First-line selpercatinib for a patient with RET fusion-positive pulmonary large cell neuroendocrine carcinoma.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an uncommon variant of non-small cell lung cancer (NSCLC), known for its aggressive behavior. This includes rapid progression, widespread metastases, and resistance to conventional chemotherapy, all of which contribute to a dismal prognosis. Consequently, managing pulmonary LCNEC remains a significant challenge. In this case report, we describe the successful use of selpercatinib, RET (rearranged during transfection) kinase inhibitor, as a first-line treatment in a patient with advanced pulmonary LCNEC harboring a RET fusion gene. Although RET fusion genes are exceedingly rare in pulmonary LCNEC, this case underscores the importance of early genetic testing in patients with pulmonary LCNEC to tailor targeted therapies effectively.

Targeted and cytotoxic inhibitors used in the treatment of lung cancers.

Lung cancer is the leading cause of cancer deaths in the United States and the world. It is divided into two major types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In the tumor-node-metastasis (TNM) cancer-staging classification system (Stages I/II/III/IV), the severity of neoplastic growth is characterized by the size of the tumor (T1 to T4), the extent of lymph node involvement (N0 to N3), and whether (M1) or not (M0) distant metastasis has occurred. Surgery is the treatment of choice for medically fit patients with Stage I/II NSCLC. Combination chemoradiotherapy and immune checkpoint inhibitor therapy are used across all NSCLC types. Oncogene-addicted tumors with sensitizing EGFR or BRAF mutations or activating ALK, ROS1 or NTRK translocations are treated with their cognate orally active small molecule protein kinase blockers. On the order of 20 % of NSCLCs bear activating mutations in EGFR and are treated with osimertinib and other kinase antagonists. SCLC, which accounts for approximately 15 % of lung cancer cases, is a deadly high-grade neuroendocrine carcinoma with a poor prognosis. Limited-stage SCLC is confined to one hemi-thorax and one radiation port and extensive-stage disease signifies those cancers that do not meet the criteria for limited-stage disease. Local treatment options to control thoracic disease include radiotherapy and surgery. In patients with extensive-stage disease, a platinum agent (cisplatin or carboplatin) combined with etoposide and an anti-PDL1 inhibitor (atezolizumab or durvalumab) for four cycles followed by anti-PDL1 maintenance therapy is the recommended first-line regimen.

Adverse event profile differences between pralsetinib and selpercatinib: a real-world study based on the FDA adverse events reporting system.

Aims: The objective of this study is to compare the adverse events (AEs) associated with pralsetinib and selpercatinib. Methods: To evaluate the imbalance of AEs linked to pralsetinib and selpercatinib in real-world data, the reporting odds ratio (ROR) was utilized to detect potential signals of AEs. Stratified analysis was conducted to examine the differences in AEs occurring among different genders and age groups taking pralsetinib and selpercatinib. Results: FAERS received 891 reports for pralsetinib and 569 reports for selpercatinib. Our analysis confirmed expected AEs like hypertension, fatigue, and elevated transaminase levels. Unexpected AEs such as rhabdomyolysis, myocardial injury and cognitive disorder were associated with pralsetinib, while selpercatinib was linked with pulmonary embolism, deep vein thrombosis, and pericardial effusion. The risk of AEs such as decreased platelet count, anemia, decreased white blood cell count, pneumonitis, asthenia, and edema caused by pralsetinib is significantly higher than that of selpercatinib. In contrast, the risk of AEs such as ascites, elevated alanine aminotransferase, and elevated aspartate aminotransferase caused by selpercatinib is significantly higher than that of pralsetinib. Women treated with pralsetinib experience higher rates of hypertension, pulmonary embolism, and blurred vision than men, who are more susceptible to rhabdomyolysis. Adults between 18 and 65 years are more likely to experience taste disorder, edema, and pulmonary embolism than individuals older than 65, who are particularly vulnerable to hypertension. For patients treated with selpercatinib, males demonstrate a significantly higher incidence of QT prolongation, urinary tract infection, and dysphagia. Individuals aged 18 to 65 are more likely to experience pyrexia and pleural effusion than those older than 65, who are more prone to hypersensitivity. Conclusion: In the clinical administration of pralsetinib and selpercatinib, it is crucial to monitor the effects of gender and age on AEs and to be vigilant for unlisted AEs.

A case of selpercatinib treatment for anaplastic thyroid carcinoma resulting in abscess formation.

Rearranged during transfection (RET) gene abnormality is a driver gene mutation that causes thyroid cancer, and selpercatinib has been shown to be useful for treating thyroid cancer with RET gene abnormalities. Anaplastic thyroid cancer is a disease with an extremely poor prognosis with no standard treatment established, and there are only one case reports of the efficacy of selpercatinib for RET fusion gene-positive anaplastic thyroid cancer. We herein report our experience treating an old Japanese woman with unresectable anaplastic thyroid cancer with selpercatinib. Surgical resection was initially attempted but was not possible due to adhesion to the common carotid artery. Postoperative genetic testing was positive for the RET fusion gene, and selpercatinib was administered. However, the administration had to be stopped due to the formation of an abscess on day 14 and a pharyngeal fistula on day 17, after which the tumor grew rapidly, and the patient died on day 65. Although selpercatinib has been reported to have a high safety profile with few adverse events, this case suggests that caution should be exercised when treating anaplastic thyroid cancer with invasion to vital organs.

Long-term safety of selpercatinib for Rearrenged during transfection (RET)-activated advanced solid tumors in LIBRETTO-001: differing patterns of adverse events over time.

BACKGROUND: Selpercatinib is a selective RET inhibitor approved for treatment of RET-activated cancers. Adverse events (AEs) are manageable with dose modifications. This post hoc analysis characterized selpercatinib's clinical safety profile after long-term follow-up in the safety population of LIBRETTO-001. PATIENTS AND METHODS: LIBRETTO-001 is an ongoing phase I/II, single-arm, open-label trial (NCT03157128). Eligible patients were ≥18 years old with diagnosis of advanced/metastatic RET fusion-positive solid tumor, RET-mutant medullary thyroid cancer, or other RET-activated tumors. In phase I, patients received selpercatinib 20 mg QD or 20-240 mg BID; patients in phase II received 160 mg BID. The analyzed population comprised all patients who received ≥1 selpercatinib dose and were followed up until data cutoff (January 13, 2023). RESULTS: For the 837 patients, median follow-up was 45.4 months (95% CI, 44.5-46.6); median time on treatment was 30.1 months (range 0.1-66.8). Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 76.2% of patients; most common events were hypertension (19.7%), ALT increased (11.8%), and hyponatremia (9.2%). Serious TEAEs were reported in 51.4% of patients. Most frequently reported any-grade AEs at <6 months of treatment were fatigue (36.6%), dry mouth (32.8%), and ALT increased (30.5%); at ≥24 months of treatment, these were edema (63.2%), diarrhea (60.7%), and fatigue (53.0%). Selpercatinib-related TEAEs leading to reduced dosage were reported in 39.3%, those leading to treatment interruption were reported in 47.1%, and those leading to discontinuation were reported in 4.3% of patients. CONCLUSION: Long-term treatment with selpercatinib is feasible. AEs are manageable with dose modifications, allowing most patients to continue safely on therapy.

Cost-effectiveness analysis of selpercatinib versus chemotherapy and pembrolizumab in the first-line treatment of rearranged during transfection fusion-positive non-small cell lung cancer in the United States.

BACKGROUND: Although selpercatinib has shown clinical benefits for rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), its cost-effectiveness requires further evaluation. AIM: This study aimed to evaluate the cost-effectiveness of selpercatinib versus chemotherapy and pembrolizumab in the first-line treatment of RET fusion-positive NSCLC from the perspective of the United States (US) payer. METHOD: A partitioned survival model was developed based on data from the LIBRETTO-431 trial. Cost and utility values for the health state were obtained from database data or published literature. The measured outcomes included quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). One-way sensitivity analysis and probabilistic sensitivity analyses (PSA) were conducted to assess the uncertainty of the model. RESULTS: Selpercatinib increased QALYs in patients with RET fusion-positive NSCLC by 0.90 compared to chemotherapy plus pembrolizumab, with an additional cost of $542,517.45, resulting in an ICER of $603,286.49/QALY, which exceeded the willingness-to-pay (WTP) threshold ($150,000) in the US. One-way sensitivity analysis suggested that the utility of progressed disease, the utility of progression-free survival, the price of selpercatinib, the discount, the price of pemetrexed, and the price of pembrolizumab had the greatest influence on the cost- effectiveness analysis process. In the PSA, 99.9% of the scatter points were distributed above the US WTP threshold of $150,000. CONCLUSION: From the perspective of the US payer, selpercatinib is not cost-effective compared to chemotherapy and pembrolizumab for first-line treatment in patients with RET fusion-positive NSCLC.

Selpercatinib prior to radioactive iodine for pediatric papillary thyroid carcinoma.

OBJECTIVES: We introduced selpercatinib prior to radioactive iodine therapy prior to radioactive iodine therapy (RAI) for pediatric papillary thyroid cancer (PTC) to enhance the tumorical effects of RAI. CASE PRESENTATION: PTC has an excellent prognosis but is commonly associated with local and distant metastases. Successful complete response to the current standard of care, thyroidectomy with lymph node resection and RAI, is achieved in only a small minority of cases with metastases. The direct effect of tyrosine kinase inhibitors (TKIs) on tumor regression has been confirmed in several randomized controlled studies, while the increased RAI uptake has been reported in small case series, but typically TKIs are currently reserved third-line. Selpercatinib is a TKI that specifically has a durable effect in RET-fusion positive malignancies. We describe a 10-year-old Hispanic girl with metastatic PTC treated with total thyroidectomy and extensive lymph node resection. Evaluation for relevant genetic drivers of the malignancy revealed a strong overexpression of the RET tyrosine kinase domain indicative of a RET gene fusion. Selpercatinib 120 mg twice daily given orally was initiated prior to the initial dose of RAI to achieve further tumor regression by a direct cytostatic effect and then secondarily enhancement of RAI uptake. Minimal side effects occurred, specifically intermittent mild skin rashes that resolved. Resolution of distal lung metastases was noted on CT imaging. RAI was then administered 9 months afterward, with ultimately achievement of a low thyroglobulin level 1.0 ng/mL 11 months after RAI. CONCLUSIONS: In conclusion, selpercatinib given prior to the initial dose of adjunctive RAI for RET-fusion positive PTC is a well-tolerated intervention that further reduces tumor burden and potentially enhances the tumorcidal effects of RAI.

Discovery of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent inhibitors of rearranged during transfection (RET) and RET solvent-front mutants for overcoming selpercatinib resistance.

Rearranged during transfection kinase (RET) inhibition has been considered a promising therapeutic approach for treatment of a variety of cancers. However, the clinical therapeutic benefits of the second-generation RET inhibitor selpercatinib are greatly compromised by acquired resistance mediated by solvent-front mutations (e.g., RETG810 R/S/C). Herein, we report a class of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent RET and RET solvent-front mutant inhibitors for overcoming selpercatinib resistance. The representative compound 20p exhibited excellent in vitro inhibitory activities against solvent-front mutations (RETG810R, RETG810S, and RETG810C) with low nanomolar range (IC50 of 5.7-8.3 nM), which was 15-29-fold more potent than selpercatinib (IC50 of 95.3-244.1 nM). Additionally, 20p exhibited acceptable pharmacokinetic properties with oral bioavailability of 30.4 %. Importantly, 20p exhibited highly impressive antitumor potency in both a Ba/F3-KIF5B-RETWT-derived xenograft mouse model and a selpercatinib-resistant Ba/F3-KIF5B-RETG810R-positive mutant xenograft mouse model. Overall, 20p represents a novel and promising drug lead for overcoming RET solvent-front mutation-based resistance to selpercatinib.

Fluctuating obliterative bronchiolitis in RET-mutant medullary thyroid cancer patient treated with selpercatinib.

Highly selective RET inhibitor selpercatinib has demonstrated notable efficacy in advanced/progressive RET-mutant medullary thyroid cancer (MTC) patients. However, despite a more tolerable toxicity profile than multikinase inhibitors, peculiar adverse events (AEs) have been described. Obliterative bronchiolitis (OB) is a respiratory disease characterized by inflammation and fibrosis in small conducting airways. We evaluated a 70-year-old man with advanced RET-mutant MTC who developed OB during treatment with selpercatinib. Radiological features of OB occurred early and persisted during selpercatinib treatment, with a waxing and waning pattern. Notably, a partial response of MTC was achieved during the treatment, and selpercatinib was never reduced or interrupted. The almost complete absence of symptoms and the fluctuating trend, without specific treatment for OB, suggested that it is necessary to carefully evaluate the risks mediated by this AE with the risks of modifying or discontinuing the anti-cancer therapy.

Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: "Shadows and Fogs".

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1-2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the 'old' multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events.

A case of organizing pneumonia in rearranged during transfection fusion-positive lung adenocarcinoma treated with selpercatinib.

Selpercatinib is the first targeted therapy for rearranged during transfection (RET) fusion-positive unresectable non-small-cell lung cancer (NSCLC). The main adverse effects of selpercatinib include hypertension, liver dysfunction, diarrhea, and QT prolongation on electrocardiograms. However, instances of drug-induced interstitial lung disease (DI-ILD) are infrequently reported. We describe the first case of a patient with RET fusion-positive NSCLC treated with selpercatinib who developed DI-ILD, confirmed pathologically. The patient, a 72-year-old woman, initiated selpercatinib treatment following the postoperative recurrence of lung adenocarcinoma. After 15 months of treatment, computed tomography scans revealed multiple infiltrates and ground-glass opacities in both lungs. A thoracoscopic lung biopsy identified organizing pneumonia, attributed to DI-ILD caused by selpercatinib. Although she was asymptomatic, the patient's selpercatinib treatment was discontinued, leading to a gradual improvement in the lung infiltrates. Despite the lack of detailed reports, DI-ILD with selpercatinib represents a potentially serious adverse event and should be approached with caution.

Target-Driven Tissue-Agnostic Drug Approvals-A New Path of Drug Development.

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAFV600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.

Efficacy and safety of selpercatinib in treating RET-altered MTC: A single-arm meta-analysis.

Background: Selpercatinib is effective in the treatment of RET-altered medullary thyroid carcinoma (MTC). This study aimed to evaluate the efficacy and safety of selpercatinib in the treatment of patients with RET-altered MTC. Methods: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from their inception to April 5, 2024. Outcomes included complete response (CR), partial response (PR), stable disease (SD), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). We carried out a meta-analysis of these studies and exploratory subgroup analyses. The effect sizes for all pooled results were presented as 95% confidence intervals with upper and lower limits. Results: The pooled CR, PR, and SD rates for all patients were 10%, 59%, and 26%, respectively. The pooled ORR in all patients was 70%, while the pooled ORR in pre-treated and non-pre-treated groups were 67% and 70%, respectively. The pooled DCR in all patients was 95%, while the pooled DCR in pre-treated and non-pre-treated groups were 96% and 95%, respectively. The most common AEs associated with selpercatinib were hypertension, alanine aminotransferase (ALT) increased and aspartate aminotransferase (AST) increased. Conclusion: Selpercatinib offers significant benefits to patients with RET-altered MTC with assessable CR, PR, SD, ORR, and grade 3-4 AEs; however, treatment-related AEs should be considered.

Combined Dacomitinib and Selpercatinib Treatment for a Patient with EGFR-Mutant Non-Small Cell Lung Cancer and Acquired CCDC6-RET Fusion.

RET rearrangements are recognized drivers in lung cancer, representing a small subset (1-2%) of non-small cell lung cancer (NSCLC). Additionally, RET fusions also serve as a rare acquired resistance mechanism in EGFR-mutant NSCLC. Only a few NSCLC cases have been reported with co-occurrence of EGFR mutations and RET fusions as an acquired resistance mechanism induced by EGFR-tyrosine kinase inhibitors (TKIs). A 68-year-old man diagnosed with lung adenocarcinoma harboring EGFR L858R mutation initially responded well to dacomitinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI). Afterward, he developed acquired resistance accompanied by a RET rearrangement. Next-generation sequencing (NGS) analysis revealed that the tumor possessed both the new CCDC6-RET fusion and the EGFR L858R mutation. Subsequently, he was treated with a combination of cisplatin, pemetrexed, and bevacizumab resulting in a partial response. Nevertheless, his condition deteriorated as the disease progressed, manifesting as hydrocephalus, accompanied by altered consciousness and lower limb weakness. The subsequent combined treatment with dacomitinib and selpercatinib resulted in a significant improvement in neurological symptoms. Here, we first identified acquired CCDC6-RET fusion with a coexisting EGFR L858R mutation following dacomitinib treatment. Our findings highlight the importance of NGS for identifying RET fusions and suggest the potential combination of dacomitinib and selpercatinib to overcome this resistance. For NSCLC patients with RET rearrangements and no access to RET inhibitors, pemetrexed-based chemotherapy provides a feasible alternative.

Primary resistance to selpercatinib in a patient with advanced medullary thyroid cancer.

Selpercatinib, a selective RET kinase inhibitor, has demonstrated remarkable efficacy in treating patients with advanced medullary (MTC) and differentiated thyroid cancer with RET alterations. Primary resistance to selpercatinib is a very uncommon situation, and its underlying mechanisms are poorly understood. We report the case of a 42-year-old female with advanced MTC harboring a somatic M918T RET mutation who exhibited a primary resistance to selpercatinib. Despite prompt treatment initiation after the diagnosis of progressive disease, the patient continued experiencing rapid spread of disease, characterized by the appearance of new metastatic lesions and increased tumor burden. Genomic analysis revealed no additional mutations associated with on-target or off-target resistance. This case highlights a rare clinical scenario of primary resistance to selpercatinib in advanced MTC. While secondary resistance mechanisms have been well-documented, primary resistance remains poorly understood. Possible explanations include tumor heterogeneity and activation of alternative signaling pathways that stills need to be elucidated. Emerging therapies targeting resistance mechanisms and next-generation RET inhibitors offer promising avenues for further investigation.

Selpercatinib attenuates bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß1 signaling pathway.

IPF is a chronic, progressive, interstitial lung disease with high mortality. Current drugs have limited efficacy in curbing disease progression and improving quality of life. Selpercatinib, a highly selective inhibitor of receptor tyrosine kinase RET (rearranged during transfection), was approved in 2020 for the treatment of a variety of solid tumors with RET mutations. In this study, the action and mechanism of Selpercatinib in pulmonary fibrosis were evaluated in vivo and in vitro. In vivo experiments demonstrated that Selpercatinib significantly ameliorated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro, Selpercatinib inhibited the proliferation, migration, activation and extracellular matrix deposition of fibroblasts by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathway, and suppressed epithelial-mesenchymal transition (EMT) like process of lung epithelial cells via inhibiting TGF-ß1/Smad pathway. The results of in vivo pharmacological tests corroborated the results obtained from the in vitro experiments. Further studies revealed that Selpercatinib inhibited abnormal phenotypes of lung fibroblasts and epithelial cells in part by regulating its target RET. In short, Selpercatinib inhibited the activation of fibroblasts and EMT-like process of lung epithelial cells by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathways, thus alleviating BLM-induced pulmonary fibrosis in mice.

Prior immune checkpoint inhibitors may enhance severe hypersensitivity related to selpercatinib in RET fusion gene-positive lung cancer.

Selpercatinib, a tyrosine kinase inhibitor approved for RET-fusion gene-positive lung cancer, can induce hypersensitivity, potentially exacerbated by prior immune checkpoint inhibitor (ICI) therapy. We present a case of severe toxicity following selpercatinib treatment in a 58-year-old female with lung adenocarcinoma, refractory to previous treatments including pembrolizumab. Symptoms included fever, rash, and multiorgan failure indicative of grade 4 hypersensitivity. Treatment involved platelet transfusion, heparin therapy, and prednisolone, leading to improvement upon selpercatinib cessation. This case highlights the importance of monitoring for hypersensitivity reactions in patients treated with selpercatinib, especially following prior ICI therapy.

LIBRETTO-431: Confirming the Superiority of Selpercatinib to Chemotherapy and the Lack of Efficacy of Immune Checkpoint Inhibitors in Advanced RET Fusion-Positive (RET+) NSCLC, Another Unique Never-Smoker Predominant Molecular Subtype of NSCLC.

Selpercatinib, a potent and highly selective RET kinase inhibitor with significant CNS activity, has recently gained US approval for the treatment of NSCLC harboring RET fusions (RET+) based on a large-scale single-arm study. The LIBRETTO-431 trial was the global pivotal registration phase 3 trial comparing selpercatinib to platinum-based chemotherapy with or without pembrolizumab as the first-line treatment of patients with advanced RET+ NSCLC. Never-smokers constituted 67.4% of the RET+ NSCLC patients enrolled. KIF5B-RET made up the vast majority (77%) of the RET+ fusion variant with known fusion partner. The results of this study demonstrated significant improvement in progression-free survival (PFS) benefit as well as impressive intracranial disease response in participants treated with selpercatinib as compared to those treated with chemotherapy, with a HR [hazard ratio] of 0.46 (95% CI 0.33-0.70; P < 0.001) for the intention-to-treat (ITT)-pembrolizumab group and HR of 0.46 (95% CI 0.31-0.70, P < 0.001) for the overall ITT-group of patients. The addition of pembrolizumab to platinum/pemetrexed chemotherapy resulted in numerically identical PFS (11.2 months). These results point to selpercatinib's superiority to traditional chemotherapy regimens in the treatment of NSCLC harboring RET fusions and add to literature on the salience of targeted precision oncology and lack of efficacy of immune checkpoint inhibitor in NSCLC patients with never-smoker predominant actionable driver mutations. RET+ NSCLC should be added to the list of molecular subtypes (EGFR+, ALK+, ROS1+) of NSCLC to be excluded in chemoimmunotherapy trial.