In 2004, Dr. Thomas Lynch and others first reported the presence of somatic mutations in the epidermal growth factor receptor (EGFR) gene in patients who exhibited great sensitivity to EGFR tyrosine kinase inhibitors (TKIs).
In 2004, Dr. Thomas Lynch and others first reported the presence of somatic mutations in the epidermal growth factor receptor (EGFR) gene in patients who exhibited great sensitivity to EGFR tyrosine kinase inhibitors (TKIs), by virtue of dramatic tumor shrinkage often associated with great durability. These EGFR mutations occur with greater frequency in patients of a certain phenotype (female, adenocarcinoma histology, Asian ethnicity, and never or light smoking status) and explain the observations seen in the original phase II trials of erlotinib (Tarceva) and gefitinib (Iressa) with regard to objective response rates.[3-5] The landmark Iressa Pan-Asian Study (IPASS) elegantly demonstrated the importance of genotype rather than phenotype when choosing first-line therapies in patients with clinically enriched advanced stage IV non–small-cell lung cancer (NSCLC). In IPASS, a total of 1,206 Asian never or former light smokers with adenocarcinoma were randomized to gefitinib versus carboplatin (Cb) and paclitaxel (P). Gefitinib was superior to CbP as judged by overall response rates (ORR) and progression-free survival (PFS) (which was the primary endpoint of IPASS) in EGFR mutation–positive patients, but it was inferior to CbP in EGFR mutation–negative patients. There are now six randomized trials demonstrating the superiority (largely based on ORR and PFS) of an EGFR TKI, compared with platinum-based chemotherapy, in EGFR mutation–positive patients,[6-11] The use of an EGFR TKI as first-line therapy in EGFR mutation–positive patients is now a paradigm "ready for prime time" and bolstered by several randomized clinical trials. Critics of the previous statement will point to the lack of a difference in overall survival (OS) in the trials cited, which is likely explained by a "cross-over" effect, as a high percentage of the mutation–positive patients randomized to chemotherapy received an EGFR TKI as second-line therapy. In my opinion, however, higher ORR and significantly improved PFS coupled with a better toxicity profile clearly establish the use of an EGFR TKI as the standard of care in the EGFR mutation–positive population and mandate routine testing to identify these patients.
In 2007, Soda and colleagues described the presence of the EML4-ALK translocation in advanced NSCLC. At the 2010 American Society of Clinical Oncology (ASCO) annual meeting, findings from a series of 82 patients with EML4-ALK translocations treated with crizotinib in a phase I/II trial were presented at the Plenary Session. ALK rearrangements were identified in these patients by fluorescence in situ hybridization (FISH), using the Vysis ALK break-apart probe set. Crizotinib was shown to have extraordinary activity in these molecularly selected patients, most of whom had been heavily pretreated. In this issue of ONCOLOGY, Dr. Husain and Dr. Rudin provide a concise and insightful review of ALK-targeted therapy in patients with advanced NSCLC. Several issues deserve comment and attention before we declare this approach as "ready for prime time."
The first issue is that of how we identify these patients. It is estimated that ALK translocations occur in approximately 4% of all lung cancer cases. Patients harboring this molecular abnormality almost always have adenocarcinoma histology and are never or former light smokers. With rare exception, ALK translocations appear to be mutually exclusive of the more common KRAS and EGFR mutations. The use of certain clinical enrichment factors (histology, smoking status) as well as molecular factors (KRAS and EGFR wild type [wt] status) will alter the frequency of finding ALK translocations. Given the activity of crizotinib in this setting, however, no patient with an ALK translocation should be denied exposure to this agent. Routine consideration of testing for an ALK translocation should be the standard of care and will increase our knowledge about the clinical spectrum of ALK-positive lung cancer. Evaluation of the prevalence of ALK-positivity in the earlier stages of NSCLC also deserves attention and would have implications potentially in the adjuvant as well as the combined-modality setting.
A second issue pertains to the optimal way in which to test. To date, FISH has been the gold standard used as an entry criterion for all clinical trials evaluating crizotinib. This technique requires adequate tissue as well as laboratory and interpretive expertise. Several recent reports[18-20] have evaluated the role of immunohistochemistry (IHC) using a variety of antibodies to ALK. The series have typically scored ALK-positivity based on the intensity and frequency of staining using an arbitrary scoring system (typically 0–3+). The sensitivity of IHC compared with FISH for the 2+ to 3+ range was excellent (nearly 100%); however, the specificity, particularly in the 1+ to 2+ range, was quite poor. These investigators have suggested a two-tiered approach with regard to screening for ALK, similar to what is done for HER2 in breast cancer. Given the high sensitivity of IHC for detecting ALK protein, one could use this approach initially, reserving confirmatory FISH testing for the IHC-positive samples. I do not believe that this approach is ready for prime time, as there is not clarity as to the optimal antibody for routine use nor is there widespread expertise in performing this assay. For the time being, FISH will remain the standard until sufficient data are available with regard to alternate testing strategies.
A third issue is our understanding of the natural history of this disease and how ALK-positive NSCLC patients fare with other therapies. The patients reported in the initial trial[13,14] were heavily pretreated yet had remarkable ORRs and PFS. Shaw and colleagues reported on a series of 19 ALK-positive patients and compared them to EGFR mutation–positive patients as well as patients who were wt for both EGFR and ALK. The suggestion from this report was that ALK-positive patients did not appear to have a differential effect from platinum-based chemotherapy compared with the wt patients. However, two recent retrospective reports[21,22] have suggested that ALK-positive patients may have superior PFS when receiving pemetrexed (Alimta)-based therapies. More data in this area are clearly needed and will have an impact on how future studies are designed in the ALK-positive population.
A fourth issue involves our understanding of resistance of ALK-positive patients to ALK-targeted therapy, and includes both de novo as well as acquired resistance. As noted by Dr. Husain and Dr. Rudin, little data exist in this area. Mandatory re-biopsy at the time of disease progression to allow molecular analysis of ALK-positive patients should be the focus of all clinical trials involving ALK-targeted therapies.
In summary, the discovery of ALK translocations in advanced NSCLC coupled with the development of inhibitors of this therapeutic target has provided this population of NSCLC patients with a therapeutic option likely to provide great clinical benefit. Although I do believe that all patients with this molecular abnormality should have access to crizotinib or other ALK inhibitors, design and completion of rational clinical trials defining the optimal manner in which to integrate ALK-targeted therapies in this population must be part of bringing this new paradigm into prime time.
Financial Disclosure:Dr. Socinski receives research support from Pfizer.
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