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RET fusions are present in 1% to 2% of NSCLCs. Although RET inhibitors like selpercatinib are effective, resistance inevitably develops. We present the case of a 28-year-old female with recurrent NSCLC and a CCDC6::RET fusion treated with selpercatinib. Testing at the time of progression revealed a new SKAP2::BRAF fusion. She was then treated with a combination of selpercatinib and trametinib, which led to a likely partial response, despite the combination demonstrating side effects. This case report details the first known instance of NSCLC with a RET fusion developing resistance by means of a BRAF fusion, treated with combined RET and MEK inhibition.

RET fusion-positive NSCLC accounts for 1% to 2% of lung carcinoma cases. Although two Food and Drug Administration–approved selective RET inhibitors, pralsetinib, and selpercatinib, have revealed efficacy in managing RET fusion-positive NSCLC, this case series is unique in its focus on the intracranial response to selpercatinib after disease progression during pralsetinib treatment. This report contributes to the literature by providing evidence of selpercatinib’s potential as a treatment option in such refractory cases. The patients described in both cases were diagnosed with metastatic RET fusion-positive NSCLC and developed intracranial metastases during pralsetinib treatment. After switching to selpercatinib, both exhibited significant intracranial responses. The first patient reported a reduction in brain metastasis size and maintained a response for over 1.5 years. The second patient also responded intracranially to selpercatinib but unfortunately passed away 8 months later owing to pulmonary hemorrhage, possibly linked to prior radiation treatment. These cases highlight the potential efficacy of selpercatinib in treating intracranial metastases in RET fusion-positive patients with NSCLC after pralsetinib-refractory progression. The key takeaway is that selpercatinib may offer a viable treatment option in such scenarios, although more extensive studies are needed to determine its role as a monotherapy or in combination with other treatments.

MET exon 14 skipping mutation has emerged as a new oncogenic driver in NSCLC with available targeted therapies, including Food and Drug Administration–approved inhibitors capmatinib and tepotinib. Potential resistance mechanisms are beginning to be described and include several on-target and off-target mutations. Here, we report an emergent secondary RET fusion in a patient with a primary MET exon 14 skipping mutation that progressed on capmatinib after the initial response. Subsequently, this patient received both a RET inhibitor (selpercatinib) followed by another MET-targeted treatment (tepotinib) without clinical benefit. Thereafter, cabozantinib, a multikinase inhibitor with activity against RET and MET was started with a rapid clinical and radiologic benefit.

Selpercatinib and pralsetinib are RET inhibitors with substantial activity in advanced RET-rearranged NSCLC. We present a case of pralsetinib-related pneumonitis and leptomeningeal and brain metastases progression during treatment suspension for pneumonitis. During recovery, selpercatinib administration led to rapid neurologic response and complete intracranial response and allowed pneumonitis resolution. This case supports the safety of selpercatinib in patients with pneumonitis on pralsetinib and highlights its marked efficacy in leptomeningeal disease.

Introduction: RET is well known as an important driver gene in NSCLC. Moreover, RET is a rare acquired resistance mechanism to EGFR-mutant NSCLC. Only 36 NSCLC cases of coexistence of EGFR and RET were reported previously worldwide. So far, there have been no reports on the following: (1) whether combination of EGFR tyrosine kinase inhibitor (TKI) and RET TKI works for meningeal metastasis; (2) the concentrations of EGFR TKI and RET TKI in the cerebrospinal fluid (CSF) and plasma; and (3) whether RET fusions and EGFR mutation happened in the same clone or not. Methods: We reported a patient with an EGFR-mutant NSCLC with acquired RET fusions and meningeal metastasis treated with pralsetinib and osimertinib; the specimen was analyzed by next-generation sequencing (Illumina NovaSeq 6000 platform). Symptom improvement and magnetic resonance imaging scan were used for effect evaluation. Furthermore, we determined the concentrations of pralsetinib and osimertinib in CSF and plasma by means of liquid chromatography tandem mass spectrometry. We also detected RET fusion and EGFR L858R mutation by methods of fluorescence in situ hybridization and immunohistochemistry with continuous sections to analyze whether RET fusions coexist with EGFR mutation in the same clone or not. Results: The allele frequency of the RET fusion was detected to be 12.88%. This patient achieved a partial response, indicating pralsetinib combined with osimertinib may be clinically beneficial for meningeal metastasis in patients harboring acquired coexistent RET fusions. The concentrations of pralsetinib in the CSF and plasma were 704.76 nM and 91.31 μM, whereas those of osimertinib in the CSF and plasma were 23.70 nM and 2148.94 nM, respectively. RET fusion was found in the same clone of EGFR L858R mutation. Conclusions: Our finding of this case indicated that RET fusion and EGFR mutation occur in the same population of cell clones, rather than in different cell clones. Combined pralsetinib may be an effective way to overcome the resistance, even for meningeal metastasis, owing to high CSF distribution of pralsetinib.

Introduction: RET rearrangements define a distinct molecular subset of NSCLC. The multikinase inhibitor ponatinib reveals potent activity in preclinical models of RET-rearranged NSCLC. Methods: In this single-arm, multicenter, phase II trial, we evaluated the clinical activity of ponatinib in patients with advanced, previously treated, RET-rearranged NSCLC (NCT01813734). RET rearrangements were identified through fluorescence in situ hybridization or next-generation sequencing. Ponatinib was administered at a dose of 30 mg once daily. Patients without a documented objective response were eligible to dose-escalate ponatinib to 45 mg daily. The primary end point was objective response rate. Results: Between August 2014 and December 2017, nine patients were enrolled. The median age was 58 years (range 49–73 y). Eight patients (89%) had a history of brain metastases. The median number of previous lines of therapy was three (range 1–5). Of the nine evaluated patients, five (55%) experienced tumor shrinkage from baseline, but no confirmed responses were observed (objective response rate 0%). The disease control rate was 55%. With a median follow-up of 9.33 months, the median progression-free survival and overall survival were 3.80 months (95% CI: 1.83–5.30) and 17.47 months (95% CI: 6.57–19.20), respectively. The most common treatment-related adverse events were rash (n = 5; 56%), constipation (n = 4; 44%), and diarrhea (n = 4; 44%). No treatment-related thromboembolic or cardiac events were observed. The study was stopped prematurely owing to slow accrual and lack of clinical activity. Conclusions: Ponatinib has limited clinical activity in patients with RET-rearranged NSCLC. Continued development of more potent and selective RET inhibitors is needed.

The era of precision medicine has resulted in the identification of a number of genomic alterations that can be targeted with novel therapies. In lung adenocarcinomas, a histology structure that accounts for nearly 50% of all cases of lung cancer, and a number of genomic targets have been linked with effective targeted therapies. For patients with advanced-stage lung adenocarcinomas, molecular testing is now a standard part of diagnostic workup; for patients that have specific driver molecular events, targeted therapies have resulted in substantial improvement in efficacy without excessive toxicity.RET gene fusions are present in approximately 1% to 2% of NSCLC. It is emerging as a new targetable driver for this population. Despite sensitivity to platinum-based chemotherapy and conflicting small reports regarding the efficacy of immune checkpoint inhibitors, there have been limited treatment approaches for this subset of patients. Multiple nonselective RET tyrosine kinase inhibitors exhibited modest anti-RET activity with an increased off-target toxicity profile that often required dose interruption, reduction, or treatment cessation. Recently, novel selective RET inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) have exhibited promising clinical activity with low adverse effect profile in early clinical trials. These new agents are poised to represent a new hope for this special subgroup with unmet needs.

Introduction: RET is well known as an important driver gene in NSCLC. Moreover, RET is a rare acquired resistance mechanism to EGFR -mutant NSCLC. Only 36 NSCLC cases of coexistence of EGFR and RET were reported previously worldwide. So far, there have been no reports on the following: (1) whether combination of EGFR tyrosine kinase inhibitor (TKI) and RET TKI works for meningeal metastasis; (2) the concentrations of EGFR TKI and RET TKI in the cerebrospinal fluid (CSF) and plasma; and (3) whether RET fusions and EGFR mutation happened in the same clone or not., Methods: We reported a patient with an EGFR -mutant NSCLC with acquired RET fusions and meningeal metastasis treated with pralsetinib and osimertinib; the specimen was analyzed by next-generation sequencing (Illumina NovaSeq 6000 platform). Symptom improvement and magnetic resonance imaging scan were used for effect evaluation. Furthermore, we determined the concentrations of pralsetinib and osimertinib in CSF and plasma by means of liquid chromatography tandem mass spectrometry. We also detected RET fusion and EGFR L858R mutation by methods of fluorescence in situ hybridization and immunohistochemistry with continuous sections to analyze whether RET fusions coexist with EGFR mutation in the same clone or not., Results: The allele frequency of the RET fusion was detected to be 12.88%. This patient achieved a partial response, indicating pralsetinib combined with osimertinib may be clinically beneficial for meningeal metastasis in patients harboring acquired coexistent RET fusions. The concentrations of pralsetinib in the CSF and plasma were 704.76 nM and 91.31 μM, whereas those of osimertinib in the CSF and plasma were 23.70 nM and 2148.94 nM, respectively. RET fusion was found in the same clone of EGFR L858R mutation., Conclusions: Our finding of this case indicated that RET fusion and EGFR mutation occur in the same population of cell clones, rather than in different cell clones. Combined pralsetinib may be an effective way to overcome the resistance, even for meningeal metastasis, owing to high CSF distribution of pralsetinib., (© 2022 Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer.)

The era of precision medicine has resulted in the identification of a number of genomic alterations that can be targeted with novel therapies. In lung adenocarcinomas, a histology structure that accounts for nearly 50% of all cases of lung cancer, and a number of genomic targets have been linked with effective targeted therapies. For patients with advanced-stage lung adenocarcinomas, molecular testing is now a standard part of diagnostic workup; for patients that have specific driver molecular events, targeted therapies have resulted in substantial improvement in efficacy without excessive toxicity. RET gene fusions are present in approximately 1% to 2% of NSCLC. It is emerging as a new targetable driver for this population. Despite sensitivity to platinum-based chemotherapy and conflicting small reports regarding the efficacy of immune checkpoint inhibitors, there have been limited treatment approaches for this subset of patients. Multiple nonselective RET tyrosine kinase inhibitors exhibited modest anti- RET activity with an increased off-target toxicity profile that often required dose interruption, reduction, or treatment cessation. Recently, novel selective RET inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) have exhibited promising clinical activity with low adverse effect profile in early clinical trials. These new agents are poised to represent a new hope for this special subgroup with unmet needs., (© 2020 by the International Association for the Study of Lung Cancer.)

Introduction: RET rearrangements define a distinct molecular subset of NSCLC. The multikinase inhibitor ponatinib reveals potent activity in preclinical models of RET -rearranged NSCLC., Methods: In this single-arm, multicenter, phase II trial, we evaluated the clinical activity of ponatinib in patients with advanced, previously treated, RET -rearranged NSCLC (NCT01813734). RET rearrangements were identified through fluorescence in situ hybridization or next-generation sequencing. Ponatinib was administered at a dose of 30 mg once daily. Patients without a documented objective response were eligible to dose-escalate ponatinib to 45 mg daily. The primary end point was objective response rate., Results: Between August 2014 and December 2017, nine patients were enrolled. The median age was 58 years (range 49-73 y). Eight patients (89%) had a history of brain metastases. The median number of previous lines of therapy was three (range 1-5). Of the nine evaluated patients, five (55%) experienced tumor shrinkage from baseline, but no confirmed responses were observed (objective response rate 0%). The disease control rate was 55%. With a median follow-up of 9.33 months, the median progression-free survival and overall survival were 3.80 months (95% CI: 1.83-5.30) and 17.47 months (95% CI: 6.57-19.20), respectively. The most common treatment-related adverse events were rash (n = 5; 56%), constipation (n = 4; 44%), and diarrhea (n = 4; 44%). No treatment-related thromboembolic or cardiac events were observed. The study was stopped prematurely owing to slow accrual and lack of clinical activity., Conclusions: Ponatinib has limited clinical activity in patients with RET -rearranged NSCLC. Continued development of more potent and selective RET inhibitors is needed., (© 2020 The Authors.)