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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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MET, HGF and EGFR inhibition in cancer

By MaverickNY on September 7, 2010

Hepatocellular Growth Factor (HGF) and MET receptor tyrosine kinase signalling play important roles in development as well tumorigenesis. In a Nature review article, Comoglio noted:

"Signals generated by the tyrosine kinase receptor Met elicit a complex biological response including cell dissociation, migration, protection from apoptosis, proliferation and differentiation."

They are also involved in liver regeneration and repair (Huh et al., 2004).

Background

HGF and MET have been shown to be active in a wide range of different cancers from bladder cancer to Wilms Tumours, although it is not yet clear in which tumours the pathway is critical to survival or merely over-expressed as a consequence of events.

The pathway is fairly complex, but here is a simple version:

Source: Angion Biomedica

There is a more detailed pathway schematic in Eder et al's paper (see reference below) for those interested.

Activation of HGF or MET, results in downstream signalling of the RAS-ERK and PI3K-mTOR pathways. The EGFR ligand has been excluded from this schematic for simplicity, but you can imagine how they can interact and thus dual inhibition of both will essentially reduce the risk of either cross-talk or feedback between the two, which reactivates the downstream pathways unless inhibited.

Inhibitors in the Pipeline

This year we have discussed several MET inhibitors on this blog, namely:

Pfizer's crizotinib, which is a weak MET inhibitor, but potent ALK inhibitor
Combination of MET and EGFR inhibition previously with ARQ-197 (Arqule/Daiichi-Sankyo) in early lung cancer

I did some research on MET inhibitors in the pipeline and was surprised to find that there are over 30 of them in development, with nearly a dozen in the clinic already. ARQ-197 is clearly leading the pack and moving into phase III soon, as I classify PF-2341066 as an ALK inhibitor, since that's where it's most active.

Here are some of the active compounds I recently came across, although not all of them may still be actively pursued:

Most of the others in the clinic are in more generic phase I allcomer solid tumour trials, as companies look for safety and efficacy signals before determining which tumour types to focus on for major development.

Several compounds appear to specifically target both HGF and MET, eg MetMAB (Roche) and AMG102 (Amgen), whereas others target purely c-MET eg ARQ-197 and some are multi-kinase Inhibitors, eg XL880 and MK-2461, so it remains to be seen which approach will ultimately work best with these agents, and in what combinations for different tumour types.

Single agent vs combination?

Undoubtedly, the data so far suggests that dual inhibition with an EGFR inhibitor such as erlotinib will be more effective than single agent targeting of MET alone.

A recent paper in Cancer Research on MET, HGF and EGFR inhibition with SGX523 (SGX Pharma and Lilly) therefore piqued my interest. I actually thought this compound had been discontinued, following unexpected toxicities two years ago (see here and here), principally compromised kidney function, but it may have been revived by the research group, as the two latest published papers are from late 2009 and last month and Lilly acquired the biotech company in 2008.

The authors looked at a SCID mouse model with the goal of predicting efficacy. Indeed, they concluded that:

"Our findings also indicate that simultaneously targeting the MET and EGFR pathways can provide synergistic inhibitory effects for the treatment of cancers in which both pathways are activated."

Looking at the data though, most of the tumour suppression occurred when SGX523 was combined with erlotinib than either alone as a single agent, suggesting this approach may have more utility in the clinic.

References:

Zhang YW, Staal B, Essenburg C, Su Y, Kang L, West R, Kaufman D, Dekoning T, Eagleson B, Buchanan SG, & Vande Woude GF (2010). MET Kinase Inhibitor SGX523 Synergizes with Epidermal Growth Factor Receptor Inhibitor Erlotinib in a Hepatocyte Growth Factor-Dependent Fashion to Suppress Carcinoma Growth. Cancer research, 70 (17), 6880-90 PMID: 20643778

Buchanan SG, Hendle J, Lee PS, Smith CR, Bounaud PY, Jessen KA, Tang CM, Huser NH, Felce JD, Froning KJ, Peterman MC, Aubol BE, Gessert SF, Sauder JM, Schwinn KD, Russell M, Rooney IA, Adams J, Leon BC, Do TH, Blaney JM, Sprengeler PA, Thompson DA, Smyth L, Pelletier LA, Atwell S, Holme K, Wasserman SR, Emtage S, Burley SK, & Reich SH (2009). SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. Molecular cancer therapeutics, 8 (12), 3181-90 PMID: 19934279

Comoglio PM (2001). Pathway specificity for Met signalling. Nature cell biology, 3 (7) PMID: 11433311

Huh CG, Factor VM, Sánchez A, Uchida K, Conner EA, & Thorgeirsson SS (2004). Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proceedings of the National Academy of Sciences of the United States of America, 101 (13), 4477-82 PMID: 15070743

Comoglio PM, Giordano S, & Trusolino L (2008). Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nature reviews. Drug discovery, 7 (6), 504-16 PMID: 18511928

Eder JP, Vande Woude GF, Boerner SA, & LoRusso PM (2009). Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 15 (7), 2207-14 PMID: 19318488

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Fluid-based early detection biomarkers in cancer

By MaverickNY on July 13, 2010

A really interesting idea that seems to be growing in popularity is the concept of fluid-based biomarkers from blood, urine, saliva etc, as opposed to invasive tumour biopsies. A recent paper in Cancer Research took a look at this novel and much needed concept (reference below).

One of the biggest challenges in oncology at the moment is finding easier and more convenient ways of identifying appropriate patients who might be best suited for a given therapy. In clinical trials, often tests are developed as useful biomarkers based on tumour biopsies. However, once a drug is approved, Community Oncologists often find their patients older, frailer and with a poorer performance status or more advanced disease and thus unresectable. Earlier detection of asymptomatic patients would also be useful, since in general, the earlier the patient is diagnosed, the better their long term chances are.

There is a lot of potential value, therefore, in developing fluid-based biomarkers and tests since the majority of cancer patients are treated in the Community, rather than Academic, setting.

In leukemias, FISH and QT-PCR testing have become standard, largely because it is easy to compare a blood sample with that of a bone marrow sample to validate test results. In solid tumours though, that has generally been less easy. Even the FISH test for HER-2 positive women with breast cancer has not been without it's controversies over the years.

At recent cancer meetings such as ASCO and AACR, I have noticed an increasing number of early surrogate markers being explored in solid tumours such as circulating tumour cells (CTCs) in prostate cancer as a more viable marker than PSA, as the authors also discussed:

"Fluid sampling has advantages over imaging as it is widely accepted, readily repeated, convenient, noninvasive, and low cost. Biomarkers in body fluids have the potential to detect a wide variety of primary tumors and metastases located throughout the body. Fluid biomarkers include a variety of components in blood, urine, or other fluids that reflect the presence of a tumor in the body. These include circulating tumor cells (CTC) and macromolecules such as lipids, proteins, RNA, microRNA, and DNA that originate from tumor cells."

Source: Martin et al.,

It was interesting to see the development of Pfizer's crizotinib in non-small cell lung cancer (NSCLC) with ALK mutations emerge recently. While Pfizer should be applauded for the speed with which they have developed the drug after the mutation was discovered, the development of the mutation test has clearly not been without its challenges.

A number of patient blogs complained about the time taken to produce the results from the tumour biopsies (several weeks to a month compared to say, 48 hrs for blood tests) and also in some cases, that their own physician ordered tests were not accepted, requiring another test validated by a central laboratory, sometimes with differing results. This does not augur well for an easy to use commercial diagnostic test for ALK if there are variations in the results.

Patients with advanced lung cancer often don't have a lot of time so this will be an issue to them and their physicians. Part of the reason for the delay is that tumour biopsy tests often require DNA sequencing to be performed, which inevitably takes time. A validated blood test would have a huge advantage in terms of time and convenience, but whether it is practically possible in an example like this, I don't know.

Whether a validated blood test is being developed in parallel isn't yet clear, but lung biopsies in the community setting are not routine in the way they are for breast cancer, for example. Finding suitable patients will therefore be akin to looking for needles in a haystack as the data so far suggests that the number of patients who were ALK positive in the NSCLC trials that looked for the mutation was around 5%. I'm not sure if this will extrapolate to the broader lung cancer universe though, as patients in a clinical trial are typically different from those in the general cancer population.

Meanwhile, another other interesting trend that is emerging is microRNA:

"In addition to proteins, mRNAs are promising biomarkers, and microarrays represent a powerful approach for their discovery in blood. A study using custom spotted arrays published in 2001 identified a signature of 12 genes whose mRNA expression was elevated in peripheral blood mononuclear cells (PBMC) of breast cancer patients."

Source: Martin et al.,

The number of articles, papers, abstracts and presentations on microRNA has increased at a tremendous rate over the last 2 years. At the AACR Molecular Targets meeting last November, it seemed as though 1 in 3 abstracts mentioned the subject in a variety of different ways from prognosis to early resistance. This is one area I'll be following to see what interesting new concepts emerge. I've had a few requests for more information on microRNA, so this will be the topic of a forthcoming blog post.

The ultimate question as always, though, is what does this all mean?

Clearly, earlier detection of disease is useful for prognosis, but predicting the impact of therapeutic intervention is also important. If we can develop biomarkers for determining which drug might work optimally for a given patient or subset, that would alleviate a lot of the pressure on healthcare systems and reducing patient exposure to drugs that would not work. At present, there are probably more tests developed than actually used in practice, but incorporating them into large scale clinical trials as part of a battery of tests may well provide more useful information in the near future across a variety of different cancer types.

Time will tell, but it makes a lot of sense to incorporate a vast battery of surrogate biomarker tests upfront and then track what happens over time, as the Medivation trial with MDV3100 has shown with PSA and CTC's in prostate cancer, to offer a practical example. You never know which of the biomarkers tested will emerge as useful in any given tumour type, so testing more rather than fewer may have a higher chance of hitting the bullseye.

Martin, K., Fournier, M., Reddy, G., & Pardee, A. (2010). A Need for Basic Research on Fluid-Based Early Detection Biomarkers Cancer Research, 70 (13), 5203-5206 DOI: 10.1158/0008-5472.CAN-10-0987

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