ROS1 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.

Our standard operating procedure (SOP) was updated to perform orthogonal confirmation testing for stand-alone equivocal NTRK1/2 and equivocal NTRK3 (5' failure), but to ignore equivocal NTRK3 (5' intact) and report as NTRK2/3 indeterminate. Re-verification showed no change to ALK, ROS1, RET, MET ex14, and NTRK1 results. Sensitivity of NTRK2 detection was significantly increased (80% after orthogonal testing).

P=N/A, N=100, Completed, Chongqing University Three Gorges Hospital（Chongqing Three Gorges Central Hospital）; Chongqing University Three Gorges Hospital（Chongqing Three

P4, N=100, Not yet recruiting, Anhui Chest Hospital; Anhui Chest Hospital

P1, N=388, Recruiting, Shanghai Chest Hospital; CSPC Megalith Biopharmaceutical Co., Ltd

Fusion detection using ctDNA CGP showed high concordance with tissue tests and accuracy in predicting therapeutic responses in patients with non-small cell lung cancer. ctDNA CGP may provide an important diagnostic tool for fusion detection.

Emerging structural variants (eSVs) were found to have a combined prevalence to be 0.7%, with only 47.5% of eSVs detected by DNA-NGS. In this cohort study, the detection of structural variants via concurrent RNA-NGS and DNA-NGS was higher across multiple NCCN-guideline recommended biomarkers compared with DNA-NGS alone, suggesting that RNA-NGS should be routinely implemented in the care of patients with advanced NSCLC.

P2, N=88, Recruiting, SWOG Cancer Research Network | Not yet recruiting --> Recruiting

Even within tumors harboring the same oncogenic fusions, a wide range of morphological, molecular and epigenetic entities can be observed. These findings highlight the need for caution when applying the fifth CNS WHO classification, as the vast majority of these fusions are not yet incorporated in the diagnosis, including grade evaluation and DNA methylation classification.

The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.

Current sub-studies: S1900E (KRAS) activated on April 2, 2021 and is studying sotorasib (AMG 510) in non-squamous NSCLC...S1900G (EGFR and MET) activated on April 3, 2023 and is studying capmatinib and osimertinib with or without ramucirumab in NSCLC. S1900K (MET exon 14 skipping) activated on December 18, 2023 and is studying tepotinib with or without ramucirumab in NSCLC. S1900J (MET amplification) is opening fall 2024 and is studying amivantamab in NSCLC...One hundred seventy-four (5%) were submitted with the classification of "Other". The most common reasons included: no sub-studies available, patient chose hospice, and patient transferred to different hospital.

Ten additional participants have experienced Grade 4 treatment-related adverse events, nine of which are non-hematologic toxicities. There is one participant with a Grade 3 treatment-related Hepatobil disorders-Other due to autoimmune hepatitis.

Our results regarding the proportion of samples with actionable mutations demonstrate the value of NGS testing for NSCLC patients in a real-world clinical diagnostic setting.

On-target mutations of the ROS1 kinase domain confer resistance to crizotinib and lorlatinib in more than one-third of acquired resistance cases with no current effective treatment option. The degrader can effectively inhibit ROS1-dependent cell proliferation and tumor growth by degrading the ROS1 kinase, thereby eliminating the active phospho-ROS1. More importantly, the degradation-based therapeutic modality can overcome on-target mutation resistance to tyrosine kinase inhibitors by efficient degradation of the mutated kinase to achieve greater potency than inhibition.

P2, N=56, Recruiting, SWOG Cancer Research Network | Not yet recruiting --> Recruiting

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

Thus, the discovery of a ROS1 ligand remains an important future priority. These findings highlight the potential for disease-associated somatic aberrations or splice variants that modify the ROS1 ECD to promote constitutive receptor activation, warranting further investigation.

This gap may be driven by the under-representation of important patient populations, including populations defined by clinical or molecular characteristics. In this review, we summarize the data outlining the evidence of ICIs in patients with poor Eastern Cooperative Oncology Group performance status (ECOG PS), underlying autoimmune disease (AID), older age, active brain metastases (BMs), and molecular aberrations such as EGFR mutations, ALK fusions, BRAF mutations and ROS1 fusions.

Despite the initial poor response to conventional chemotherapy, the patient exhibited an exceptional and sustained response to crizotinib, with a progression-free survival of 94 months and complete metabolic response on PET scan. This case underscores the importance of molecular profiling in guiding treatment decisions and highlights the efficacy of targeted therapies for ROS1-positive NSCLC.

PLX4720 may be a suitable treatment for the high-risk patient population...Personalized therapy may play an essential role in treatment. We further investigated the role of ICAM5 in inhibiting the malignant bioactivity of LUAD cells.

Infantile high-grade glioma should be regarded as a unique tumor entity and a multidisciplinary approach is paramount in improving survival for this group of patients.

A 3-tier reporting system for ROS-1 SP384 IHC testing combining previous interpretation criteria and diffuse and homogeneous immunoreactivity may better predict ROS1 fusion status without decreasing specificity.

Discover how 3D genomics identifies clinically actionable fusions and complex structural rearrangements that traditional methods miss. Learn how the Aventa FusionPlus test can be used to: • Double the detection rate of gene fusions (NTRK, ROS1, EGFR, RET, ALK) in patients who may be eligible for targeted therapies • Increase the detection rate of deleterious HRR mutations in patients who may be eligible for PARP inhibitors • Resolve diagnostic dilemmas in translocation-driven tumors

Both larotrectinib and entrectinib are tropomyosin receptor kinase inhibitors with tissue-agnostic approvals for the treatment of patients with solid tumors harboring an NTRK fusion. To our knowledge, this is the first report of a patient with an infantile HGG receiving targeted therapy as first-line treatment with prolonged stable disease. A prospective study of larotrectinib in patients with newly diagnosed infant HGG is ongoing, and will hopefully help answer questions about durability of response, the need for additional therapies, and long-term toxicities seen with TRK inhibitors.

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.

P2 | N=166 | Completed | Sponsor: SWOG Cancer Research Network | Active, not recruiting ➔ Completed | Trial completion date: Jul 2024 ➔ Jan 2024

P2, N=64, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Jul 2024 --> Jan 2025

The EGFR mutation, ALK fusion gene, and MET exon 14 skipping mutation were detected in patients with pulmonary sarcomatoid carcinoma in clinical practice, and some patients achieved long survival times after receiving targeted therapy. Further investigation is necessary to evaluate the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma.

TEs occurred later with EGFR and ALK , while earlier with ROS1 or KRAS with STK11, KEAP1 or SMARCA4 co-mutations compared to those with KRAS mutations alone. $$table_{7740CBC2-774F-48DA-932A-077113E7FED5}$$

TEs occurred later with EGFR and ALK , while earlier with ROS1 or KRAS with STK11, KEAP1 or SMARCA4 co-mutations compared to those with KRAS mutations alone. Cumulative incidence of venous and arterial TEs % 0 6 weeks 6 months 1 year 2 years 3 years Overall 2.8 6 11.7 15.8 21.5 26.2 ALK 5.3 10.7 12 14.8 14.8 17 BRAF 2.1 5.8 12.9 16.3 19.5 27.9 EGFR 2 5.8 10.2 14 17.9 23 HER2 0 3.5 7.2 9.2 19.5 23 KRAS 2.7 5.1 11.3 15.3 22.5 27.1 MET 14 6.8 11.3 21.2 21.2 23.9 27.7 RET 13.3 23.3 33.3 36.6 44.5 50.1 ROS1 12 20 34.2 34.2 45.1 53.3

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

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.

Importantly, co-occurrence of rare fusions and EGFR classical activating mutations in patients pre-treated with anti-EGFR therapy suggests a potential resistance mechanism and consideration of upfront, dual mutation, targeted treatment to improve outcomes. Further clinical studies are needed to validate the best treatment options for these patients with rare fusions.

High ERBB3 expression was associated with better survival. These data support the role of HER3 as a viable therapeutic target across multiple molecular subsets.

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.

The results from this study are consistent with clinical trial data and, taken collectively, supports crizotinib as a safe and effective treatment across different lines of therapy in patients with ROS1 aNSCLC in the real-world setting.

P1, N=309, Recruiting, Daiichi Sankyo | Active, not recruiting --> Recruiting | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Jan 2022 --> Mar 2026

Considering the current pricing of entrectinib, it is not deemed cost-effective as a first-line or second-line therapy for patients with ROS1 fusion-positive advanced NSCLC when compared to chemotherapy. Alternatively, reserving entrectinib exclusively for second-line therapy might strike a balance between healthcare expenditures and patient outcomes.

Further research on next-generation TKIs regarding the localization of ROS1 and its fusion partners, binding sites for targeted drugs, and coadministration with other drugs is required. The correlation between TKIs and chemotherapy or immunotherapy in clinical practice requires further study.

We discuss the role of NGS as well as its potential benefit in patients with unresectable, ALK-negative metastatic disease. Considering this case and previous literature, we support the use of NGS for patients requiring systemic treatment.

Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation...Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1...Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (NGS) expands personalized therapies by identifying guideline-recommended molecular alterations.