Advances in the molecular characterization of non–small cell lung cancer (NSCLC) have led to the identification of molecularly defined distinct subsets of patients who derive benefit from targeted therapies. Currently, two such groups of agents have moved widely into clinical practice: epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors—erlotinib, gefitinib (Iressa), and afatinib (Gilotrif)—in patients with NSCLCs harboring activating mutations within the kinase domain of the EGFR gene; and crizotinib (Xalkori), an inhibitor of oncogenic anaplastic lymphoma kinase (ALK) in tumors with the rearranged ALK gene.
In both subsets of patients, new therapeutics have proved more effective than standard chemotherapy and are currently considered treatments of choice. Further research on mechanisms of resistance to these agents is likely to lead to even larger clinical benefit of respective patient groups, as exemplified by the promising activity of third-generation EGFR inhibitors.
ROS1 Rearrangement
Identification of c-Ros 1 (ROS1) oncogene rearrangement was initially reported in glioblastomas, and the rearrangement was subsequently found in other tumor types, including NSCLC. The ROS1 gene is partially homologous to ALK, and is a potent oncogenic driver with a physiologic role in postnatal maturation of epididymis epithelium. As demonstrated by in vitro studies, crizotinib—an ALK inhibitor—may also inhibit ROS1 kinase. Activity of crizotinib in patients with tumors harboring ROS1 rearrangement has been heralded in case reports1-3 and has now been confirmed in a large clinical study reported by Shaw and colleagues4 and recently reviewed in The ASCO Post (December 15, 2014).
The efficacy of crizotinib has proved to be unprecedented—both response rate (72%) and the estimated duration of response (17.6 months) were far above those seen with conventional chemotherapy, even though ROS1-rearranged tumors seem to be particularly sensitive to pemetrexed (Alimta).5 Similar results have been recently reported in the European Trial on Crizotinib in the ROS1 Translocated Lung Cancer (EUCROSS) study.6 Interestingly, crizotinib also seems to be more effective in ROS1, compared to ALK fusion-positive tumors. Hence, ROS1-positive NSCLC represents a novel patient subset that derives apparent clinical benefit from crizotinib therapy.
Fusion-positive ROS1 tumors constitute only around 1% to 2% of all NSCLC cases and occur almost exclusively in adenocarcinomas. However, they affect specifically a growing population of nonsmoking patients and may show aggressive clinical behavior.7,8
Diagnostic Process
Similarly to ALK, ROS1 rearrangements are routinely indentified with break-apart fluorescence in situ hybridization (FISH), a cumbersome and relatively expensive method, and this may hamper the widespread diagnostic process. Despite similar clinicopathologic features, ROS1 rearrangements are mutually exclusive from KRAS and EGFR mutations and ALK rearrangements. Hence, to increase the yield, a search for ROS1 changes has been frequently confined to “triple-negative” NSCLCs—ie, those that lack the three above-mentioned genetic abnormalities.
Reverse transcriptase–polymerase chain reaction (RT-PCR) is also an option, but this method requires multiple primer sets and may miss rare rearrangements. Most recently, widely available and less-expensive immunohistochemistry staining has been shown to serve as a reliable method of screening for ALK and ROS1 rearrangements9,10 and, after standardization and validation, may possibly replace FISH as a routine primary assay. Next-generation sequencing of selected multi-oncogene panels is rapidly entering clinical application, with hopes of providing clinically relevant information on all targetable molecular aberrations, including ROS1 rearrangement, with acceptable turnover time.
Ongoing Research
Although crizotinib provides impressive responses in ROS1 fusion–positive patients, most patients will eventually develop progression owing to the acquisition of resistant mutations in the kinase domain of ROS1 or activation of other signaling pathways. Ongoing research has identified specific molecular resistance mechanisms to ROS1 inhibitors and has led to the development of next-generation compounds, such as cabozantinib (Cometriq) and the investigational agent foretinib, which may overcome the resistance.11,12 Other molecules, such as RXDX-101, which shares ALK, ROS1, and pan-TRK inhibitory activity, are being developed in early-phase clinical trials exclusively in molecularly defined subsets of patients.
In summary, we are witnessing an important step in the development of targeted therapies for NSCLC. Similarly to EGFR mutations and ALK rearrangements, ROS1 fusions constitute a driving oncogenic genetic alteration with rationally designed and effective targeted therapy. These three mutations combined account for about 20% of all NSCLCs.
Furthermore, the group of new potential therapeutic targets in NSCLC, particularly in adenocarcinoma, is growing (eg, RET, MET, HER2, and BRAF), and clinical trials assessing such targets are underway. These therapies provide new opportunities for treating NSCLC and will hopefully change the current grim landscape in this malignancy. ■
Disclosure: Dr. Jassem reported no potential conflicts of interest. Dr. Dziadziuszko is on the advisory boards of Pfizer, Novartis, and Clovis.
References
1. Bergethon K, Shaw AT, Ou SH, et al: J Clin Oncol 30:863-870, 2012.
2. Ou S-HI, Bang Y-J, Camidge DR, et al: 2013 ASCO Annual Meeting. Abstract 8032.
3. Chiari R, Buttitta F, Iacono D, et al: Clin Lung Cancer 15:470-474, 2014.
4. Shaw AT, Ou S-HI, Bang Y-J, et al: N Engl J Med 371:1963-1971, 2014.
5. Kim HR, Lim SM, Kim HJ, et al: Ann Oncol 24:2364-2370, 2013.
6. Mazieres J, Zalcman G, Crino L, et al: 2014 ASCO Annual Meeting. Abstract 11035. Presented June 2, 2014.
7. Li C, Fang R, Sun Y, et al: PLoS One 6:e28204, 2011.
8. Kim MH, Shim HS, Kang DR, et al: Lung Cancer 83:389-395, 2014.
9. Cha YJ, Lee JS, Kim HR, et al: PLoS One 9:e103333, 2014.
10. Boyle TA, Masago K, Ellison KE, et al: Clin Lung Cancer. October 24, 2014 (early release online).
11. Katayama R, Kobayashi Y, Friboulet L, et al: Clin Cancer Res. Oct 28, 2014 (early release online).
12. Davare MA, Saborowski A, Eide CA, et al: Proc Natl Acad Sci USA 110:19519-19524, 2013.
