Advances and future directions in ROS1 fusion-positive lung cancer

Abstract

ROS1 gene fusions are an established oncogenic driver comprising 1%-2% of non-small cell lung cancer (NSCLC). Successful targeting of ROS1 fusion oncoprotein with oral small-molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment landscape of metastatic ROS1 fusion-positive (ROS1+) NSCLC and transformed outcomes for patients. The preferred Food and Drug Administration-approved first-line therapies include crizotinib, entrectinib, and repotrectinib, and currently, selection amongst these options requires consideration of the systemic and CNS efficacy, tolerability, and access to therapy. Of note, resistance to ROS1 TKIs invariably develops, limiting the clinical benefit of these agents and leading to disease relapse. Progress in understanding the molecular mechanisms of resistance has enabled the development of numerous next-generation ROS1 TKIs, which achieve broader coverage of ROS1 resistance mutations and superior CNS penetration than first-generation TKIs, as well as other therapeutic strategies to address TKI resistance. The approach to subsequent therapy depends on the pace and pattern of progressive disease on the initial ROS1 TKI and, if known, the mechanisms of TKI resistance. Herein, we describe a practical approach for the selection of initial and subsequent therapies for metastatic ROS1+ NSCLC based on these clinical considerations. Additionally, we explore the evolving evidence for the optimal treatment of earlier-stage, non-metastatic ROS1+ NSCLC, while, in parallel, highlighting future research directions with the goal of continuing to build on the tremendous progress in the management of ROS1+ NSCLC and ultimately improving the longevity and well-being of people living with this disease.

Keywords: ROS1; drug resistance; non–small cell lung cancer; targeted therapy; tyrosine kinase inhibitor.

Figure 1.

Timeline of advances in ROS1 fusion-positive non–small cell lung cancer (NSCLC), including the discovery of ROS1 gene fusions, approval of ROS1 tyrosine kinase inhibitors, and development of investigational ROS1 inhibitors. Crizotinib and entrectinib are also approved by the European Medicines Agency (EMA) and globally. *Lorlatinib is not approved by the FDA for the treatment of patients with metastatic ROS1 fusion-positive NSCLC but is recommended as a subsequent treatment option by the NCCN guidelines and included in the ESMO guidelines.

Figure 2.

Approach to treatment of metastatic ROS1 fusion-positive non–small cell lung cancer. Preferred FDA-approved first-line therapy options include crizotinib, entrectinib, or repotrectinib. *Investigational next-generation ROS1 inhibitors taletrectinib and zidesamtinib can also be considered in the first-line setting. At disease progression, the selection of subsequent treatment should be determined based on the pattern of progressive disease and (for addressing systemic progression with switch in systemic therapy) mechanism of drug resistance, if known through rebiopsy. **In addressing CNS progression on a ROS1 inhibitor, multidisciplinary evaluation to assess the optimal use of surgery, radiation, versus switch in systemic therapy is essential. ***Consider continuing ROS1 TKI for nontransformed clones. ****Consider also for polyclonal resistance or concurrent on- and off-target resistance. Abbreviations: TKI, tyrosine kinase inhibitor; ROS1+, ROS1 fusion-positive; CNS, central nervous system.

Figure 3.

Mechanisms of resistance to ROS1 inhibitors. The mechanisms of resistance are broadly categorized as on-target (ie, ROS1 resistance mutations^,,,) and off-target resistance (ie, bypass pathway activation or histologic transformation^,). Polyclonal resistance (or concurrent on- and/or off-target mechanisms of resistance) may also occur. Abbreviation: TKI, tyrosine kinase inhibitor. Created with BioRender.com.