KIF5B-RET fusion

Of four patients with PD-L1 overexpression (>50%) one received pembrolizumab and the other three patients received pemetrexed, carboplatin, and pembrolizumab or camrelizumab. Fifteen patients received selective RET inhibitors (pralsetinib and selpercatinib), resulting in an ORR of 53.3% (8/15) and median PFS of 10.0 months (95% CI 5.2-14.9). ICIs for PD-L overexpression and treatment naive patients offer comparable benefits for RET fusion-positive NSCLC, warranting further investigation.

C-LCNEC with adenocarcinoma and squamous cell carcinoma is rare and highly aggressive cancer. Surgical resection and adjuvant chemotherapy with SCLC regimen may improve the disease-free survival and overall survival. The accumulation of similar cases will clarify the profile and management of the disease.

RET fusions were identified in multiple tumor types. With a higher median TMB and commonly MSI-H, RET fusion positive CRC may be a unique molecular subset of CRC.

This study revealed a unique immune landscape at the single-cell level in rare-mutant NSCLC undergoing neoadjuvant chemo-immunotherapy. These findings may have implications for the development of personalized therapeutic strategies for patients with rare mutations in locally advanced NSCLC.

7 studies were invalid for both ADN&RNA,in 5 for DNA, one for ARN and in two cases without CNV detection.T% median was 90%(mean 75.4%). Among patients with invalid results 10 were rebiopsied. Thirty two patients have no genomic aberrations (24.4%).Co-ocurring molecular alterations-rate was 47,5%.Molecular alterations in KRAS and EGFR genes were the most frequent identified in 37(33%) and 22(16%) cases respectively.

P2, N=86, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2023 --> Jul 2026 | Trial primary completion date: Jul 2023 --> Jul 2026

"This study revealed the comprehensive mutational landscape of advanced NSCLC through liquid biopsy, providing novel biomarkers for clinical diagnosis and targeted therapy mechanism studies."

RNA fusions such as TMPRSS13-TMPRSS13, SUPT6H-ESR1, PTPRK-RSPO3, and KIF5B-RET were investigated and fusion junctions were successfully determined. Gene partners from multiple fusion pairs (e.g., SUPT6H-ESR1 and KIF5B-RET) were found to have an oncogenic role in lung cancer. Mutations in KIF5B and RET genes were found to associate with poor survival in the TCGA dataset suggesting that the novel RNA fusions may also play an oncogenic role in lung cancer.

PD-L1 expression did not show significant difference between pts with positive vs negative EGFR or HER3 staining (p=1).Conclusions EGFR and HER3 had variable expression in RET+ NSCLC, deserving further exploration for novel treatment strategies. HER2 expression was not found in our RET cohort.

9.5% of our tumors have oncogenic fusions that may be clinically relevant, which suggests patients with advanced cancers should have comprehensive molecular profiling that includes RNA sequencing. Additional studies are needed to determine the function of the identified unclassified gene fusions to assess potential clinical significance. Table- Unclassified Fusions (number per total unclassified fusions)Tumor Type (Total Number of Samples Profiled)Fusion Positive samplesUnclassified FusionsProstate adenocarcinoma (89)8 (32%)BMPR1B-PDLIM5 (2 patients), CDC13-SUGCT, NIPBL-RAI14, TTC6-MIPOL1, NFIB-UBE3B, GALNT7-SPOCK3, TBCA-AP3B1Breast cancer (224)8 (32%)NIPBL-PIEZO1, ETV6-RINT1, PAK1-TEX14, PAK1-MMP20, PAK1-LOC101928896, TTC6-MIPOL1, BMPR1B-PDLIM5, CMTM8-OSBPL10Non-small cell lung cancer (751)4 (16%)PANX1-PRPF19 (2 patients), TTC6-MIPOL1, GALNT7-SMIM8Head and neck cancer (177)2 (8%)ETV6-DNAH14, TP53BP1-SND1Salivary gland tumor (22)1 (4%)NFIB-CHCHD7Pancreatic adenocarcinoma (186)1 (4%)CMTM8-GPD1LOvarian cancer (362)1 (4%)NIPBL-SLC1A3Total Number of Fusions25

Our data suggest that cell proliferation and invasiveness in KIF5B-RET fusion cells are regulated by the upregulation of STAT5A and FOXA2 through the continuous activation of multiple RET downstream signal cascades, including the ERK and AKT signaling pathways. We found that TGF-β1 mRNA, where significant increments were observed in KIF5B-RET fusion cells, is regulated at the transcriptional level by FOXA2.

Our case indicates that RET is one of the main driver oncogenes of PSC and provides useful information for precise RET inhibitor administration in the future. Thus, the use of comprehensive genomic profiling may provide important treatment options for PSC.

Approximately 25% of MTC tumors lack activating point mutations in RET or RAS genes. Analysis of actionable fusion mutations should be considered if there is metastatic disease. High serum calcitonin levels are not pathognomonic for MTC and tumor histology may overlap with neuroendocrine lung cancers, creating a diagnostic challenge.

The use of optimal testing assays for RET alterations across patients with NSCLC remains low and many HCPs continue to lack awareness of appropriate targeted therapy for patients with RET–fusion positive NSCLC > 2 years after the first approved indication for this biomarker. These results underscore a lag in adoption of optimal precision medicine approaches for NSCLC among oncology HCPs and the need for expert guidance and educational activities to optimize individualized, biomarker-driven treatment approaches. An analysis of patterns by HCP role (MD, NP/PA, RN, Pharmacist) will be presented.

There was no correlation between RET fusion partners and MSI status. Table: 72P Conclusions Outside of approved indications of NSCLC and thyroid cancers, RET fusions were identified in multiple tumor types such as colorectal, breast, cancer of unknown primary and pancreatic cancer.

Conclusions Pralsetinib is active in RET fusion+ NSCLC, regardless of fusion partner or prior treatment. CCDC6 RET-driven disease may have a better prognosis vs KIF5B.

Our study systematically evaluated the genetic landscape underlying RET fusions as a rare driver gene and provide important insights into secondary resistance to EGFR TKIs in Chinese NSCLCs, which will be important considerations in improving the efficacy and clinical outcome of existing RET inhibitors and facilitating the development of new therapeutics.

Analysis of actionable fusion mutations should be considered if there is metastatic disease. Science Topic(s) for Thryoid: Thyroid Neoplasia and Cancer (also see Tumor Biology)

P2, N=86, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2022 --> Jul 2023 | Trial primary completion date: Jul 2022 --> Jul 2023

Both IHC and FISH demonstrated lower sensitivity for NCOA4-/others-RET fusions. Clinical benefit with chemotherapy is different between CCDC6-RET and KIF5B-RET fusion patients, optimal treatment should be considered when selecting therapies for patients with RET-rearranged lung cancers.

We also compared our results with other studies and found conflicting results presumably because of the multiplicity of antibody clones and platforms, the difference of cutoffs for assigning PD-L1 expression levels, and the variation in study populations. Our study can help to understand the utility and validity of PD-L1 as biomarker of response to immune checkpoint inhibitors.

Frontline therapy consisted of bevacizumab combined with pemetrexed and carboplatin and achieved a progression-free survival (PFS) of 14 months with best response of stable disease. We provided additional evidence supporting MET amplification as an acquired mechanism of resistance to selective RET inhibition. In addition, the apparent lack of response to selpercatinib plus crizotinib in this case highlights the need for future cohort studies for examining the value of combining RET and MET inhibitors in treating RET-rearranged, MET-amplified NSCLC.

In this study, using the hybrid capture based next generation sequencing (NGS) techniques, we revealed the genomic profiling for the patients with RET fusion-positive NSCLC. To the best of our knowledge, this is the first study that exhibited the detailed breakpoints of Chinese NSCLC patients with RET rearrangement, and we found a novel new partner PLCE1. The results provided genomic information for patients with RET fusion which is significant for personalized clinical management in the era of precision medicine.

Distinct molecular driver alterations at osimertinib resistance co-exist with initial EGFR mutations in single cancer cells. The clonal evolution of cancer cell populations emphasized their heterogeneity leading to osimertinib relapse. Combining two targeted treatments is effective to achieve clinical benefit.

Precision medicine is dependent on diagnostic methods such as NGS to identify patients who might benefit from targeted therapies. Selective inhibitors of molecular oncogenic drivers are usually effective and well tolerated.

P2, N=86, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2021 --> Jul 2022 | Trial primary completion date: Jul 2021 --> Jul 2022

Currently, several approved multikinase inhibitors such as vandetanib and cabozantinib demonstrate clinical activity in patients with RET-rearranged or RET-mutant cancers...Herein, we designed and synthesized a series of RET inhibitors based on the structure of selective RET inhibitor BLU-667 and investigated their biological activities...In mouse xenograft models, compound 9 repressed tumor growth driven by KIF5B-RET-Ba/F3 cells in a dose-dependent manner. Based on its exceptional kinase selectivity, good potency and high exposure in tumor tissues, compound 9 represents a promising lead for the discovery of RET directed therapeutic agents and the study of RET-driven tumor biology.

Furthermore, we describe the genomic sequences in 4 of these cases, 2 of which have previously described KIF5B-RET fusion and 2 of which had a novel LMNA-RET fusion. We believe this report significantly contributes to our current knowledge regarding Spitz neoplasms and describes characteristics features which can help with recognition of the RET subgroup of Spitz.

Previous studies in pts treated with selpercatinib or pralsetinib have reported the shared emergence of recurrent RET G810 mutations at the solvent front of the ATP pocket, which lead to a steric clash and loss of binding potency for both drugs. These data suggest that LOX-18228, as well as closely related compounds, represent promising next-generation RET inhibitor candidates that could be used to further extend durable disease control for pts with RET-altered cancers following the development of acquired resistance to current agents. An IND is planned for 2021.

Initiation of targeted therapy for advanced NSCLC was feasible based only on identification of actionable mutations by cfDNA testing in 9% of the cases for which tissue diagnosis could not be obtained. Actionable targets were identified by cfDNA in 20% of the samples sent at diagnosis. A substantial number of patients benefited from cfDNA testing at initial diagnosis because it identified actionable mutations that led to appropriate targeted treatments.

No abstract available

Since clinically significant results were obtained only in non-smoker patients, we suggest smoking status as a potential clinical driver for selecting aNSCLC patients for NGS analyses in a real-world context. NGS testing of smokers might be considered within the research setting.

Unique genetic characteristics and poor prognosis are found in female patients with lung cancer harboring RET fusion gene. Immune checkpoint inhibitors are a potential option for patients with high expression of PD-L1.

The profiling pilot of the PMT initiative shows how strong foundations within the Exactis pan-Canadian network and streamlined NGS testing and reporting are resulting in fast, high quality and meaningful molecular data for Canadian cancer patients.

Legal entity responsible for the study: Chun-wei Xu. Funding: Has not received any funding.

For treatments, 14.75% (9/61) patients chose cabozantinib, other patients chose chemotherapy or chemoradiotherapy, and case examples of advanced RET fusion driven NSCLC patients responding to cabozantinib were actively being sought thru our database. Patients with advanced RET fusion NSCLC showed a relatively good outcome of cabozantinib with relatively large side effects, which strengthen the need for effective RET-targeted drugs in clinical practice.

For treatments, 14.75% (9/61) patients chose cabozantinib, other patients chose chemotherapy or chemoradiotherapy, and case examples of advanced RET fusion driven NSCLC patients responding to cabozantinib were actively being sought thru our database. Patients with advanced RET fusion NSCLC showed a relatively good outcome of cabozantinib with relatively large side effects, which strengthen the need for effective RET-targeted drugs in clinical practice.

In mouse xenograft models, 9x repressed tumor growth driven by both wild type KIF5B-RET-Ba/F3 and gatekeeper mutant KIF5B-RET(V804M)-Ba/F3 cells in a dose-dependent manner. Together, these data establish that 9x provides a good starting point for the development of targeted therapeutics against RET-positive cancers, especially NSCLC.

In RET rearranged NSCLC, selective RET TKI therapy is associated with improved survival outcomes, especially in CCDC6-RET positive patients. Immunotherapy has poor efficacy. NGS and FISH testing methods may also result in significant discordance.

At the fusion level, we identified EML4-ALK (5.2%), KIF5B-RET(1.7%) and MET exon 14 skipping (3.4%) in NSCLC participants and we identified RSPO3 (3%) and RSPO2 (2%) fusion in colorectal cancer participants. The profiling pilot of the PMT initiative shows how strong foundations within the Exactis pan-Canadian network is resulting in fast, high quality and meaningful molecular data for Canadian cancer patients.

These results suggest that pleural effusions are important specimens for oncogene mutation analysis and enable targeted therapy for patients with lung adenocarcinoma. Research Funding: None