#AACR lung cancer meeting report: ELM4-ALK inhibitors
At the AACR meeting on the molecular origins of lung cancer yesterday, Dr Roy Herbst, head of thoracic medical oncology at the University of Texas M. D. Anderson Cancer Center in Houston opened the press briefing with a brief summary of the state of play today:
“Lung cancer is a very vexing problem. In the US, approx. 200,000 people will be diagnosed this year and the sad part of it, is almost as many will die. This disease tends to present having already spread, and it’s very heterogeneous. If we’re going to make the next hurdle of personalised care, we need to better understand the tumour and use that knowledge to treat patients in more specific, effective and less toxic ways.
Lung cancer receives a lot less funding than most other cancers despite being the single biggest cause of death. It lags behind in both private and public funding, as several of the panel members were quick to point out. Of course, the disease is associated with smoking, with concomitant negative connotations.
Not all patients are smokers though. Adenocarcinomas, for example, tend to
occur in non-smokers and younger patients (under 50 yo) who are often Asian and female. Why? No one really knows yet. Take a look at this inspiring patient story –
from a young, fit and otherwise healthy white male who had never smoked, which we discussed in this post last October:
Source: Lung Cancer Alliance via Inspire.com (click image to see larger version)
It’s ultimately a story that serves as a vivid reminder that no matter who we are or what we are doing, a fatal illness can strike anytime. There is a glimmer of hope though, because the trial the brave young man participated in was for a new drug class that targets the ELM4-ALK mutation, which is very rare, occurring in approximately 4% of adenocarcinoma patients. It was probably the first public report of a positive response to the targeted agent. I remember reading it about a week or so after the initial posting and followed the gentleman’s progress over time until sadly, I noticed he was no longer posting. A cruel turn of fate indeed.
That said, research in lung cancer has come a long way over the last decade as Dr Paul Bunn, another panel member, who is Executive Director of IASLC and Dudley Professor,
Univ. of Colorado Cancer Center illustrated:
Source: Dr Paul Bunn, AACR Press Briefing 1/12/2009 (click to enlarge image)
The ELM4-ALK mutation is a fusion oncogene that arises out of a translocation and has at least 7 variants. It was first identified and reported in 2007 in Nature by Soda et al.:
“The EML4–ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.”
The fact that we have have inhibitors in development is an indication of how fast can sometimes move in response to findings in basic research. Interestingly, the drug in the trial (Pfizer’s PF-02341066) was originally developed as a MET inhibitor, but it was subsequently noticed that it also effectively inhibited the ELM4-ALK mutation and since Soda and colleagues had identified a target, it was clearly worth pursuing further. It is now ongoing in phase III clinical trials. There are other inhibitors in this class, but this one is currently furthest along in the development pipeline than the others.
There was also some interesting research reported in several studies across North America, EU and Asia to determine the frequency of the ELM4-ALK mutation. Shaw et al., (2009) reported on the clinical features of patients with the ELM4-ALK mutation from a North American population, but similar features and frequency were reported in other studies. Essentially, it was concluded that patients were of either sex, predominantly never or light smokers with an adenocarcinoma histology. Several studies have shown that the approximate incidence of ELM4-ALK mutations in adenocarcinoma is in the order of 2-4%.
These distinguishing features also make screening patients for the trials much easier than an allcomers trial where you have no idea which patients will respond. As our knowledge of basic science and biology of the disease improves, so does the ability to focus more targeted therapies on particular aberrations that are driving the tumour growth and survival.
This more targeted approach may well lead to better and more effective therapies in the long run as well as more efficient use of resources because the patients receiving a given drug will be more likely to respond having been pre-selected upfront.
References:
Soda, M., Choi, Y., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S., Watanabe, H., Kurashina, K., Hatanaka, H., Bando, M., Ohno, S., Ishikawa, Y., Aburatani, H., Niki, T., Sohara, Y., Sugiyama, Y., & Mano, H. (2007). Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer Nature, 448 (7153), 561-566 DOI: 10.1038/nature05945
Shaw, A., Yeap, B., Mino-Kenudson, M., Digumarthy, S., Costa, D., Heist, R., Solomon, B., Stubbs, H., Admane, S., McDermott, U., Settleman, J., Kobayashi, S., Mark, E., Rodig, S., Chirieac, L., Kwak, E., Lynch, T., & Iafrate, A. (2009). Clinical Features and Outcome of Patients With Non-Small-Cell Lung Cancer Who Harbor EML4-ALK Journal of Clinical Oncology, 27 (26), 4247-4253 DOI: 10.1200/JCO.2009.22.6993
