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On the future of cancer treatment and research

By MaverickNY on June 27, 2011

This week I’m preparing an in depth mini series on the molecular target landscape associated with prostate cancer, which will be scheduled for next week, so do check back if that is a topic of interest to you.

In the meantime, I came across this video from MD Anderson, where the new President-elect Dr Ronald DePinho talks about the near term future of cancer research and where he thinks we will be going.

It’s less than four minutes long, easily understandable and well worth watching:

http://youtu.be/pWAUd1PV8Ao

For those of you interested in my perspectives on some of the early clinical trial approaches, there’s a guest blog post on PharmaLive’s R&D Directions entitled “ASCO followup: Patients, pathways, progress in practice” today – check it out!

Does maintenance therapy with chemotherapy improve PFS in non-squamous lung cancer?

By MaverickNY on June 24, 2011

In the final article on the lung cancer mini series this week, it’s time to discuss one of my least favourite topics – chemotherapy.

Regular readers will remember the guest post from Dr Al Lalani just prior to ASCO on the acronymania that pervaded the abstract book this year for various clinical trials. I was therefore much amused to play ‘buzzword bingo’ at the meeting and see how many of his list I came across 😉

One trial in particular stood out in a session on lung cancer called PARAMOUNT. Three years ago, I wrote about the FDA approval of pemetrexed (Alimta) in front line treatment of NSCLC in non squamous histology.

The new phase III data looked at whether it was safe and effective to continue pemetrexed as maintenance therapy after initial induction treatment with the pemetrexed plus cisplatin doublet for four cycles. A total of 939 patients with advanced nonsquamous NSCLC were enrolled in the study.

Patients whose disease had not progressed during the induction, and had a good performance status of 0-1 (n=439), were randomized to receive either:

Pemetrexed maintenance (500 mg/m2 on day one of a 21-day cycle) plus best supportive care (n=359) OR
Placebo plus best supportive care (n=180) until disease progression.

All patients received vitamin B12, folic acid and dexamethasone. The main goal of the trial was to determine if progression-free survival (PFS) was improved by maintenance therapy with pemetrexed.

The final analysis demonstrated that the primary endpoint was met:

Median PFS of 3.9 months (95% CI: 3.0-4.2) in the pemetrexed arm versus 2.6 months (95% CI: 2.2-2.9) in the placebo arm.
In addition, disease control rate (% patients with response/stable disease) was 71.8% in the pemetrexed group and 59.6% in the placebo arm (P=0.009).

Toxicities were in line with those expected for pemetrexed based on previous studies, ie anemia, fatigue and neutropenia were all greater than placebo. Discontinuations due to AEs were 5.3% with ALIMTA and 3.3% with placebo.

Overall, when considering the question of whether pemetrexed improves PFS as maintenance therapy for non-squamous NSCLC patients, it looks to be a safe and viable option, albeit with a small additional increase of 1.3 months in survival.

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MET amplifications and resistance to EGFR therapy in lung cancer

By MaverickNY on June 23, 2011

Continuing our mini series on molecular targets and lung cancer this week, today I’m going to focus on MET amplications for this post.

A few years ago, Jeffrey Engelman’s group at Mass General (see Reference section below) reported that MET amplication leads to resistance with EGFR inhibitors such as gefitinib (Iressa) by activating ERBB3 signalling:

“MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)–dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors.”

Others have shown similar results in non-small cell lung cancer (NSCLC) with erlotinib.

Subsequent to this, a number of MET inhibitors have entered the clinic looking at the impact of combining a MET inhibitor with erlotinib in adenocarcinomas that are EGFR mutation positive.

Two of the leading compounds in phase II/III development are described below:

ARQ-197 (ArQule/Daiichi Sankyo) a small molecule inhibitor of c-MET
METMab (Roche/Genentech) a monoclonal antibody to c-MET

ArQule currently has two phase III trials both in the refractory setting looking at non-squamous NSCLC in combination with erlotinib versus erlotinib alone – one is currently enrolling while the other will soon be open to recruitment.

Of course, there are other MET inhibitors in earlier development (eg crizotinib is a weak inhibitor of c-MET, but is being evaluated in ALK translocated NSCLC).

What was interesting at ESMO last September was the phase II data that was presented on both agents in the same session. The ARQ-197 data grouped all the patients together as one group and showed a trend in favour of the combination arm vs erlotinib plus placebo (7.3 vs 3.6 months) in terms of time to new metastases.

Since then, the ArQule phase III trials have been set up and appear to be looking at:

“The status of the following biomarkers will be collected in this study: EGFR and KRAS mutation status prior to randomization, and MET status post randomization.”

I think that is a good approach, because the METMab data at that conference clearly showed that MET High and MET Low patients had very different outcomes, based on the limited phase II data I saw at ESMO.

Meanwhile, the final METMab phase II data was presented from the OAM4458g study at ASCO this month, with no major change from the interim data presented last Fall ie MET High patients appear to have superior responses with the combination than erlotinib monotherapy. The results clearly illustrate the importance of accurate biomarker analysis in these types of studies because while some patients did well on the combination, others did not, some did worse and the unselected group overall showed no difference.

Which begs the all important question – which patients did well on METMab plus erlotinib?

Those who had high MET expression, confirming the theory that resistance can be attenuated, at least for a while, with a dual combination approach of MET plus EGFR inhibitors but only in a very select subgroup of patients.

To illustrate this we can see that the addition of METMAb to erlotinib almost doubled the median time that those who were MET High (positive) were free of disease from 1.5 months to 2.9 months (HR 0.53; P=0.04) as you can see in the table from the ASCO abstract. The combination also tripled median OS from 3.8 months to 12.6 months (HR 0.37; P=0.002):

I would imagine that a phase III trial in NSCLC will evolve very soon and it will be most interesting to see how the design and patient selection criteria for the trial will evolve, based on the known findings to date. These factors may determine whether a successful difference can be seen with the combination based on biomarkers to define a more homogenous group.

Interestingly, a phase II study is currently enrolling with METMab in triple negative breast cancer. This is a complex three arms design looking at the impact of:

MetMAb + bevacizumab + paclitaxel
MetMAb + placebo + paclitaxel
Placebo + bevacizumab + paclitaxel

In theory, this should tell us whether eith METMab or bevacizumab have any advantage over paclitaxel chemotherapy.

What does the data with MET inhibitors mean?

The trials with both ARQ-197 and METMab teach us some important lessons in NSCLC:

Catch-all studies of homogenous groups are a recipe for the dreaded words, “there was no significant difference in survival between the two groups”
The importance of biomarkers in teasing out those most likely to respond
The importance of careful patient selection in achieving those aims

When we think about this year’s ASCO conference theme of “Patients. Pathways. Progress,” we should be mindful of the fact that in order to match the therapy to the patient’s mutations, we need to continue to devise studies that seek to do exactly that – sometimes good drugs fail, not because they didn’t work, but because the relevant biomarker wasn’t found to illustrate which patients did respond. When that happens, it’s a failure of R&D, not the drug itself.

Going back to the quote above from the Engelman et al., (2007) paper, I do wonder if MET plus erlotinib is the ideal combination in the relapsed/refractory setting with adenocarcinomas, even allowing for MET-High status? Would a pan-EGFR inhibitor that also inhibits HER3 be a better partner with MET inhibitors than erlotinib in these patients? Who knows, but hopefully someone will test that hypothesis out in a phase II trial at some point.

References:

Engelman, J., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J., Lindeman, N., Gale, C., Zhao, X., Christensen, J., Kosaka, T., Holmes, A., Rogers, A., Cappuzzo, F., Mok, T., Lee, C., Johnson, B., Cantley, L., & Janne, P. (2007). MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling Science, 316 (5827), 1039-1043 DOI: 10.1126/science.1141478

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Update on new targets in squamous cell carcinoma of the lung

By MaverickNY on June 22, 2011

Over the last couple of days we have looked at targeted therapies designed to inhibit some of the molecular peculiarities associated with non-squamous lung cancer, and adenocarcinomas in particular.

Squamous Cell Lung Cancer

As far as I know, there are no approved targeted therapies specifically for squamous cell carcinoma (SCC) of the lung, so chemotherapy is very much the standard of care still, although response rates tend to be disappointing. Unlike adenocarcinomas, this subset is more often associated with smoking. It also represents a large group of approximately 25% of NSCLC.

Previously, we have discussed FGFR1 mutations in SCC as a potential target, but although there a several FGFR inhibitors in the clinic, I couldn’t find any specifically being tested in SCC lung cancer.

Recently though, Peter Hammerman and Matthew Myerson (Dana Farber) published interesting data at the annual AACR meeting identifying a potential new therapeutic target, discodin domain receptor 2 (DDR2), in squamous cell carcinoma of the lung.

What does this new research on DDR2 tell us?

Cancer Discovery from AACR

I’ve been meaning to write about this exciting development since the AACR meeting, but the data was published in the new journal Cancer Discovery.

Somewhat perversely, the DOI references are not yet showing up in PubMed or Research Blogging, so I finally resorted to adding the reference manually.

If the link in the Reference section at the end of the blog post doesn’t work, you can download the article (open access PDF) below:

Mutations in the DDR2 Kinase Gene identify a Novel therapeutic target in squamous cell lung cancer

Essentially, Sanger sequencing was employed to look at the tyrosine kinome and determine whether any relevant mutations existed in 290 SCC samples. The schema for the Hammerman et al’s (2011) research is described below:

DDR2 is a receptor kinase that binds collagen as its exogenous ligand and has previously been shown to promote cell migration, proliferation and survival when activated.

Ultimately, DDR2 mutations were observed in 11 of the 290 samples in the validation screen. The researchers observed that these DDR2 mutations occurred in 3.8% of lung squamous cell carcinomas, and in xenograft models these appeared to show a sensitivity to dasatinib (Sprycel), a multi-kinase inhibitor approved for the treatment of Ph+ chronic myeloid leukemia (CML).

Several kinase inhibitors were evaluated, including imatinib, but dasatinib was found to be particularly sensitive. The reason is that has a much lower fluorescent resonance energy transfer (FRET) measurement (5.4 nM) than imatinib (71.6 nM) for recombinant DDR2. Interestingly, both nilotinib (35.4 nM) and ponatinib (5.4 nM) also showed activity in SCC cell lines harbouring DDR2, although ponatinib appeared to be the more potent of the two, with activity in line with dasatinib in this setting.

Subsequently, it was observed that a SCC lung patient with a DDR2 mutation responded well to a combination of dasatinib and erlotinib therapy, suggesting a clinical trial might be in order to determine efficacy and also safety on a broader scale, since dasatinib is associated with adverse events such as pleural and pericardial effusions in CML, possibly from off-kinase Src activity.

For those interested, you can listen to a short podcast via Cancer Discovery with Matthew Myerson on the DDR2 mutation.

Conclusions

Overall, the landscape in lung cancer is rapidly changing as more molecular targets are being identified, along with therapies that specifically inhibit the driving cancerous activity.

EGFR mutations were the first major breakthrough in targeted therapies, but with the discovery of ALK translocations, T790M mutations (all adenocarcinomas) and now with FGFR1 and DDR2 (squamous), we have exciting opportunities to potentially match therapies to patients in non-small cell lung cancer in a new era of molecularly targeted and personalised therapy, assuming clinical trials corroborate the promise of the targets, that is.

I can see a time in the not too distant future that we will start diagnosing, testing and treating people with lung cancer based on their molecular abnormalities on a more routine basis with targeted therapies, rather than merely test for histology, which is a rather crude and heterogeneous way of looking at the conundrum. Of course, we would still need to research and tackle the adaptive resistance pathways that emerge, but it would certainly be a huge improvement on toxic chemotherapies we have now… and that would be a major step forward for this devastating disease.

Check back tomorrow for the next article in the series on lung cancer targets!

References:

Peter S. Hammerman, Martin L. Sos, Alex H. Ramos, Chunxiao Xu, Amit Dutt, Wenjun Zhou, Lear E. Brace, Brittany A. Woods, Wenchu Lin, Jianming Zhang, Elisabeth Brambilla, Christian Brambilla, Philippe Lorimier, Odd Terje Brustugun, Åslaug Helland, Iver Petersen, Joachim H. Clement, Harry Groen, Wim Timens, Hannie Sietsma, Erich Stoelben, Jürgen Wolf, David G. Beer, Ming Sound Tsao, Megan Hanna, Charles Hatton, Michael J. Eck, Pasi A. Janne, Bruce E. Johnson, Wendy Winckler, Heidi Greulich, Adam J. Bass, Jeonghee Cho, Daniel Rauh, Nathanael S. Gray, Kwok-Kin Wong, Eric B. Haura, Roman K. Thomas, & Matthew Meyerson (2011). Mutations in the DDR2 Kinase Gene identify a Novel therapeutic target in squamous cell lung cancer Cancer Discovery, 1 (1), 78-89 : 10.1158/2159-8274.CD-11-0005

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Update on EGFR inhibitors, KRAS and T790M mutations in lung cancer

By MaverickNY on June 21, 2011

Yesterday we discussed ELM4-ALK translocations associated with adenocarcinomas in non-small cell lung cancer (NSCLC). Before ALK was identified, the main molecular target in this disease was EGFR mutations, which have been shown to be associated with improved responses when EGFR inhibitors such as erlotinib are given.

EGFR mutations

Although erlotinib is the EGFR inhibitor of choice in the US for patients with lung cancer who have EGFR mutations, unfortunately approx. 50% of them with development resistance as a new mutation evolves, known as T790M. In addition, patients with EGFR mutant disease generally don’t respond well to erlotinib.

There are a number of EGFR inhibitors now in development for lung cancer, specially adenocarcinomas, and this market is rapidly getting fairly crowded, as the table shows:

EGFR Inhibitors

Note: *Although gefitinib was approved, there is very little use of this agent in the US since the FDA modified the PI to include mention of no overall survival benefit.

This table does not include all EGFR inhibitors in clinical development, since those focused on HER2+ breast and gastric cancers (trastuzumab, lapatinib, pertuzumab) and KRAS wt colorectal cancer (cetuximab and panitumumab) were excluded from this analysis. There are, no doubt, other EGFR inhibitors also being evaluated in lung cancer, but these are the main ones I’m following – it’s for illustrative purposes only!

What we can see here is that the EGFR market in lung cancer is getting pretty competitive in terms of clinical trials and is a much more mature market than the ALK one discussed yesterday, although only erlotinib is still currently available in the US for treatment of EGFR+ mutations.

Beyond that, there are at least three inhibitors in phase III trials alone:

Afatinib, which reported rather indifferent data in the LUX-LUNG1 trial at ESMO last September, with an improvement in response rate over placebo, but no advantage in overall survival, the primary endpoint of the trial.
Necitimumab, a monoclonal antibody being tested in squamous histology in combination with gemcitabine and cisplatin.
Nimotuzumab, another monoclonal antibody to EGFR, which is in phase III for oesophageal and H&N cancers, but currently enrolling in several phase II lung cancer trials at the moment.

Aside from the sheer awkwardness of trying to say either of the last two generic names and resorting, like many people to calling them Nessie and Nemo, I also have trouble remembering which one is which or my eyes glaze over! The tongue twisters that are cropping up for a multitude of targeted therapies is more challenging than ever. On top of that is the dreadful tendency of late to choose ugly brand names for cancer drugs that seem to have been purchased as a job lot from Eastern Europe brand agencies.

T790M confers resistance to erlotinib

We have known for a while that EGFR inhibitors do not work in all patients:

They are effective in wild type but not mutant EGFR
Some patients on EGFR therapy develop resistance due to a new mutation, T790M, appearing (see Hammerman et al., 2009).

There has been little progress in either of these two areas of late, although a multitude of clinical trials are now ongoing and we are awaiting data readouts.

Dr Jack West, Swedish Cancer Institute

Dr Jack West from the Swedish Cancer Institute in Seattle blogged about his enthusiasm for the irreversible EGFR inhibitor, PF299804, in lung cancer last summer, based on the two small studies (one American and one Asian) that were reported at the time. Another small Australian study on EGFR mutations and PF299804 was also presented at ASCO last year.

The Asian study looked promising enough at the time for Park et al., (2010) to conclude that the data from the Korean patients with KRAS wild-type NSCLC (adenocarcinoma histology) who were refractory to platinum-based chemotherapy and erlotinib (E) or gefitinib (G) that:

“Preliminary data consistent with Western trials show that in heavily treated Asian pts with NSCLC after E or G failure, PF299 is well tolerated and has antitumor activity without adversely impacting pts’ HRQOL. These results support the ongoing global P3 trial in pts with refractory NSCLC.”

KRAS mutations in NSCLC

I distinctly remember at ASCO in 2010 one of the three groups stated that a phase III trial (BR26) would be forthcoming in KRAS wt patients. This trial is is now enrolling patients in the refractory setting after failure of erlotinib in both KRAS mutant and wild type patients, so we are unlikely to get a readout of this study before the end of 2012 at the earliest.

Dr Nathan Pennell, Taussig Cancer Center

What was also interesting was another more recent post on GRACE by one of the faculty, Dr Nathan Pennell, discussing the combination of afatinib and cetuximab in EGFR+ lung cancer.

Like Dr Pennell, I would not have been enthusiastic about this potential combination after seeing the LUX-LUNG data presented by Dr Vincent Miller at ESMO last September, and knowing that cetuximab has shown weak activity in lung cancer at best, both alone and in combination with erlotinib.

However, as Dr Pennell described, the results with the afatinib plus cetuximab combination were much better than expected in erlotinib refractory lung cancer patients:

“The confirmed overall response rate in the first 45 evaluable NSCLC patients was 40%, with the response rate in the T790M patients being 50% unconfirmed (unconfirmed means they had not yet done a second set of scans to see if the tumor was still responding over 2 time points).”

Understandably, he was quietly excited by the outcome:

“This is the first time anyone has described activity for any targeted drug in the T790M EGFR population, and this provides the first glimmer of hope for the many patients out there who face the reality of knowing that their tumors are still dependent on EGFR mutations but for whom Tarceva simply doesn’t work anymore.”

This is most interesting, because while afatinib is a TKI that works similarly to erlotinib and gefitinib inside the cell on the EGFR ligand, cetuximab is a monoclonal antibody that works on the outside of the ligand, suggesting that targeting the ligand upstream and downstream may well be necessary to ensure complete EGFR inhibition in these patients ie EGFR, KRAS and T790M, we don’t know for sure, but now doubt a paper will be published soon explaining the scientific phenomenom.

The result is certainly a big surprise given the previous disappointing data for cetuximab combined with erlotinib (no responses out of 19 patients evaluated), so I’m not sure why afatinib is different given it is also a small molecule TKI. Further large scale trials will needed to confirm these promising results. A phase I trial with cetuximab and afatinib in NSCLC is currently enrolling patients.

For those interested, you can check out the simply stunning waterfall plot that Dr Pennell found for the combination of afatinib and cetuximab, with both EGFR+ and EGFR- patients responding. I confess I nearly fell off my chair when I looked – the data is not what was expected at all!

Meanwhile, Pfizer also appear to be looking at PF299804 in HER2+ gastric cancer, which is logical given the activity previously demonstrated by trastuzumab. There are over 20 studies with this pan-EGFR agent. Although I’m sure I read somewhere that PF299804 specifically targets the T790M mutations that develop with erlotinib, it will be interesting to see what happens with wild-type and mutant subsets, since we know that erlotinib and gefitinib only work in wild type not mutant EGFR. Another clinical trial is also enrolling patients with Pfizer’s pan-EGFR (PF299804) and MET inhibitor (crizotinib) in NSCLC. More on c-MET inhibitors will follow in another post.

All that said, the rationale for targeting T790M mutations in erlotinib-refractory disease is fairly compelling in theory, but the trials will not be easy as there are several challenges that must be overcome:

Design and implementation – patient and inhibitor selection will be crucial
High risk, especially if the compound is a weak inhibitor
Heavily pre-treated refractory patients tend to be sick with a higher tumour burden that is more resistant to therapy
It is a small, difficult to treat subset
Finding patients with good performance status who meet all the eligibility criteria is never easy in small refractory subset populations
Would combinations be superior to single agent therapy or should sequencing be investigated?
An upfront trial as a head to head with erlotinib would clearly be easier to execute, but also high risk if the agent is too similar

The more you look at the conundrum, the more one realises that addressing it is not as easy as it first looks. Some basic research looking at sequencing versus combinations in cells lines and xenografts with different agents may be a useful starting point.

That said, the news last Friday that Ariad are advancing their dual EGFR-ALK inhibitor AP26113 into the clinic later this year is good news for patients with lung cancer, because more available options is always better than fewer. It will be interesting to see how the drug fares in either ALK-refractory patients (refractory to crizotinib) or in EGFR mutations (refractory to erlotinib) as potential fast track to market strategies.

Conclusions

Overall, the landscape in lung cancer is rapidly changing as new molecular targets are being identified, along with new targeted therapies that specifically inhibit the driving cancerous activity.

EGFR mutations were the first major breakthrough in targeted therapies for lung cancer, but with the discovery of ALK translocations, T790M mutations, MET and FGFR1 ampliflication, and DDR2 mutations, we now have exciting opportunities to potentially match therapies to patients in across a range of different non-small cell lung cancer subsets in a new era of molecularly targeted and personalised therapy.

Beyond erlotinib, there is a clear high unmet medical need for new targeted therapies that specifically inhibit either the T790M mutation associated with resistance to initial therapy or will work in KRAS mutant EGFR lung cancers. The afatinib + cetuximab combination in erlotinib refractory NSCLC looks very promising and I’m very much looking forward to watching all the new developments evolve in this area.

Disclosure: I am an unpaid member/volunteer of the GRACE Board.

References:

Hammerman PS, Jänne PA, & Johnson BE (2009). Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. Clinical Cancer Research, 15 (24), 7502-7509 PMID: 20008850

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Update on emerging therapies in ALK+ lung cancer

By MaverickNY on June 20, 2011

Last week’s post on FGFR1 mutations in squamous cell lung cancer and the new EGFR/ALK combination agent, AP26113 (Ariad) drew a lot of attention from readers, with many writing in for more details or correctly suggesting an update in squamous cell carcinoma was long overdue.

Oddly, there wasn’t much in the way of new or exciting data in lung cancer at the recent American Society of Clinical Oncology (ASCO), but there are some recent developments that are worth looking at in EGFR, ALK+ and squamous cell carcinoma.

Let’s take a look at each in turn over a series of blog posts.

In the old days, lung cancer was first divided into Small Cell Carcinoma (SCC) and Non-Small Cell Lung Carcinoma (NSCLC), which have a broad split of about 20:80. As we learned more about the disease, NSCLC was eventually divided further in squamous and non-squamous histology, as therapies such as pemetrexed (non-squamous) and bevacizumab (non-squamous) emerged.

Erlotinib was found to work best in adenocarcinomas, ie EGFR mutation-positive tumours. As far as I know, there are no approved targeted therapies for the treatment of squamous histology and much of the focus has been in mutations associated with adenocarcinomas, which mostly (but not always) tend to be associated with non-smokers.

ELM4-ALK translocations

Within adenocarcinomas, we are learning that EGFR isn’t the only mutation that might be a potential target, as the recent data in crizotinib published in the NEJM by Kwak et al., (2010) on ELM4-ALK translocations has shown.

For those of you interested in the development of the ALK translocations in lung cancer, Dr Ross Camidge also provided an excellent overview when we interviewed him on Pharma Stratgy Blog last year. It’s worth checking out if you missed it, and has become one of our most popular posts since last October.

Dr Jack West from GRACE has diligently curated a huge volume of posts, interviews and webcasts on lung cancer, including this nifty chart showing the currently identified mutations in adenocarcinomas:

Source: GRACE

Of course, as luck would have it, EGFR mutations and ALK translocations tend to be mutually exclusive, so there would probably be little benefit in combining agents that target EGFR or ALK mutations, even in adenocarcinomas.

Crizotinib, the first ALK inhibitor to successfully make it past phase II trials, has already been filed by Pfizer for approval with the FDA and should provide a new option for lung cancer patients with this translocation very soon. This is an exciting development because oncologists will be able to order a FISH test using the companion diagnostic developed by Abbott (also submitted to the FDA) to determine if their patients will be suitable for crizotinib therapy.

Although crizotinib was originally developed as a c-MET inhibitor, its activity there was very weak (the Roche and ArQule compounds, MET-Mab and ARQ197 respectively, are much more potent and continue to look promising in phase II trials), the discovery of the ALK translocation changed the clinical development plan dramatically and for the better.

Unsurprisingly, there aren’t too many ALK inhibitors in development to date, with crizotinib being the lead compound:

ALK Inhibitors

This is a small, but rapidly growing niche; already we can see that compounds are emerging into the clinic hot on crizotinib’s heels. The Infinity compound is a little different – it’s a heat shock protein (Hsp), while both the Novartis and Astellas agents are small molecule TKIs. As far as I know, there isn’t a monoclonal antibody or antibody drug conjugate in the clinic for this particular target yet.

Like crizotinib, AP26113 is also a small molecule TKI, but differs in that it appears to be a dual inhibitor of ALK and EGFR, including the T790M mutation that has been shown to confer resistance to EGFR inhibitors such as erlotinib in adenocarcinomas (see Hammerman et al., 2009).

Conclusions

The time between the discovery of the ELM4-ALK translocation in adenocarcinomas and moving crizotinib into clinical trials was pretty rapid, and a tribute to Pfizer’s scientists and clinicians who made that happen so expeditiously. It will be interesting to how this niche develops once FDA approval has occurred, and whether the other inhibitors in development will be merely ‘me-too’ agents or able to raise the bar beyond crizotinib in terms of efficacy, safety or overcoming resistance due to the structure forming a different binding shape in the kinase domain. Time will tell.

Disclosure: I am an unpaid member/volunteer of the GRACE Board.

{UPDATE: Thanks to Luke Timmerman of Xconomy tweeting about Tesaro, I noticed they now have a deal as of March with Amgen for unnamed ALK inhibitors in their pipeline.}

References:

Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, & Iafrate AJ (2010). Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. The New England Journal of Medicine, 363 (18), 1693-703 PMID: 20979469

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FGFR1 mutations in squamous cell lung cancer

By MaverickNY on June 17, 2011

“Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes–WHSC1L1, LETM2, and FGFR1–is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas.”

Dutt et al., (2011)

This snippet from a paper in PLoSOne caught my attention, because while we have seen a number of molecular targets identified and therapies developed for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma.

Squamous cell carcinomas account for 25% of new lung carcinoma cases and 40,000 deaths per year in the United States, a not inconsiderable number of patients.

This isn’t a new finding per se, as we have discussed FGFR1 amplification in lung cancer previously on this blog. However, what was also interesting and novel about the paper, is that the authors went on to note:

“Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition.”

In this study, the pan-FGFR inhibitor PD173074 (Pfizer) was used to test whether cell growth was attenuated or not. There are a number of FGFR inhibitors in development, which we discussed in the last blog post on this topic in December.

All this sounds very encouraging indeed, although there are caveats that should be stated, for example, preclinical research is no guarantee of success in the clinic and amplification of a mutation or gene (as opposed to mutation) does not mean that it is a driver of the disease – it could be a passenger or overexpression as a consequence of other things happening as a result of the tumour proliferation.

Still this is a promising finding well worth exploring, because as the authors rightly point out, “no FDA-approved targeted therapies for squamous cell lung cancer.”

The critical key to exploring mutations, amplifications and targeted therapies in the clinic going forward will be to have well designed iterative phase II trials with very careful patient selection based on the known biology to tease out the patients most likely to respond rather than catch-all studies where the chances of finding responders over non-responders is much lower.

Why do this? Overall, I think it is better to have high response rates in a small subset than a low response rate in an unselected population where people who have no chance of doing well are exposed to the systemic side effects unnecessarily.

We can see this trend clearly emerging with the well designed trials ELM4-ALK translocations for crizotinib, for example. Interestingly, ALK and lung cancer mutations (seen in adenocarcinomas) are very much in the news this month, following some excellent data at ASCO for Pfizer’s crizotinib that augers well for FDA approval and Ariad announcing that they are progressing their dual ALK-EGFR inhibitor, AP26113, into the clinic. Preclinically, this agent has also been shown to inhibit the T790M mutant that is resistant to EGFR inhibitors. You can read more from Ariad on their EGFR-ALK inhibitor.

Oddly, Ariad’s other drug in phase II clinical development for CML, ponatinib, also inhibits FGFR and FLT3 as well as BCR-ABL, the critical target in CML; this will be an interesting company to watch out for over the next few years.

References:

Dutt A, Ramos AH, Hammerman PS, Mermel C, Cho J, Sharifnia T, Chande A, Tanaka KE, Stransky N, Greulich H, Gray NS, & Meyerson M (2011). Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung Cancer. PloS one, 6 (6) PMID: 21666749

3 Comments

Is NOTCH a new target in leukemia?

By MaverickNY on June 16, 2011

Over the last five years I’ve been involved in quite a bit of market research relating to chronic lymphocytic leukemia (CLL) and have been struck how the core therapies are still largely chemotherapy based. CLL is an indolent disease of the bone marrow, where it produces too many lymphocytes (white blood cells), whereas chronic myeloid leukemia (CML) is an excess production of myeloid cells:

CLL is characterised by an excess of lymphocytes

Source: cancer.gov

Interestingly, while we know a fair bit about the biology of CML in terms of the driver mutation, ie Philadelphia chromosome that occurs as a result of the translocation from the 9 and 22 chromosomes thereby producing a new gene, BCR-ABL, we don’t half as much about the underlying biology pertaining to CLL.

Compare the simple elegance of CML biology to CLL, as Fabbri et al., (2011) noted:

“The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown. The full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified.”

This means that in CML, we have a valid target (BCR-ABL) and several highly effective tyrosine kinase inhibitors (TKIs) are now approved to treat the disease, turning CML from a certain death sentence into a cancer now be managed as a chronic condition.

By contrast, in CLL (which tends to have an older population than CML), we largely stuck with various immunotherapies and chemotherapies such as:

fludarabine (F)
cyclophosphamide (C)
bendamustine/Treanda (B)
chlorambucil/Leukeran (L)
doxorubicin/Adriamycin (A)

These are often used in combination with each other, or with the monoclonal antibody, rituximab (R) eg FCR, FC, FR, BR etc.

Other monoclonal antibodies in use include alemtuzumab (Campath) and ofatumumab (Arzerra), although these are often reserved for the refractory setting because FCR or FC or FR are usually preferred upfront, with BR often preferred as second line therapy. Alternative therapies that are beginning to emerge in clinical practice in the refractory setting (based on clinical trials) are bortezomib (Velcade) and lenalidomide (Revlimid), although both are currently approved for multiple myeloma and not CLL.

The challenge though, is the same old chestnut that exists for many tumour types – a heterogeneous disease without clear molecular targets means that patients cycle through various chemotherapies or immunotherapies, which prolong outcomes at the cost of relatively poor quality of life due to the extensive side effects of chronic treatment that ends up with weary, beaten up and worn out people.

With that somewhat depressing landscape in mind, my interest was piqued by Fabbrio et al’s (2011) paper on CLL and mutations that has just been published this week.

What’s new in CLL?

Basically, the group undertook an analysis to look at the mutations found in the genes of CLL patients at different stages of the disease. They found several mutations not previously linked with CLL, but most patients had relatively few genetic mutations compared to some other types of cancer.

However, they did find something very interesting:

“Mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%), as well as in chemorefractory CLL (20.8%).”

That was one of those “ooh” moments that made me read on and see what else they have to say and what the implications are. Is NOTCH1 a good molecular target that might change things for people with CLL for better?

They went to say:

“Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival.”

A dysregulated pathway can be a useful target to start with, but there are no guarantees, since it may turn out to be a passenger rather than a driver mutation. The only way to find out is to see what happens in clinical trials with CLL patients and to determine what combinations might be useful.

Clinical trials with NOTCH inhibitors

There are currently 54 trials ongoing with NOTCH inhibitors, either alone or in various combinations. Roche have the lead compound in this area, with a broad and deep program already established across multiple potential indications. The table below shows the key players, their NOTCH/gamma secretase inhibitors and the tumour types being evaluated:

Notch

This is still in very early clinical research with mostly phase I (solid tumours or advanced cancers) and only a few phase II trials started, so the race is wide open. Breast cancer and leukemia appear for two of the compounds, although I should point out that the latter tend to be in Acute Lymphoblastic Leukemia (ALL) rather than CLL. This may change with time.

This should be an interesting field to follow and I look forward to writing more about the class as the data matures…

{Update: The Howard Hughes Medical Institute send me a link via Twitter, showing that NOTCH may also have a role to play in a rarer form of leukemia, Chronic Myelomonocytic Leukemia (CMML). They also have a very cool (and free) app for ipods and ipads, which allows you to read their quarterly magazine online. It’s beautifully produced and I very much much enjoy reading it – if only it came out monthly :)}

References:

Fabbri, G., Rasi, S., Rossi, D., Trifonov, V., Khiabanian, H., Ma, J., Grunn, A., Fangazio, M., Capello, D., Monti, S., Cresta, S., Gargiulo, E., Forconi, F., Guarini, A., Arcaini, L., Paulli, M., Laurenti, L., Larocca, L., Marasca, R., Gattei, V., Oscier, D., Bertoni, F., Mullighan, C., Foa, R., Pasqualucci, L., Rabadan, R., Dalla-Favera, R., & Gaidano, G. (2011). Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation Journal of Experimental Medicine DOI: 10.1084/jem.20110921

Highlights from the European Hematology Association EHA 2011 meeting

By MaverickNY on June 15, 2011

This weekend heralded the sixteenth annual meeting of the European Hematology Association (EHA) conference at the ExCel centre in the London Docklands. Completing back to back ASCO and EHA conferences across two continents will test any delegates stamina!

Like ASCO, this year was a relatively quiet one at EHA, with most of the data already known or presented elsewhere. There were some gems in the program though.

In the latest video highlights I discuss three things that caught my attention:

Is high dose cytarabine (ara-C) really necessary in AML?
Brentuximab vedotin in anaplastic large cell lymphomas (ALCL)
Adherence with chronic TKI therapy in CML

We have previously covered the excellent data for brentuximab vedotin (Adcetris) in Hodgkin Lymphoma, but the new data presented in ALCL in the poster session was, in ways, even more dramatic as you can see from the before and after pictures included.

You can see from the video, shot on location, that the damp windy weather and rundown surroundings created a rather industrial ambience – not quite the image many may have of the Docklands and Canary Wharf, which is a couple of stops earlier on the Docklands Light Railway (DLR).

Of course, there are unplanned escapades, such as nearly missing the 8am session on Sunday morning after the Jubilee line didn’t begin until 7.20am (first train at 7.35am), then the DLR had a “system failure” at Canning Town. A quick dash down to the adjacent bus station, a frantic climb over a fence in glad rags and a rare taxi was thankfully secured for the mad dash to the ExCel centre!

Still, there is something rather edgy about hosting convention centres in marginal areas in the middle of nowhere-land, quite a trek on the Tube and DLR from the Central London:

All in all, I enjoyed the meeting in my hometown and the more relaxed academic atmosphere after the frenetic pace of ASCO, but by the end of ten days on the road it was nice to return home. It’s not all work and no play though, as you can see from this post about some of the pomp and circumstance that inevitably goes with being in London.

{UPDATE: The day after this posted, Seattle Genetics announced they have an ODAC scheduled for July 14th. The PDUFA date is August 30th, so with any luck, we may see this drug approved by the FDA sooner rather than later – great news for patients in the US!}

The cancer research paradigm is slowly changing

By MaverickNY on June 14, 2011

Over the rest of this week I’m going to take some topics related to oncology and discuss them in more detail as part of a mini series about how cancer research is changing.

We all know that cancer isn’t one disease, but actually a myriad of different subsets, often even within each tumour type. You can see the gradual shift aware from treating a type of cancer eg breast, lung, lymphoma, leukemia, melanoma etc to finding the driving the mutations and matching the patient to the therapy.

Having just returned from the European Hematology Association (EHA) meeting in London, I can say I was absolutely fascinated by the phase II data on brentuximab vedotin or Adcetris as it is now known (Seattle Genetics and Millennium), the antibody drug conjugate (ADC) in anaplastic large cell lymphoma (ALCL). Previously, we discussed the amazing data in Hodgkin Lymphoma but the photos of the patient responses in ALCL before and after treatment were amazing.

The connection?

Targeting the CD30 antibody on the surface of the cancer cells.

We can clearly see that as we learn more from basic research about the underlying mechanisms of growth, proliferation, survival and metastases, so our knowledge and ability to slow down disease progression and perhaps even stop the disease in it’s tracks also improves dramatically in some areas.

In the future, I can see triple negative breast cancer being segmented in various subtypes, for example, each with a different driving mutation and treating accordingly with carefully selected therapies, rather than treating them all as one homogenous subset of breast cancer, when they are in fact, heterogeneous.

There are several areas where we have made huge strides over the last five years:

Earlier diagnosis
Chemoprevention and slowing the inflammatory response
Identifying biomarkers, both prognostic and predictive of responses
Preventing metastases
Translational scientist-clinicians

Over the next few days, I’m going to take a deeper look at these areas and discuss some of the new technology and research that is emerging in oncology as part of an updated landscape overview in cancer research.

If you have any other areas you would like covered, please do make suggestions in the Comments below.

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