Over the last couple of years, our knowledge and understanding of non-small cell lung cancer (NSCLC) has improved as mutations and translocations that drive tumour growth and survival have been identified.
Unfortunately, while we have many new targeted agents in the clinic, few have so far made it to market for broader use in every day clinical practice. EGFR inhibitors such as erlotinib (Tarceva) and gefitinib (Iressa) were probably the first to gain people’s attention and soon we will hopefully have crizotinib for ALK translocations, since Pfizer have begun the rolling NDA submission to the FDA.
Lowly and Carbonne (2011) discussed the progress with lung cancer subsets in a short piece in Nature Reviews Clinical Oncology that is well worth checking out (see reference below). They point out that identifying these groups based on their molecular peculiarities is important because patients can be identified and better response rates obtained in a more targeted population:
“Patients with lung cancers harboring EGFR mutations have dramatically greater clinical responses when treated with the oral EGFR tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib, compared with patients without these mutations. In 2009, two seminal trials (the Iressa Pan-Asia Study [IPASS] and the Spanish Lung Cancer Group) demonstrated response rates of around 70% to EGFR TKIs in this cohort of patients, compared to a response rate of 30–40% with traditional platinum-based chemotherapy.”
They went onto describe the molecular subsets found to date:
Note that approx. half of the aberrant mutations have yet to be found and about one-eighth have been identified, but clinical trials are still ongoing with various inhibitors, so there is more hope for the future if any of these pan out with positive data.
Of course, what everyone wants to know is what is the next target that may emerge after crizotinib and ALK. I think PI3-kinase inhibitors look the most promising and there are a few being evaluated in trials right now. However, my suspicion is that we will be very lucky to get it right first time and it may well take some more creative combinations than at present before we figure it out. We may see a few failures before someone cracks the optimal solution based on biomarker and research into resistance mechanisms.
I’ll be off to San Francisco later this month to attend the AACR meeting on the PI3-kinase/mTor pathway in cancer to see what progress is being made. Watch this space for updates on what the key opinion leaders think.
Lovly, C., & Carbone, D. (2011). Lung cancer in 2010: One size does not fit all Nature Reviews Clinical Oncology, 8 (2), 68-70 DOI: 10.1038/nrclinonc.2010.224