like a completely different person! Of course, there are a number of questions that need to be addressed next:

Is survival prolonged in heavily refractory patients accustomed to immunotherapy?
How reproducible and durable are these responses on a large scale?
How can the redistribution of the lymphocytes be addressed? Will chemotherapy help here?
Is there value in combining a PI3Ki with immunotherapy in earlier stage disease?

All of these questions are being evaluated in the next phase of the GS-1101 clinical trials. I was impressed with the progress and where Gilead are going with the compound.

There are some questions that remain in my mind though. CLL and iNHL have an embarrassment of riches in pipeline agents at the moment, with several promising compounds in development.

The obvious rival to PI3K delta inhibitors are the bruton kinase inhibitors (BTK) such as Pharmacyclics/J&J’s ibrutinib (PCI-32765), which reported impressive data at ASH last December, followed up by new data at ASCO on the combination of ibrutinib with an approved CD20 antibody, ofatumumab.

This got me thinking…

1) If we assume that both agents are lucky enough to get approved by the FDA sometime in the near future, how will oncologists and hematologists decide which agent to give which patient? Can patients be stratified in any way in order to define selection for treatment?

2) Is there any data on whether combining these agents together would be synergistic? (I don’t think so, yet)

3) If a PI3K-delta and a BTK inhibitor were synergistic preclinically, what are the chances emerging of a combination trial between the four companies involved in the development of GS-1101 and ibrutinib? Sadly, a cynic would shake their head and say very low, but we need an answer on 2) from academic research before we get too excited.

4) What are the mechanisms of adaptive resistance in patients to both classes of agents in CLL and NHL? If we know the answer to this critical question, then rational combinations could be investigated further.

5) Would combining GS-1101 with CD20 antibody immunotherapies such as rituximab and ofatumumab be an interesting approach to see if better response rates and outcomes will be achieved? These are indeed being planned, along with a combination with bendamustine, another drug often used in relapsed/refractory NHL and CLL.

6) How will sequencing be important? If a patient is eligible for either therapy, which one should be tried first? This area is rather murky right now.

We’ve come a long way so far with both of these compounds, but there’s still an even longer way to go before we have some clarity on how they might change clinical practice and help improve outcomes for patients with NHL and CLL.

This is definitely an exciting area to watch out for, even if we have more questions than answers right now.

ASCO 2012 Update 1: Advanced Lung Cancer

By MaverickNY on June 26, 2012

It’s been a crazy busy time since the American Society of Clinical Oncology (ASCO) meeting earlier this month.

This year’s meeting had a lot of hidden gems in both the tumour oral and poster sessions, which will be covered in a series of blog posts.

One theme that clearly emerged was how much effort is being devoted to identifying the causes of acquired resistance to a variety of TKI single agent therapies in order to determine logical combination strategies for the clinic.

Two areas that stood out for their combined translational-clinical efforts at this years ASCO were advanced lung cancer and metastatic melanoma.

I’m delighted to announce that my first guest blogs are appearing on Chemical and Engineering News this week on these topics. For those of you interested in advanced melanoma, check back on PSB on Thursday for the link.

The good news is that the lung cancer one has posted today. Some of the topics from ASCO 2012 covered in the post include:

Does a pan-ErbB inhibitor produce better results upfront than chemotherapy?

What new advances are there for patients with KRAS mutations?

How do we overcome ALK resistance? 

Does chemotherapy produce better responses than Tarceva for EGFR wild-type in second-line NSCLC?

You can check it out here!

Interested in the PI3K-AKT-mTOR pathway in cancer research?

By MaverickNY on June 20, 2012

Here’s a quick update on the next conference I’m planning to attend in New York next week. It’s hosted by the New York Academy of Sciences (NYAS) in their downtown New York headquarters by the World Trade Center, which has fantastic panoramic views of uptown Manhattan and Brooklyn from the 40th floor. More importantantly though, judging by the last few meetings I’ve attended there on cancer metabolism and a most fascinating lecture on ink and tattoos from Carl Zimmer, it should be a very good event and well worth attending.

The latest conference is a two day affair on “Inositol Phospholipid Signaling in Physiology and Disease” otherwise known as the PI3K-AKT-mTOR pathway, which is a key process that is dysregulated in many cancers:

The organizing committee of William Kerr (Suny), Christina Mitchell (Monash Univ) and Christian Rommel (Intellikine) have done an excellent job putting together a comprehensive program that covers a wide variety of related topics from both academia and industry across the globe.

I’m really looking forward not only to the science feast, but also to the networking opportunities to mix and mingle with some of the top researchers in the PI3K field, including Lew Cantley (Harvard), Neal Rosen (MSKCC), Bart Vanhaessebroeck (Barts, London) and David Solit (MSKCC) amongst many others.

For those of you interested in registering for this event, you can obtain a 15% discount when you click on the graphic or link above and enter the coupon code INOSITOL15 on checkout, as I’m delighted to say Icarus Consultants was invited to be one of the media partners for the event.

For those who cannot attend, I’ll post a short synopsis of the conference on PSB after the event later next week. In the meantime, I hope to see you there!