RET fusion

Genomic profiling yields clinically actionable information for approved therapies and evidence of resistance, and it may uncover rational therapeutic opportunities regardless of tumor type.

This report offers a thorough characterization of expected prevalence and expression levels for CSFs and NDFs with an NGS study of a broad scope. We describe ESR1 fusions in a cohort of thousands of breast tumors and show lower median expression levels relative to NDFs such as ALK, ROS1, and RET fusions. Our findings suggest that some CSFs, like ESR1 fusions in breast cancer, may be the result of tandem duplication with upstream partners, and may be subclonal and acquired later in cancer progression.

The routine use of RNA-based CGP analysis allows for the comprehensive detection of oncogenic fusions in patients with cancer. The diversity of tumor types in which actionable fusions were detected supports the broader utilization of CGP to potentially increase targeted therapy usage and improve outcomes across cancer subtypes.

P1/2, N=856, Active, not recruiting, Loxo Oncology, Inc. | Recruiting --> Active, not recruiting

P2, N=13, Recruiting, Children's Hospital of Philadelphia | Not yet recruiting --> Recruiting | Initiation date: Nov 2024 --> Jul 2024

This study encapsulates the research endeavors and treatment advancements of RET rearrangement solid tumors within the Chinese healthcare landscape, specifically highlighting the diverse real-world therapeutic approaches and their effectiveness in managing advanced RET rearrangement NSCLC among Chinese patients. Notably, targeted RET inhibitors like Pralsetinib have emerged as potent therapeutic agents, exhibiting remarkable efficacy and a manageable safety profile in this patient cohort. These findings underscore the potential of Pralsetinib and similar targeted therapies as novel treatment options for individuals with RET fusion-positive NSCLC.

The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.

These findings underscore the importance of TERT alterations in aggressive phenotypes and offer insights into molecular mechanisms guiding targeted therapies. Further research is necessary to confirm their significance as diagnostic and prognostic markers in thyroid cancer.

These tumors demonstrate the potential for aggressive local growth and regional metastasis. We propose a unifying diagnostic term for these lesions to reflect their common morphologic and molecular features and, most importantly, low malignant potential.

Neoadjuvant use of tyrosine kinase inhibitors seems extremely effective in downstaging surgically unresectable differentiated thyroid cancers to achieve R0 resection while avoiding unnecessary surgical morbidities. A multidisciplinary approach with early genomic profiling to guide personalized neoadjuvant use of tyrosine kinase inhibitors is essential. Prospective studies are urgently needed to define the potential role of neoadjuvant tyrosine kinase inhibitors in advanced thyroid cancer management.

Long-term treatment with selpercatinib is feasible. AEs are manageable with dose modifications, allowing most patients to continue safely on therapy.

Patients with NSCLC harboring select AGAs, including EGFR and ALK alterations, have a higher risk for TF, shorter median time to TF, and diminished pathological regression after neoadjuvant ICIs. The suboptimal efficacy of neoadjuvant chemotherapy-sparing, ICI-based regimens in this patient subset underscores the importance of tumor molecular testing prior to initiation of neoadjuvant ICI therapy in patients with resectable NSCLC.

P2, N=30, Recruiting, Massachusetts General Hospital | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Mar 2024 --> Mar 2025

One patient was found to have RET fusion and responded favorably to selpercatinib for over 42 months...One of the additional two cases who underwent BostonGene testing was found to have NTRK1 fusion. RNA and TME analysis by Boston Gene of the two cases reported immune desert features and relatively lower RNA levels of CEACAM5, CD47, CD74, and MMP1 and higher RNA levels of CDH6 compared with PDAC.

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.

The patient in case 2 had no other known tumors at the time of diagnosis, but no follow-up is available. We believe the reported cases represent a hitherto unrecognized variant of "NTRK-rearranged spindle cell neoplasms" of the uterine cervix with novel EGFR mutations.

He was treated simultaneously with intrapleural plus systemic Tislelizumab injection combined chemotherapy, thereby achieving an excellent clinical benefit maintaining control of pleural effusion for over 6 months. Hence, we would like to discuss intrapleural immunotherapy as an additional treatment method in refractory malignant pleural effusion while demonstrating good treatment tolerance.

P1, N=110, Active, not recruiting, Eli Lilly and Company | Trial primary completion date: Jun 2025 --> Sep 2024

As demonstrated in our PTC cohort, DNA CGP and RNA CGP may be complementary for fusion detection in certain tumor types. RNA CGP complements DNA CGP by detecting fusions that cannot be efficiently baited on DNA CGP, while DNA CGP may complement RNA CGP by detecting fusions in poor quality (e.g., old archival) samples when RNA sequencing may not be not technically feasible. Clinically relevant fusions detected in this retrospectively profiled PTC cohort included therapeutically targetable fusion events (e.g., RET, NTRK, ALK) and a PAX8::PPARG fusion, which is suggestive of a follicular variant PTC.

Objective: In 2022, the OncomineTM Dx Target Test (ODxTT) was approved in Japan as a companion diagnostic for selecting patients eligible for selpercatinib for advanced thyroid cancer, introducing a multigene test for thyroid cancer... A total of 571 patients were enrolled. There were 357 women (62.5%) and 214 men (37.5%) with a mean age of 65.9 ± 14.2 years. Four hundred and 18 (73.2%) were papillary carcinoma (PTC), 56 (9.8%) follicular carcinoma (FTC), 31 (5.4%) poorly differentiated carcinoma (PDTC), 38 (6.7%) anaplastic carcinoma (ATC), 21 (3.7%) medullary carcinoma (MTC), and 7 (1.2%) others.

While recurrence data were not available for this series of radiation-induced PTCs, Type 3 and advanced Type 1/2 cancers defined by Thyroid GuidePx® had more aggressive clinical features, including a higher rate of RET fusions, a surrogate marker for recurrence risk in radiation-induced PTC.

The patient recovered well after surgery, demonstrating the potential efficacy of neoadjuvant pralsetinib in locally advanced RET-rearranged lung adenocarcinoma. However, further clinical validation is required to establish the role of neoadjuvant targeted therapy and postoperative adjuvant therapy in this patient population.

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.

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.

This multicenter registration study investigated tissue-based NGS for a specific patient population with NSCLC in Taiwan.

SAMS is on a morphologic and molecular genetic spectrum with EFH, with a similar body site distribution, frequent clinical presentation as an exophytic skin tumor, and invariably benign outcomes; we conclude that SAMS should be considered a histologic variant of EFH. Some morphologically typical examples harbor alternate RET and NTRK3 fusions, such that SAMS is not an appropriate designation for this morphologic class; instead, to highlight the clinicopathologic similarities to EFH, we propose the diagnostic term "myxoid spindle cell variant of epithelioid fibrous histiocytoma."

The study observed high biomarker testing rates at initial diagnosis for early- and advanced-stage RET fusion-positive NSCLC patients in China. The heterogeneous treatment pattern of advanced patients suggests the need for more precise, evidence-based treatment to guide clinical decisions. Given the existing therapeutic regimens fall short of adequately addressing treatment needs, targeted therapies are essential to improve outcomes.

There is a potential for pralsetinib as a neoadjuvant treatment in PTC with RET-fusion.

P2, N=13, Not yet recruiting, Children's Hospital of Philadelphia | Trial completion date: Aug 2031 --> Nov 2031 | Initiation date: Aug 2024 --> Nov 2024 | Trial primary completion date: Aug 2030 --> Nov 2030

Selective RET inhibitors, such as selpercatinib and pralsetinib, have revolutionized the treatment of cancers with RET gene alterations. The findings suggest that FDG-PET has the potential to serve as a non-invasive biomarker for monitoring treatment response in patients with RET-positive cancers. However, further research is required to establish standardized criteria for interpreting FDG-PET scans in the context of selective RET inhibitors and to uncover the broader applications of FDG-PET in precision oncology.

These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.

EGFR inhibition with afatinib or cetuximab in combination with RET TKIs was effective in addressing drug persistence. Consistently, knocking out EGFR or RET led to high sensitivity to RET or EGFR inhibitor respectively. Here, we have provided a comprehensive analysis of adaptive and acquired resistance against RET-rearranged NSCLC.

Pralsetinib demonstrated promising activity in patients with advanced NSCLC harboring RET fusion with a favorable safety profile.

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.

Overall, the chromatographic technique established in this study can effectively separate pralsetinib and its impurities, providing reliable assurance for the accurate detection and quantification of impurities. The chromatographic method developed in this study can be utilized for the detection of pralsetinib and its impurities, offering a crucial reference for research on the quality of pralsetinib.

These findings suggest that cfDNA & cfRNA extraction and double detection strategy recommended in this study improve the accuracy of driver genes mutations test, especially for RNA-based assay.

This suggests that additional factors beyond the immune environment may also influence immunotherapy responses in LUAS, highlighting the need for further investigation. Table 1: Genomic/Immune landscape of LUAS, AC, SCC along with LUAS primary and metastatic sites Adenosquamous (LUAS, n =374) Squamous (SCC, n = 9635) Adenocarcinoma (AC, n = 25665) p-value (SCC vs LUAS) p-value (AC vs LUAS) Overall Actional Alteration Prevalence EGFR, ALK, ROS1, RET fusions /rearrangements, METex14, BRAF V600E, KRAS G12C, NTRK fusions, HER2 110 (29.4%) 343 (3.67%) 9267 (36.22%) 1%) 228 (65.5%) 5293 (59.8%) 12789 (53.7%) 0.033 50%) 110 (31.6%) 2119 (26.3%) 6218 (31.2%) 0.0293 0.1843 PD-L1 low (1-49%) 112/348 (33.9%) 3009/8045 (37.8%) 6177/20023 (30.8%) 0.048 0.512 No PDL1 (0%) 126/348 (36.2%) 2917/8045 (35.9%) 7628/20023 (38.1%) 0.984 0.3621 TMB High ( > 10 Mut/MB) 112 (30.6%) 3488 (38.47%) 8159 (32.94%) 0.002 0.344 Tumor microenvironment LUAS Median cell fraction (%) SCC Median cell fraction (%) AC Median cell fraction (%) p-value (SCC vs LUAS) p-value (AC vs LUAS) Monocytes 0.02 0.06 0.10 0.138 0.017 T cells CD4 0.04 0.07 0.11 0.274 0.130 Neutrophils 5.57 5.23 4.85 0.165 0.020 NK cells 2.68 2.49 2.94 0.005 <0.001 T cells CD8 0.39 0.11 0.27 <0.001 0.164 Macrophages M2 6.08 4.65 6.19 <0.001 0.172 Macrophages M1 4.57 2.64 5.12 <0.001 0.005 B cells 4.08 4.19 3.87 0.092 0.160 Dendritic cells 0.61 1.07 0.54 <0.001 0.049 Tregs 2.92 1.75 2.76 <0.001 0.365 Immune-related genes LUAS Median Gene expression median ((Log2 (TPM+1)) SCC Median Gene expression median ((Log2 (TPM+1)) AC Median Gene expression median ((Log2 (TPM+1)) p-value (SCC vs LUAS) p-value (AC vs LUAS) PDCD1LG2 1.447 1.319 1.284 0.009 <0.001 PDCD1 0.817 0.711 0.790 0.003 0.251 CTLA4 1.914 1.629 1.638 <0.001 0.001 CD86 3.534 3.218 3.482 <0.001 0.337 ID01 2.850 2.300 2.241 <0.001 <0.01 CD274 3.210 3.122 3.031 0.717 0.132 CD80 2.888 2.569 2.798 <0.001 0.453 HAVCR2 4.511 3.999 4.499 <0.001 0.739 LAG3 1.037 1.043 0.865 0.466 0.001 IFNG 0.841 0.697 0.691 0.026 0.025

Conclusions : The integration of ODxTT alongside single gene tests provides significant additional information without compromising the performance of single gene tests. With ODxTT's high success rate, this integration expands the scope of comprehensive therapeutic strategies for advanced lung cancer.

However, NGS had a 12-day longer TAT compared to EGFR PCR. Gene fusion-panel PCR and NGS identified an additional 11.6% of patients harboring actionable alterations who may benefit from FDA-approved targeted therapies.

In a real-world, retrospective analysis of a cohort of advanced NSCLC patients, most oncologists utilized CGP to identify and treat patients with guideline-recommended variant matched targeted therapy, with adherence rates varying by variant. Importantly, even patients that received CGP results prior to FDA approval of novel therapies, received matched therapy once they were included in guidelines.

Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR-altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

Although RET-positive tumors have been treated with multikinase inhibitors such as vandetanib or RET-selective inhibitors, ultimately resistance to them develops...Increased mitochondria were also observed in post-TKI biopsy specimens in 13/20 cases of NSCLC, suggesting a potential strategy targeting mitochondria to treat resistant tumors. Our data propose new promising therapeutic options to combat resistance to RET inhibitors in NSCLC.