Crizotinib as emerging lung cancer treatment with promising clinical results

¶ … revolution in understanding genetic contributions to the susceptibility for developing particular diseases and disorders has been the development of the notion of "personalized medicine." The "personalized" connotation of this growing facet in the practice does not refer to individualized treatments as much as it refers to a personalizing of treatments targeted at a specific subset of patients, for example the development of certain drugs that can target specific cancer-causing genes found in patients' tumors. A drug currently being reviewed by the FDA for release is crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor. ALK is believed to be active in several different types of tumors, including about five percent of non-small-cell lung carcinomas (NSCLC). In patients with advanced NSCLC it has been found that those carrying the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion gene possess a protein product of this fusion that contains a constitutive kinase activity that is carcinogenic (Christensen et al., 2007). EML4-ALK is a fusion oncogene. It was first discovered in 2007 and is found predominantly in people who do not smoke or in light smokers with a 10 pack or less history of tobacco use. It is also found in younger patients and those with adenocarcinoma histology (Ku & Lima Jopes Jr., 2011). Crizotinib is a direct inhibitor of the enzyme produced by the mutated gene.

Treatment with crizotinib offers two main advantages: 1) it is vastly superior to chemotherapy which only is effective in about 10% of such advanced cancers, and 2) because the targeted gene is not found in healthy cells treatment with crizotinib results in far fewer serious side effects than chemotherapy. Trials of crizotinib for use in the treatment of NSCLC have been underway since 2006. About 10,000 of the 222,000 Americans diagnosed with non-small-cell lung cancer each year could be expected to have the genetic abnormality and it is estimated that 50,000 people worldwide have it (Christensen et al., 2007). The medication was shifted to the fast track category by the Food and Drug Administration (FDA) so that Pfizer Inc., the drug's manufacturer, could submit efficacy data to the FDA without waiting for studies to be completed. The empirical evidence supporting crizotinib is impressive.

In Phase II clinical trial of 82 patients with ALK-rearranged advanced non-small-cell lung cancer oral crizotinib was administered on a continuous daily schedule. The overall response rate at a mean treatment duration of 6.4 months was 57%, an unheard of response rate for refractory lung cancer (Kwak et al., 2010). The researchers expected to see results in only about 10% of the 82 initial patients in the study, all of whom were in advanced stages of the disease. Instead, there were reports of tumor shrinkage in over 90% of the cases (Bang et al., 2010). A total of 63 of the 82 patients continued to receive crizotinib at the time of data cutoff with an estimated probability of 6-month progression-free survival of 72%. Crizotinib produced few side effects; in this study the drug produced mild gastrointestinal side effects and mild visual symptoms that wore off over time (Bang et al., 2010; Kwak et al., 2010).

Dr. Alice Shaw of the Massachusetts General Hospital Cancer Center reported the results of 119 patients with ALK-positive lung cancer treated with crizotinib. At a one year follow-up 74% of the patients were still alive; after a two-year follow-up 54% were still living. Treatment with the drug led to shrinkage in a majority of tumors in the patients and a dramatic response in more than 60% of the sample lasting about 48 weeks. This study did not have a control group, but studies following similar patients treated with chemotherapy have found a 44% survival after one year follow-up and a 12% survival rate after two years (Shaw & Solomon, 2011).

Phase III trials appear to be nearing completion at the time of this writing and it appears that Pfizer will have the go ahead to release the drug later this year. NSCLC is one of the most frustrating cancers to treat and often proves resistant to standard therapies. One of the benefits of personalized care is that developers of new medications have been targeting new markers for different cancers and identifying specific patient populations that will respond to more targeted therapies. There has been a lot of excitement of the effectiveness of crizotinib for NSCLC even though a relatively small proportion of all NSCLC patients are likely to benefit.

The success and the fervor over crizotinib is warranted as it does appear to be promising in the treatment of some case of NSCLC and perhaps in several other cancers; however, it certainly is not a panacea. Of course one would not choose to use crizotinib in patients without the identified EML4-ALK fusion gene and its associated abnormal protein. In addition, in the Phase I/II studies it also appeared that some patients may have possessed a further mutation such that crizotinib was not effective for them. However, the real breakthrough here is the advancements in personalizing treatments. Personalized medicine is the real innovation here. In the past, health care and standards of care have always been based on epidemiological research performed on large patient cohorts. But as we are learning, the use of large cohorts does not consider the genetic variability in people. The development of drugs like crizotinib has the potential to lead to a paradigm shift in medicine. Using crizotinib as an example we can see how this paradigm shift might emerge. First, we have now recognized that perhaps certain conditions/diseases that share similar presentations are composed of a number of conditions with slightly different genetic alterations. By identifying the specific genetic variables in the diseases and the genetic variations that lead to resistance to treatment we can design specific treatments that can aid in the recovery of smaller cohorts of individuals. Over time, the identification of increasing different smaller cohorts of genetic variations in disease can lead to more and more personalized treatments for these cohorts. This relies on the systematic use of genetic or other personalized information to be able to select or optimize that patient's preventative and therapeutic care (Mehta, Jain, & Badve, 2011).