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Over the past decade, molecular characterization has led to change the management of advanced non-small cell lung cancer (NSCLC) harboring driver mutations. Rearranged during transfection (RET) gene fusions, occurring in 1% to 2% of NSCLC, have emerged as an oncogenic druggable target. Systemic targeted therapies with highly selective RET inhibitors (RETi), selpercatinib and pralsetinib, represent a recent clinical breakthrough. While the development of RETi has improved survival, with their increasing use, it is crucial to be aware of the risks of rare but serious adverse events (AEs). A particular challenge for clinicians in applying targeted therapies is not only diagnosing but also interpreting rare mutations. Herein, we report a case of a 43-year-old Caucasian advanced NSCLC patient diagnosed with a rare RET gene fusion, ANK3::RET, identified with Next Generation Sequencing (NGS). Selpercatinib has been initiated at the recommended initial dose after one incomplete chemotherapy cycle due to a severe infusion reaction, but it subsequently required a dose adjustment following grade 3 (G3) AEs. During treatment, we used a particular selpercatinib dosage (160 mg in the morning and 80 mg in the evening) with good tolerance and without compromising effectiveness. Our finding broadens the range of RET fusion types in not-Asian NSCLC. To the best of our knowledge, our case demonstrates, for the first time, a clinical and radiological response to frontline highly selective RETi selpercatinib, expanding the spectrum of potential oncogenic RET fusion partners in newly diagnosed NSCLC patients. Furthermore, to our knowledge, this is the first case describing a RET fusion-positive (RET+) NSCLC patient treated with a modified selpercatinib dosage outside the drug data sheet and demonstrating a safe and effective use. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemoimmunotherapy has demonstrated significant benefit for resectable non-small-cell lung cancer (NSCLC) excluding known EGFR/ALK genetic alterations. Recent evidence has shown that neoadjuvant chemoimmunotherapy could be clinically valuable in resectable localized driver gene-mutant NSCLC, though the data still lack robust support, especially for rare oncogenic mutations. Here, we report a patient with stage IIIA lung adenocarcinoma with a RET fusion gene and high expression of PD-L1 who underwent neoadjuvant chemoimmunotherapy and successfully attained a pathologic complete response. The patient has survived for 12 months with no recurrence or metastases after surgery. Our case suggests that this treatment strategy may be an alternative therapeutic option for resectable RET fusion-positive NSCLC patients. [ABSTRACT FROM AUTHOR]

Over the past decade, molecular characterization has led to change the management of advanced non-small cell lung cancer (NSCLC) harboring driver mutations. Rearranged during transfection (RET) gene fusions, occurring in 1% to 2% of NSCLC, have emerged as an oncogenic druggable target. Systemic targeted therapies with highly selective RET inhibitors (RETi), selpercatinib and pralsetinib, represent a recent clinical breakthrough. While the development of RETi has improved survival, with their increasing use, it is crucial to be aware of the risks of rare but serious adverse events (AEs). A particular challenge for clinicians in applying targeted therapies is not only diagnosing but also interpreting rare mutations. Herein, we report a case of a 43-year-old Caucasian advanced NSCLC patient diagnosed with a rare RET gene fusion, ANK3::RET, identified with Next Generation Sequencing (NGS). Selpercatinib has been initiated at the recommended initial dose after one incomplete chemotherapy cycle due to a severe infusion reaction, but it subsequently required a dose adjustment following grade 3 (G3) AEs. During treatment, we used a particular selpercatinib dosage (160 mg in the morning and 80 mg in the evening) with good tolerance and without compromising effectiveness. Our finding broadens the range of RET fusion types in not-Asian NSCLC. To the best of our knowledge, our case demonstrates, for the first time, a clinical and radiological response to frontline highly selective RETi selpercatinib, expanding the spectrum of potential oncogenic RET fusion partners in newly diagnosed NSCLC patients. Furthermore, to our knowledge, this is the first case describing a RET fusion-positive (RET+) NSCLC patient treated with a modified selpercatinib dosage outside the drug data sheet and demonstrating a safe and effective use.

RET fusions occur in 1-2% of non-small cell lung cancer. Selpercatinib and pralsetinib are selective RET inhibitors with significant improvement of outcome in patients with tumor harboring RET fusion; however, resistance mechanisms appear frequently, mainly driven by MAPK pathway bypass, secondary RET mutations, or in 5% via MET amplification. Co-inhibition of RET and MET is a compelling strategy for overcoming MET-dependent resistance to RET inhibitors and potentially other inhibitors. To our knowledge, this is the first report of a novel ISOC1-RET fusion lung cancer with a durable complete response to selpercatinib, with resistance via MET amplification, which was overcome by the successful combination of selpercatinib and capmatinib. [ABSTRACT FROM AUTHOR]

RET fusions occur in 1–2% of non-small cell lung cancer. Selpercatinib and pralsetinib are selective RET inhibitors with significant improvement of outcome in patients with tumor harboring RET fusion; however, resistance mechanisms appear frequently, mainly driven by MAPK pathway bypass, secondary RET mutations, or in 5% via MET amplification. Co-inhibition of RET and MET is a compelling strategy for overcoming MET-dependent resistance to RET inhibitors and potentially other inhibitors. To our knowledge, this is the first report of a novel ISOC1-RET fusion lung cancer with a durable complete response to selpercatinib, with resistance via MET amplification, which was overcome by the successful combination of selpercatinib and capmatinib.

The LIBRETTO-001 trial demonstrated the activity of the selective rearrangement during transfection (RET) inhibitor selpercatinib in advanced RET fusion-positive non-small cell lung cancer (NSCLC) and resulted in the drug's approval for this indication. A cohort that included neoadjuvant and adjuvant selpercatinib was opened on LIBRETTO-001 for early-stage RET fusion-positive NSCLC with the primary endpoint of major pathologic response. A patient with a stage IB (cT2aN0M0) KIF5B-RET fusion-positive NSCLC received 8 weeks of neoadjuvant selpercatinib at 160 mg twice daily followed by surgery. While moderate regression in the primary tumor (stable disease, Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1) was observed radiologically, assessment via an Independent Pathologic Review Committee revealed a pathologic complete response (0% viable tumor). This consensus assessment by three independent pathologists was aided by RET fluorescence in situ hybridization testing of a reactive pneumocyte proliferation showing no rearrangement. Neoadjuvant selpercatinib was well-tolerated with only low-grade treatment-emergent adverse events. The activity of prospective preoperative selpercatinib in this case establishes proof of concept of the potential utility of RET inhibitor therapy in early-stage RET fusion-positive NSCLC. [ABSTRACT FROM AUTHOR]

Background: Cancer recurrence remains a significant problem, and most postoperative recurrences of non-small cell lung cancer (NSCLC) develop within 5 years after resection. We present a rare case of ultra-late recurrence of NSCLC accompanying choroidal metastasis with KIF13A-RET fusion 14 years after the definitive surgery. Case description: A 48-year-old female patient who had never-smoked presented with decreased visual acuity. She had been treated with right upper lobe lobectomy followed by adjuvant chemotherapy 14 years prior. Fundus photographs revealed bilateral choroidal metastatic lesions. Positron emission tomography-computed tomography (PET-CT) scans showed extensive bone metastases and focal hypermetabolism in the left uterine cervix. An excision biopsy of the uterus showed primary lung adenocarcinoma with immunohistochemistry of TTF-1+. Plasma next-generation sequencing (NGS) identified the presence of KIF13A-RET fusion. After 6 months of selpercatinib therapy, PET-CT revealed a partial response for bone and uterine metastasis and stable disease for choroidal lesions. Conclusion: In this case report, we are reporting a rare case of ultra-late recurrence of NSCLC in a patient with choroidal metastasis. Furthermore, the diagnosis of NSCLC with RET fusion was based on liquid-based NGS rather than tissue-based biopsy. The patient showed a good response to selpercatinib, which supports the efficacy of selpercatinib as a treatment for RET-fusionpositive NSCLC with choroidal metastasis. [ABSTRACT FROM AUTHOR]

Patients with metastatic pancreatic cancer have limited treatment options and a dismal prognosis. While RET fusion is rare (0.6%) in pancreatic cancer, the efficacy of RET-targeted treatment in patients with TRIM33-RET fusion has not been previously reported. Herein, we presented a case of a 68-year-old man with pancreatic cancer harboring TRIM33-RET fusion who responded remarkably to pralsetinib despite being intolerant to chemotherapy. To our knowledge, this is the first report on the clinical value of a single TRIM33-RET fusion in pancreatic cancer, which may benefit from the targeted therapy. [ABSTRACT FROM AUTHOR]

Large-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of non-smallcell lung cancer associated with a poor prognosis. LCNEC is genetically heterogeneous, and studies have revealed distinct molecular subtypes of LCNEC, which may have therapeutic implications. Herein, we present a case of a patient with stage IV LCNEC harboring a KIF5B-RET fusion whose disease responded to the selective RET inhibitor selpercatinib both extra- and intracranially, highlighting the importance of comprehensive molecular testing in LCNEC for selection of optimal treatment. [ABSTRACT FROM AUTHOR]

The LIBRETTO-001 trial demonstrated the activity of the selective rearrangement during transfection (RET) inhibitor selpercatinib in advanced RET fusion-positive non-small cell lung cancer (NSCLC) and resulted in the drug’s approval for this indication. A cohort that included neoadjuvant and adjuvant selpercatinib was opened on LIBRETTO-001 for early-stage RET fusion-positive NSCLC with the primary endpoint of major pathologic response. A patient with a stage IB (cT2aN0M0) KIF5B-RET fusion-positive NSCLC received 8 weeks of neoadjuvant selpercatinib at 160 mg twice daily followed by surgery. While moderate regression in the primary tumor (stable disease, Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1) was observed radiologically, assessment via an Independent Pathologic Review Committee revealed a pathologic complete response (0% viable tumor). This consensus assessment by three independent pathologists was aided by RET fluorescence in situ hybridization testing of a reactive pneumocyte proliferation showing no rearrangement. Neoadjuvant selpercatinib was well-tolerated with only low-grade treatment-emergent adverse events. The activity of prospective preoperative selpercatinib in this case establishes proof of concept of the potential utility of RET inhibitor therapy in early-stage RET fusion-positive NSCLC.

Large-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of non-small-cell lung cancer associated with a poor prognosis. LCNEC is genetically heterogeneous, and studies have revealed distinct molecular subtypes of LCNEC, which may have therapeutic implications. Herein, we present a case of a patient with stage IV LCNEC harboring a KIF5B–RET fusion whose disease responded to the selective RET inhibitor selpercatinib both extra- and intra-cranially, highlighting the importance of comprehensive molecular testing in LCNEC for selection of optimal treatment.

Lung cancer has very high morbidity and mortality worldwide, and the prognosis is not optimistic. Previous treatments for non-small cell lung cancer (NSCLC) have limited efficacy, and targeted drugs for some gene mutations have been used in NSCLC with considerable efficacy. The RET proto-oncogene is located on the long arm of chromosome 10 with a length of 60,000 bp, and the expression of RET gene affects cell survival, proliferation, growth and differentiation. This review will describe the basic characteristics and common fusion methods of RET genes; analyze the advantages and disadvantages of different RET fusion detection methods; summarize and discuss the recent application of non-selective and selective RET fusion-positive inhibitors, such as Vandetanib, Selpercatinib, Pralsetinib and Alectinib; discuss the mechanism and coping strategies of resistance to RET fusion-positive inhibitors.

Great progress has been made in the treatment of driver gene-positive Non- Small Cell Lung Cancer (NSCLC) in recent years. RET fusion was seen in 0.7% to 2% of NSCLC and was associated with younger age and never-smoker status. The pralsetinib and selpercatinib for RET fusion NSCLC was recommended by the 2021 NSCLC treatment guidelines. This review outlines the research progress in the treatment of RET fusion NSCLC, identifies current challenges and describes proposals for improving the outlook for these patients. [ABSTRACT FROM AUTHOR]

The acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is inevitable and heterogeneous. The strategies to overcome acquired resistance are significant. For patients with secondary T790M-positive after early generation EGFR-TKIs, osimertinib is the standard second-line therapy. In patients resistant to prior early generation EGFR-TKIs, the acquired T790M mutation overlaps with other driver gene resistance, such as HER2-and MET amplification, accounting for 4–8%. The efficacy of osimertinib is unclear in patients with concurrent multiple driver gene resistance. We here report a patient who acquired EGFR T790M, STRN-ALK fusion, and EGFR amplification after gefitinib progression and subsequent MET amplification acquired from osimertinib. The other patient acquired EGFR T790M and MET amplification post-dacomitinib and acquired CCDC6-RET fusion after osimertinib treatment. Besides, subsequent new bypass activations were the possible resistance mechanisms to second-line osimertinib. Both patients had progression-free survival (PFS) less than 4 months and limited benefits from osimertinib second-line therapy. The T790M accompanying driver gene resistance will be a new subtype after EGFR-TKIs progression, needing effective treatment options. [ABSTRACT FROM AUTHOR]

Great progress has been made in the treatment of driver gene-positive Non- Small Cell Lung Cancer (NSCLC) in recent years. RET fusion was seen in 0.7% to 2% of NSCLC and was associated with younger age and never-smoker status. The pralsetinib and selpercatinib for RET fusion NSCLC was recommended by the 2021 NSCLC treatment guidelines. This review outlines the research progress in the treatment of RET fusion NSCLC, identifies current challenges and describes proposals for improving the outlook for these patients.

BackgroundBrain metastasis mainly originates from lung cancer. Napsin A and TTF-1 factors have frequently been detected in lung adenocarcinoma cases. Brain metastasis tumors with napsin A and TTF-1 positive are easily classified as lung adenocarcinoma origin. However, some thyroid cancers also exhibit these clinical features. Besides, lung is the most common metastasis of undifferential thyroid cancer. Therefore, it requires development of novel diagnostic tools to aid in distinguishing between pulmonary and thyroid origin.Patient FindingsWe reported a case that was initially diagnosed as brain metastatic lung cancer based on immunohistochemistry results. Analysis of next-generation sequencing (NGS) data from the brain lesion revealed that the cancer may have originated from the thyroid. We detected combo mutations in TERT promoter mutation, RET fusion and TP53, which are common in undifferential thyroid cancer (UTC), but rare for lung cancer. These results, coupled with identification of PAX8, indicated that this patient had UTC. Additionally, her three sons, despite being asymptomatic, were all diagnosed with papillary thyroid carcinoma.SummaryThe patient received anlotinib treatment and showed good clinical outcomes. One month after anlotinib treatment, the pulmonary nodules were found to be controlled, and the thyroid tumor drastically reduced, and tracheal compression relieved. She continued anlotinib treatment for the following two months, but died one month later because the treatment stopped owing to financial reasons. All her sons underwent total thyroidectomy with lymph node dissection.ConclusionsAlthough NGS has been reported to assist in diagnosis of the origin of some tumors, this is the first evidence of NGS for the determination of the origin of thyroid tumors. To our knowledge, this is the first time that a combination of multiple mutations has been used to help determine the origin of a tumor, compared with the previous single mutant gene. Moreover, this is the first evidence on the use of anlotinib for treatment of UTC with distant metastasis. Besides, all three sons of the patient had thyroid carcinoma in subsequent examinations, indicating high-risk for familial non-medullary thyroid cancer in UTC patients and necessity for performing thyroid ultrasound testing in other family members.

Background: Brain metastasis mainly originates from lung cancer. Napsin A and TTF-1 factors have frequently been detected in lung adenocarcinoma cases. Brain metastasis tumors with napsin A and TTF-1 positive are easily classified as lung adenocarcinoma origin. However, some thyroid cancers also exhibit these clinical features. Besides, lung is the most common metastasis of undifferential thyroid cancer. Therefore, it requires development of novel diagnostic tools to aid in distinguishing between pulmonary and thyroid origin. Patient Findings: We reported a case that was initially diagnosed as brain metastatic lung cancer based on immunohistochemistry results. Analysis of next-generation sequencing (NGS) data from the brain lesion revealed that the cancer may have originated from the thyroid. We detected combo mutations in TERT promoter mutation, RET fusion and TP53 , which are common in undifferential thyroid cancer (UTC), but rare for lung cancer. These results, coupled with identification of PAX8, indicated that this patient had UTC. Additionally, her three sons, despite being asymptomatic, were all diagnosed with papillary thyroid carcinoma. Summary: The patient received anlotinib treatment and showed good clinical outcomes. One month after anlotinib treatment, the pulmonary nodules were found to be controlled, and the thyroid tumor drastically reduced, and tracheal compression relieved. She continued anlotinib treatment for the following two months, but died one month later because the treatment stopped owing to financial reasons. All her sons underwent total thyroidectomy with lymph node dissection. Conclusions: Although NGS has been reported to assist in diagnosis of the origin of some tumors, this is the first evidence of NGS for the determination of the origin of thyroid tumors. To our knowledge, this is the first time that a combination of multiple mutations has been used to help determine the origin of a tumor, compared with the previous single mutant gene. Moreover, this is the first evidence on the use of anlotinib for treatment of UTC with distant metastasis. Besides, all three sons of the patient had thyroid carcinoma in subsequent examinations, indicating high-risk for familial non-medullary thyroid cancer in UTC patients and necessity for performing thyroid ultrasound testing in other family members. [ABSTRACT FROM AUTHOR]