Clinicians hypothesize that a recent rare case of drug resistance in a patient with advanced non–small cell lung cancer (NSCLC) was caused by a novel genetic mutation known as RUFY1-RET fusion, according to a recent case report published in Oncotarget.
The report, authored by Jenny L. Wu and Wade T. Iams of the Vanderbilt-Ingram Cancer Center, documents “the first reported case of a RET fusion as a potential mechanism of resistance to lorlatinib.” The patient at the center of the case was 42 years old with stage IV CD-74-ROS1 fusion NSCLC. He had never smoked and was diagnosed by a chest CT, which revealed “a hilar mass, a mass in the lung, a small pleural effusion, and necrotic mediastinal lymphadenopathy.”
The investigators explained that ROS1 and RET fusions are “targetable mutations” that occur in a subset of patients with NSCLC. According to the report, “When these genes are rearranged with different fusion partners, they produce constitutively active proteins which drive oncogenesis.”
The patient underwent genetic testing through RNA next-generation sequencing (RNA NGS), which showed several genetic mutations at the time of diagnosis. His initial treatment regimen included carboplatin, pemetrexed, pembrolizumab, and clinical trial–derived novel immunotherapy, which resulted in an “initial partial response and a duration of response of 10 months.”
After the initial progression of disease, the patient was treated with docetaxel plus ramucirumab. However, disease progression occurred again within two months. After progression, the patient was treated with gemcitabine, which led to disease control for four months.
The investigators explained that upon treatment with gemcitabine, a biopsy was collected from the patient on a progressing site. The biopsy underwent DNA and RNA NGS testing, which showed a CD74-ROS1 chromosomal rearrangement. The patient was then treated with entrectinib for 10 months before imaging revealed further progression, at which point he was administered lorlatinib, per National Comprehensive Cancer Network (NCCN) guidelines.
After six months of treatment with lorlatinib, disease progression reemerged, prompting clinicians to add vinorelbine to the patient’s treatment and conduct repeat DNA and RNA NGS testing on an additional biopsy. The biopsy led to the discovery of a RUFY1-RET rearrangement. Clinicians halted vinorelbine and treated the patient with a combination of reduced-dose lorlatinib and pralsetinib to specifically target the RET gene alteration. Although the patient initially responded to the adjusted treatment with no severe adverse events, after four months, he died of respiratory failure due to disease progression.
In the discussion section of the case report, the researchers highlighted the heightened sensitivity of RNA NGS as one of several “novel components of contemporary advanced NSCLC care,” which was demonstrated through the patient’s biopsy test results. RNA NGS revealed both the patient’s initial ROS1 fusion, which indicated the disease would be responsive to treatment with lorlatinib, and the subsequent RUFY1-RET fusion, which researchers hypothesize likely caused resistance to the drug.
The investigators concluded that “this case adds to the literature on bypass signaling as a mechanism of resistance to lorlatinib, providing evidence for RET activation as a novel escape mechanism and documenting tolerability and modest therapeutic efficacy with combination lorlatinib and pralsetinib in this rare scenario.”
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