Non–small cell lung cancer (NSCLC) is a heterogeneous disease with diverse molecular alterations. Two of the most common genetic abnormalities found in advanced NSCLC are mutations in the epidermal growth factor receptor (EGFR) and rearrangements in the ROS proto-oncogene 1 (ROS-1). Although these two alterations are typically mutually exclusive, there have been reports of their co-occurrence in a small subset of NSCLC patients. The discovery of this comutation has recently become apparent due to the increased use of more sensitive whole genome sequencing. We share our experience with two cases of coexisting EGFR and ROS-1 alterations. The first case is a 60-year-old man diagnosed with advanced adenocarcinoma of the lung with metastasis to bone and left adrenal gland. The second case is a 49-year-old woman diagnosed with stage IV lung adenocarcinoma with metastasis to the contralateral lung and diffuse abdominal lymphadenopathy. The first case was treated with osimertinib, and currently has had a stable disease on this medication for more than 3 years. The second case had a short interval of stable disease on osimertinib; then she developed progressive disease with poor response to anti–ROS-1 therapy. We believe patients with advanced NSCLC may have a higher incidence of coalterations, especially in the areas of the world with higher EGFR mutations and in the era of higher usage of whole genome sequencing. The presence of comutations will allow for a good long-term response to anti-EGFR therapy. This highlights the importance of the use of next-generation sequencing whenever possible and considers variant allele frequency as a factor in directing the therapy. There are many other unanswered questions, such as the best treatment sequencing or even the combined targeted therapy approach. This case series may add some information to the current literature.

This content is only available as a PDF.

Competing Interests

Sources of Support: None. Conflicts of Interest: None.

This work is published under a CC-BY-NC-ND 4.0 International License.