A Case Against Empiric Therapy

Molecular testing can help identify alternative treatment options other than those that would be selected purely based on initial clinical presentation. For patients like "Henry," after his lung cancer worsened on chemotherapy, he typically would have been treated with erlotinib or more cytotoxic chemotherapy. However, identification of an EML4-ALK translocation through molecular testing revealed a potentially more effective, less toxic treatment option that had just been approved for use in such a case.

About "Henry"

In this molecular profile, our fictional patient, Henry, is a 56 year-old man who never smoked. He was exposed to second-hand smoke during his childhood and in an office where he worked years ago. Two months ago, he began noticing unusual headaches. Over the next few weeks, he noticed weakness in his left arm.

Concerned about his symptoms, Henry went to the emergency room at his local hospital. Magnetic Resonance Imaging (MRI) revealed evidence of a mass in his brain, and further imaging showed a tumor in his lungs. Biopsy of his lung mass indicated he had non-small cell lung cancer with adenocarcinoma histology.

When Henry’s cancer progressed while on first-line treatment, his physician chose to send his original biopsy tissue for EGFR testing to see if he was a candidate for erlotinib. However, rather than only sending it for EGFR testing, he wanted to ensure he got as much information as he could from the small amount of tissue Henry had available for testing, so he ordered several molecular diagnostic tests. Henry’s tumor was negative for the EGFR mutations that predict sensitivity to EGFR tyrosine kinase inhibitors such as erlotinib; however, the testing revealed an uncommon gene rearrangement which predicts sensitivity to crizotinib, another targeted therapy.

Actionable Information

• EML4-ALK or other ALK gene rearrangements are detected in 3-7% of lung cancers.^{1, 2}
• Clinical reports have suggested that this translocation is more common in adenocarcinoma histology, never smokers and patients of Asian ethnicity; there is also a slight male preponderence.³ However, none of these factors is sufficiently reliable to predict the presence or absence of this alteration.
• A phase I trial of 82 patients with a confirmed EML4-ALK rearrangement who were treated with crizotinib, a small-molecule ALK inhibitor, showed a 57% response rate, with an estimated probability of 6-month progression-free survival of 72%.⁴
• Crizotinib is now an FDA-approved therapy for NSCLC patients with the ALK positive tumors.

References

1. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-6.
2. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14:4275-83.
3. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-53.
4. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-703.

Note: This fictional, composite story, which includes data from actual representative patient cases, conveys how information from comprehensive genomic testing may impact treatment for management and care of people suffering from cancer.