ALK-Targeted Therapy in NSCLC: Likely to Be of Benefit but Not Quite Ready for Prime Time

Oncology, ONCOLOGY Vol 25 No 7, Volume 25, Issue 7

In 2004, Dr. Thomas Lynch[1] and others[2] 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[1] and others[2] 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,[6] 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.[12] 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.[13] ALK rearrangements were identified in these patients by fluorescence in situ hybridization (FISH), using the Vysis ALK break-apart probe set.[14] 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.[15] Patients harboring this molecular abnormality almost always have adenocarcinoma histology and are never or former light smokers.[16] With rare exception,[17] 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[16] 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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2. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101:13306-11.

3. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290:2149-58.

4. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 2003;21:2237-46.

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7. Zhou Y-LW, Chen G, Feng J, et al, on behalf of the OPTIMAL investigators. Efficacy results from the randomised phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM), in Chinese advanced non-small-cell lung cancer (NSCLC) patients (PTS) with EGFR activating mutations. Ann Oncol. 2010;21(Suppl 8):1.

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9. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121-8.

10. Lee JS, Park K, Kim S-W, et al. A randomized phase III study of gefitinib (IRESSA) versus standard chemotherapy (gemcitabine plus cisplatin) as a first-line treatment for never-smokers with advanced or metastatic adenocarcinoma of the lung (abstract PRS4). J Thorac Oncol. 2009;4(9 Suppl 1):PRS4.

11. F. Hoffmann-La Roche Ltd.: Early Successful Readout of Tarceva Study in a Distinct Form of Lung Cancer [press release]. January 28, 2011. Available at Accessed April 14, 2011.

12. 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.

13. Bang Y, Kwak EL, Shaw AT, et al. Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-positive patients with non-small cell lung cancer (NSCLC) (abstract 3). J Clin Oncol. 2010;28(18 Suppl):3.

14. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-1703.

15. Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol. 2009;4:1450-4.

16. 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.

17. Tiseo M, Gelsomino F, Boggiani D, et al. EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer. 2011;71:241-3.

18. Yi ES, Boland JM, Maleszewski JJ, et al. Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. J Thorac Oncol. 2011;6:459-65.

19. Paik JH, Choe G, Kim H, et al. Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: correlation with fluorescence in situ hybridization. J Thorac Oncol. 2011;6:466-72.

20. Mino-Kenudson M, Chirieac LR, Law K, et al. A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res. 2010;16:1561-71.

21. Camidge DR, Kono SA, Lu X, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011;6:774-80.

22. Altavilla G, Santarpia M, Arrigo C, et al. EML4-ALK fusion gene in lung adenocarcinoma: a retrospective analysis of the outcome of cisplatin plus pemetrexed treated patients (abstract 7610). J Clin Oncol. 2010;28(15 Suppl):7610.