ROS1 Fusion Research Articles

Discovery of Oral Degraders of the ROS1 Fusion Protein with Potent Activity against Secondary Resistance Mutations.

The development of therapeutic resistance in the majority of patients limits the long-term benefit of ROS1 inhibitor treatment. 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. As an alternative to stoichiometric inhibition, proteolytic degradation of ROS1 could provide an effective tool to combat resistance generated by these mutations. Our study has identified a potent, orally active ROS1 degrader with an excellent pharmacokinetics profile. 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.

EP.12B.03 Cognitive Impact of Lorlatinib Administration in Advanced Non Small Cell Lung Cancer with ALK and ROS1 Fusions

EP.12B.03 Cognitive Impact of Lorlatinib Administration in Advanced Non Small Cell Lung Cancer with ALK and ROS1 Fusions

Novel insight into mechanisms of ROS1 catalytic activation via loss of the extracellular domain.

The ROS1 receptor tyrosine kinase (RTK) possesses the largest extracellular amino-terminal domain (ECD) among the human RTK family, yet the mechanisms regulating its activation are not fully understood. While chimeric ROS1 fusion proteins, resulting from chromosomal rearrangements, are well-known oncogenic drivers, their activation mechanisms also remain underexplored. To elucidate the role of the ROS1 ECD in catalytic regulation, we engineered a series of amino-terminal deletion mutants. Our functional studies compared the full-length ROS1 receptor, the CD74-ROS1 oncogenic fusion, and ECD-deleted ROS1 constructs, identifying the ECD regions that inhibit ROS1 tyrosine kinase activity. Notably, we found that deletion of the ROS1 ECD alone significantly increases constitutive catalytic activation and neoplastic transformation in the absence of an amino-terminal fusion partner, challenging the presumed necessity for a dimerization domain in the activation mechanism of kinase fusions in cancer. Our data suggest that inter-genic deletions resulting in the loss of the ECD may be underappreciated oncogenic drivers in cancer. Furthermore, our studies demonstrate that RNASE7 is not a ligand for the ROS1 receptor as previously reported, confirming that ROS1 remains an orphan receptor. 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.

Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer Under-Represented by Clinical Trials.

Since the initial US FDA approval of an immune checkpoint inhibitor (ICI) for the treatment of non-oncogene-driven non-small-cell lung cancer (NSCLC) nine years ago, this therapeutic strategy has been cemented as a crucial component of treatment for most of these patients. However, there is a clear efficacy-effectiveness gap whereby patients in the 'real world' seem to have more modest clinical outcomes compared to those enrolled in landmark clinical trials. 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.

Additional reporting of diffuse and homogeneous ROS-1 SP384 immunoreactivity enhances prediction of ROS1 fusion-positive non-small cell lung cancer.

ROS-1 immunohistochemistry (IHC) is a common method for screening ROS1 fusion in the clinical management of non-small cell lung cancer. The interpretation criteria for ROS-1 SP384 IHC, however, remain unestablished. Sixty-five non-small cell lung cancer cases underwent AmoyDx ROS1 fusion real-time polymerase chain reaction (PCR) study and ROS-1 SP384 IHC tests, which were retrieved for analysis. ROS-1 IHC tests were interpreted based on the established classifiers as well as the presence of diffuse homogeneous immunoreactivity. The diagnostic accuracies of these ROS-1 IHC interpretation methods were evaluated by comparing them with the ROS1 real-time PCR results. Previous ROS-1 IHC classifiers demonstrated high sensitivity for positive ROS1 real-time PCR results (100%), but they showed low specificities (25%-50%) and overall accuracies (58%-72%). In contrast, the diffuse homogeneous ROS-1 immunoreactivity predicted positive ROS1 real-time PCR results with much higher specificity (94%) and overall accuracy (95%), albeit with a slightly lower sensitivity (97%). Some cases that showed discrepancy between diffuse homogeneous ROS-1 immunoreactivity and real-time PCR results involved rare ROS1::LDLR fusion and suboptimal IHC staining. 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.

Registry of Genetic Alterations of Taiwan Non-Small Cell Lung Cancer by Comprehensive Next-Generation Sequencing: A Real-World Cohort Study-Taiwan Cooperative Oncology Group T1521.

Tissue-based next-generation sequencing (NGS) analysis is highly recommended for patients with advanced/metastatic non-small cell lung cancer (NSCLC). We investigated a specific patient population with NSCLC that required tissue-based NGS analysis. We enrolled 500 patients with advanced/metastatic (1) epidermal growth factor receptor (EGFR) mutations or anaplastic large-cell lymphoma kinase (ALK) rearrangement-positive NSCLC who had failed at minimum one line of tyrosine kinase inhibitor (TKI) therapy, (2) EGFR-/ALK-negative nonsquamous, and (3) non- or light-smoker patients with squamous NSCLC who were treatment-naïve or had failed at maximum two lines of systemic treatment. These patients were divided into five cohorts. Comprehensive tissue-based NGS testing (ACTOnco+) was conducted. Cohort 1: EGFR TKI-pretreated EGFR-mutated population (50.0%, n = 250), cohort 2: ALK inhibitor-pretreated ALK-positive population (1.6%, n = 8), cohort 3: treatment-naïve EGFR-/ALK-negative population (28.2%, n = 141), cohort 4: pretreated EGFR-/ALK-negative population (16.8%, n = 84), and cohort 5: squamous cell carcinoma (3.4%, n = 17). In cohort 1, 11.2% (28/250) of the patients had MET amplification, 32.4% (81/250) had been treated with osimertinib, and EGFR C797S was detected in 6.2% (5/81) of these patients. In cohort 2, resistance ALK mutation was detected in 37.5% (3/8) of the patients. In cohorts 3 and 4, targetable genetic alterations, including EGFR mutation (13.3%), ERBB2 mutation (9.3%), MET exon 14 skipping (5.3%), KRAS G12C mutation (4.4%), ROS1 fusion (2.7%), RET fusion (1.8%), and BRAF V600E mutation (1.3%), were detected. In cohort 5, MET exon 14 skipping was detected in 29.4% (5/17) of the patients. This multicenter registration study investigated tissue-based NGS for a specific patient population with NSCLC in Taiwan.

An observational study on the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma

BackgroundPulmonary sarcomatoid carcinoma is a rare tumor that is resistant to cytotoxic agents. This observational study aimed to evaluate the detection rate of driver gene alteration and the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma.MethodsWe established a database of patients with pulmonary sarcomatoid carcinoma and their clinical information, including EGFR mutation, ALK fusion gene, ROS1 fusion gene, BRAF mutation, and MET exon 14 skipping mutation. The present study retrieved and analyzed the data of patients with pulmonary sarcomatoid carcinoma in whom driver gene alterations were evaluated, and the survival duration after the initiation of treatment with targeted therapy was examined.ResultsA total of 44 patients were included in the present study. The EGFR mutation, ALK fusion gene, and MET exon 14 skipping mutation were detected in 2/43 patients (4.7%), 2/34 patients (5.9%), and 2/16 patients (12.5%), respectively. The ROS1 fusion gene (0/18 patients) and BRAF mutation (0/15 patients) were not detected. Female patients (P = 0.063, Fisher’s exact test) and patients without smoking history (P = 0.025, Fisher’s exact test) were the dominant groups in which any driver mutation was detected. Five patients with driver gene alterations were treated with targeted therapy. Progression-free survival (PFS) was 1.3 months and 1.6 months in 2 of the patients treated with gefitinib. Two patients with the ALK fusion gene showed 2.1 and 14.0 months of PFS from the initiation of treatment with crizotinib, and a patient with the MET exon 14 skipping mutation showed 9.7 months of PFS from the initiation of treatment with tepotinib.ConclusionThe 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.

Advances and future directions in ROS1 fusion-positive lung cancer.

ROS1 gene fusions are an established oncogenic driver comprising 1%-2% of non-small cell lung cancer (NSCLC). Successful targeting of ROS1 fusion oncoprotein with oral small-molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment landscape of metastatic ROS1 fusion-positive (ROS1+) NSCLC and transformed outcomes for patients. The preferred Food and Drug Administration-approved first-line therapies include crizotinib, entrectinib, and repotrectinib, and currently, selection amongst these options requires consideration of the systemic and CNS efficacy, tolerability, and access to therapy. Of note, resistance to ROS1 TKIs invariably develops, limiting the clinical benefit of these agents and leading to disease relapse. Progress in understanding the molecular mechanisms of resistance has enabled the development of numerous next-generation ROS1 TKIs, which achieve broader coverage of ROS1 resistance mutations and superior CNS penetration than first-generation TKIs, as well as other therapeutic strategies to address TKI resistance. The approach to subsequent therapy depends on the pace and pattern of progressive disease on the initial ROS1 TKI and, if known, the mechanisms of TKI resistance. Herein, we describe a practical approach for the selection of initial and subsequent therapies for metastatic ROS1+ NSCLC based on these clinical considerations. Additionally, we explore the evolving evidence for the optimal treatment of earlier-stage, non-metastatic ROS1+ NSCLC, while, in parallel, highlighting future research directions with the goal of continuing to build on the tremendous progress in the management of ROS1+ NSCLC and ultimately improving the longevity and well-being of people living with this disease.

AB055. Infantile high-grade glioma (IHG)-a case series of Hong Kong experience.

Infantile high-grade glioma (IHG) is diagnosed in patients less than 12 months of age. Studies have shown that it displays a more stable genome and is usually single mutation-driven. The most identifiable mutations are receptor tyrosine kinase (RTK) fusion, such as neurotrophic tyrosine receptor kinase (NTRK) family, reactive oxygen species (ROS1), anaplastic lymphoma kinase (ALK), and mesenchymal-epithelial transition (MET) factor. The current principal treatment remains to be surgery, but it is challenging for a complete resection due to hemispheric involvement. Use of chemotherapeutic drugs for IHG is still under debate, with targeted therapy showing efficacy in promoting tumor shrinkage. Despite being a challenging central nervous system (CNS) tumor, the overall survival of IHG is superior to other high-grade gliomas. This is a retrospective review of local IHG patients and their outcome. Up till the end of 2022, we identified eight IHG patients in our local data. Mean age of diagnosis was 3 months. There were four males and four females. Seven patients had histological diagnosis of glioblastoma and one patient had a diagnosis of anaplastic astrocytoma. One patient had her tumor located in the infratentorial region. Four patients had multilobar involvement. NTRK fusion was found in four patients (ETV6-NTRK3 fusion and TPR-NTRK1 fusion). ALK fusion was found in one patient (HMBOX1-ALK). ROS1 fusion was found in one patient (ZCCHZ8-ROS1). All patients underwent chemotherapy, with four patients switched to NTRK inhibitors and one patient to ROS1 inhibitors afterward. Surgery was performed at various time points for these patients. Two patients passed away, at 22 and 35 months of age at submission of this abstract. 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.

Performances of the Idylla GeneFusion Assay: contribution to a rapid diagnosis of targetable gene fusions in tumour samples

AimsWe aimed to evaluate the performances of the Idylla GeneFusion Assay (IGFA) designed to detect, in a single, rapid and fully automated assay, ALK, ROS1, RET, NTRK1, NTRK2 and NTRK3...

ROS1 fusions in resected stage I-III adenocarcinoma: Results from the European Thoracic Oncology Platform Lungscape project

BackgroundROS1 fusion is a relatively low prevalence (0.6–2.0%) but targetable driver in lung adenocarcinoma (LUAD). Robust and low-cost tests, such as immunohistochemistry (IHC), are desirable to screen for patients potentially harboring this fusion. The aim was to investigate the prevalence of ROS1 fusions in a clinically annotated European stage I-III LUAD cohort using IHC screening with the in vitro diagnostics (IVD)-marked clone SP384, followed by confirmatory molecular analysis in pre-defined subsets. MethodsResected LUADs constructed in tissue microarrays, were immunostained for ROS1 expression using SP384 clone in a ready-to-use kit and Ventana immunostainers. After external quality control, analysis was performed by trained pathologists. Staining intensity of at least 2+ (any percentage of tumor cells) was considered IHC positive (ROS1 IHC + ). Subsequently, ROS1 IHC + cases were 1:1:1 matched with IHC0 and IHC1 + cases and subjected to orthogonal ROS1 FISH and RNA-based testing. ResultsThe prevalence of positive ROS1 expression (ROS1 IHC + ), defined as IHC 2+/3+, was 4 % (35 of 866 LUADs). Twenty-eight ROS1 IHC + cases were analyzed by FISH/RNA-based testing, with only two harboring a confirmed ROS1 gene fusion, corresponding to a lower limit for the prevalence of ROS1 gene fusion of 0.23 %. They represent a 7 % probability of identifying a fusion among ROS1 IHC + cases. Both confirmed cases were among the only four with sufficient material and H-score ≥ 200, leading to a 50 % probability of identifying a ROS1 gene fusion in cases with an H-score considered strongly positive. All matched ROS1 IHC- (IHC0 and IHC1 + ) cases were also found negative by FISH/RNA-based testing, leading to a 100 % probability of lack of ROS1 fusion for ROS1 IHC- cases. ConclusionsThe prevalence of ROS1 fusion in an LUAD stage I-III European cohort was relatively low. ROS1 IHC using SP384 clone is useful for exclusion of ROS1 gene fusion negative cases.

Discovery of a first-in-class protein degrader for the c-ros oncogene 1 (ROS1)

The c-ros oncogene 1 (ROS1), an oncogenic driver, is known to induce non-small cell lung cancer (NSCLC) when overactivated, particularly through the formation of fusion proteins. Traditional targeted therapies focus on inhibiting ROS1 activity with ROS 1 inhibitors to manage cancer progression. However, a new strategy involving the design of protein degraders offers a more potent approach by completely degrading ROS1 fusion oncoproteins, thereby effectively blocking their kinase activity and enhancing anti-tumour potential. Utilizing PROteolysis-TArgeting Chimera (PROTAC) technology and informed by molecular docking and rational design, we report the first ROS1-specific PROTAC, SIAIS039. This degrader effectively targets multiple ROS1 fusion oncoproteins (CD74-ROS1, SDC4-ROS1 and SLC34A2-ROS1) in engineered Ba/F3 cells and HCC78 cells, demonstrating anti-tumour effects against ROS1 fusion-driven cancer cells. It suppresses cell proliferation, induces cell cycle arrest, and apoptosis, and inhibits clonogenicity. The anti-tumour efficacy of SIAIS039 surpasses two approved drugs, crizotinib and entrectinib, and matches that of the top inhibitors, including lorlatinib and taletrectinib. Mechanistic studies confirm that the degradation induced by 039 requires the participation of ROS1 ligands and E3 ubiquitin ligases, and involves the proteasome and ubiquitination. In addition, 039 exhibited excellent oral bioavailability in a mouse xenograft model, highlighting its potential for clinical application. In conclusion, our study presents a promising and novel therapeutic strategy for ROS1 fusion-positive NSCLC by targeting ROS1 fusion oncoproteins for degradation, laying the foundation for the development of further PROTAC and offering hope for patients with ROS1 fusion-positive NSCLC.

HGG-30. TARGETED THERAPY OF PEDIATRIC HIGH GRADE GLIOMAS

Abstract BACKGROUND The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Recent advances in understanding tumor biology facilitate utilization of targeted therapies (TT) in pediatric neuro-oncology. METHODS We analyzed the efficacy of targeted therapy in patients with progressive pHGG treated with TT according to molecularly-identified actionable events. Molecular characterization of the tumor included DNA panel and transcriptomic RNA sequencing. RESULTS Eighteen patients were included (median age 3.7 years, range 0.1-17.7) with anaplastic pleomorphic xanthoastrocytoma (n=10), infant-type hemispheric glioma (n=4), and diffuse high-grade glioma (n=4). Metastatic disease was present in 3/18 patients. Molecular genetic alterations included BRAF V600E mutations (n=8), NTRK1/2/3 fusions (n=4), ROS1 fusions (n=4), MET fusion (n=1), KIT P627L mutation (n=1). Eight patients received an NTRK/ALK/ROS1 inhibitor (entrectinib), seven patients received combination therapy with BRAF and MEK inhibitors (dabrafenib and trametinib), and one patient anti-BRAF monotherapy (dabrafenib). Two patients were treated with a multi-tyrosine kinase inhibitor (cabozantinib). The median duration of targeted therapy was 10.6 months (1-42). Most patients tolerated treatment well with no grade 4-5 toxicities. The overall response rate was 66% (12/18), including 4 complete (22%) and 8 partial responses (44%). At 12 months, PFS was 86% with dabrafenib/trametinib and 42% with entrectinib; at 18 months PFS was 44 % with dabrafenib plus trametinib and 42% with entrectinib. Three out of four patients with ROS1 rearranged glioma experienced disease progression on entrectinib after an initial good response in all cases; two of them subsequently received lorlatinib with clinical benefit. All four patients with NTRK1/2/3 rearranged gliomas remain on entrectinib therapy without signs of progression. Cabozantinib therapy resulted in prolonged complete and partial responses in both cases. CONCLUSIONS TT for patients with progressive pHGG is feasible and provides unexpectedly good clinical efficacy.

HGG-35. SIGNIFICANT RESPONSE TO LAROTRECTINIB AS FIRST LINE THERAPY IN INFANT WITH INFANT-TYPE HEMISPHERIC GLIOMA

Abstract BACKGROUND Infant-type hemispheric gliomas represent a recent WHO classification of high grade pediatric brain tumors that are often characterized by NTRK, ROS1, MET or ALK fusions. Novel agents may target their driver mutations but are not yet considered front line therapy. METHODS Patient data was reviewed retrospectively through chart review. RESULTS A 7 day old male infant who presented with vomiting, shaking and a full fontanelle was found to have a 8.7 x 7.2 x 9.3 cm solid and cystic mass with internal hemorrhage in the right parietal and occipital lobes associated with significant mass effect and midline shift. He underwent VP shunt placement and tumor biopsy, but later developed seizures and declining mental status. Cyst decompression was used as stabilizing measure. Due to his very small size and tenuous clinical status full tumor resection was not feasible at that time. Pathology revealed an infant-type hemispheric glioma with ETV6-NTRK3 fusion. Although cytogenetic testing for NTRK alterations was negative, the fusion was confirmed by NGS. Given his age and the risks for electrolyte imbalances and cytopenias in a patient with recent hemorrhage, we elected to treat with Larotrectinib instead of traditional cytotoxic chemotherapy. He had notable disease response within 8 weeks and remains on drug 18 months later with continued response. His tumor now measures 2 x 1.5 x 1.6 cm. He has had one grade 3 toxicity with neutropenia, which was likely impacted by viral bone marrow suppression. He is currently meeting most developmental milestones but does have orthotics and sees speech therapy. CONCLUSIONS Targeted agents may represent a viable front line therapy to decrease tumor mass and temporize very young patients until they can undergo definitive resection and therapy. Future clinical trials will need to compare efficacy to current standards of care.

Serial Cell-Free DNA Sequencing in ROS1 Fusion-Positive Lung Cancers During Treatment With Entrectinib.

Patients with metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC) are effectively treated with entrectinib, a multikinase inhibitor. Whether serial targeted gene panel sequencing of cell-free DNA (cfDNA) can identify response and progression along with mechanisms of acquired resistance to entrectinib is underexplored. In patients with ROS1 fusion-positive NSCLC, coclinical trial plasma samples were collected before treatment, after two cycles, and after progression on entrectinib (global phase II clinical trial, ClinicalTrials.gov identifier: NCT02568267). Samples underwent cfDNA analysis using MSK-ACCESS. Variant allele frequencies of detectable alterations were correlated with objective response per RECIST v1.1 criteria. Twelve patients were included, with best response as partial response (n = 9, 75%), stable disease (n = 2, 17%), and progressive disease (PD; n = 1, 8%). A ROS1 fusion was variably detected in cfDNA; however, patients without a ROS1 fusion in cfDNA had no other somatic alterations detected, indicative of possible low cfDNA shedding. Clearance of the enrolling ROS1 fusion or concurrent non-ROS1 alterations (TP53, CDH1, NF1, or ARID1A mutations) was observed in response to entrectinib therapy. Radiologic PD was accompanied by redemonstration of a ROS1 fusion or non-ROS1 alterations. On-target resistance was rare; only one patient acquired ROS1 G2032R at the time of progression. Several patients acquired new off-target likely oncogenic alterations, including a truncating alteration in NF1. Serial cfDNA monitoring may complement radiographic assessments as determinants of response and resistance to entrectinib in ROS1 fusion-positive lung cancers in addition to detecting putative resistance mechanisms on progression.

Novel genome-wide significant germline genetic variants associated with venous thrombo-embolism (VTE) and arterial embolism (ATE) risk in patients with ALK and ROS1 fusion non-small cell lung cancer (NSCLC).

12092 Background: In a recent meta-analysis, non small cell lung cancers (NSCLC) with ALK or ROS1 fusions had higher rates of VTE compared to KRAS or EGFR mutant NSCLC, and were associated with increased ATE risk, particularly around diagnosis. The underlying mechanisms of how these somatic fusions affect thrombosis remain unclear. We examined clinico-demographic and germline genetic factors associated with VTE and ATE in NSCLC patients with ALK/ROS1 fusions in this first comprehensive genome wide association analysis (GWAS). Methods: In this prospective cohort, germline DNA from whole blood was obtained from 150 patients with ALK fusions and 32 with ROS1 fusions at Princess Margaret Cancer Centre (recruited 2014- 2023). Clinico-demographic, treatment and outcome data were collected from electronic medical charts. Overall survival (OS) by VTE or ATE status was assessed via Cox regression, treating ATE and VTE as time-varying covariates. Genotyping utilized the Infinium Global Screening Array (v3.0 Illumina); quality-control removed 3 patients from final analysis. Using linear regression, outcomes were weighted; no VTE/ATE events (0), one VTE/ATE event (1), or multiple ATE/VTEs (>2). Global significance was set at p < 5 x10-8 and adjusted for age, sex, body mass index (BMI), and ethnic/population stratification (top 3 principal components). Results: There were 97 females (54%) and 82 males (46%), mean age was 57.4 years, 70% had stage 4 disease, 96% adenocarcinoma; 35% experienced VTE/ATE at any time; 13% had 2+ VTE/ATE events. For those with VTE, 32 scored 1, 22 scored 2 and 6 scored 3 on Khorana score. Higher BMI was a significant risk factor for VTE/ATE (adjusted odds ratio 1.59 per 5-unit increase, p=0.01). Shorter OS was observed in patients with VTE (Hazard ratio (HR)=3.15, p<0.001) and ATE (HR=2.51, p=0.036), compared to those without. Two novel GWAS gene peaks on the Manhattan plot (previously not reported to be associated with VTE/ATE) had globally significant associations with risk of VTE/ATE: at Chromosome 6q15 (intergenic region between RNGTT and LOC101928936; 5/10 top variants with top risk-allele p=3.594E-09) and at 15p22 ( TLN2 gene; 2/10 top variants p=1.095E-08). TLN2 is a cytoskeletal protein involved in the assembly of actin filaments and linkages with extracellular matrices. Additional identified variants potentially associated with VTE/ATE in ALK/ROS1 fusion patients were found in: CTBP2, NALCN, WDR7, PAX7, ZNF385D, SORBS2, and CSMD1. Conclusions: Two novel globally significant variants, associated with VTE/ATE, are unique to patients with ALK/ROS1 fusion NSCLC. If validated, these biomarkers may help identify ALK/ROS1 patients who are at highest risk of VTE/ATE who may benefit from prophylactic anticoagulation. Further investigation and clinical evaluation are warranted.

Efficacy and safety of entrectinib in children with extracranial solid or primary central nervous system (CNS) tumors harboring NTRK or ROS1 fusions.

10000 Background: Entrectinib previously yielded durable responses in children with NTRKor ROS1fusion-positive extracranial solid or primary CNS tumors in STARTRK-NG (NCT02650401). We present updated data from STARTRK-NG, TAPISTRY (NCT04589845) and STARTRK-2 (NCT02568267): pediatric patients from these trials were combined to enable an integrated efficacy and safety analysis on a larger cohort than previously. Methods: Eligible patients were TRK or ROS1 inhibitor naïve and aged < 18 years, had locally advanced or metastatic extracranial solid or primary CNS tumors harboring an NTRK or ROS1 fusion, and had measurable or evaluable-only disease. Once enrolled, patients received ≥1 daily dose of oral entrectinib until disease progression, unacceptable toxicity, or consent withdrawal. Tumor responses were confirmed by blinded independent central review (BICR) per RECIST v1.1 or RANO criteria. Patients were included if they had been followed for ≥6 months. The primary endpoint was confirmed objective response rate (ORR) per BICR. Key secondary endpoints included ORR in patients with baseline measurable disease per BICR, duration of confirmed response (DoR), time to confirmed response (TTR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results: At clinical cutoff (16 July 2023), out of 91 safety-evaluable patients (regardless of fusion), 44 patients in the NTRKcohort and 20 patients in the ROS1cohort were efficacy evaluable. Median duration of survival follow-up was 24.2 months ( NTRK: range 1–66) and 27.6 months ( ROS1: range 1–73). The ORR was 68.2% (95% CI 52.4–81.4) in the NTRK cohort and 65.0% (95% CI 40.8–84.6) in the ROS1 cohort. In patients with baseline measurable disease, the ORR was 77.8% ( NTRK: n = 28/36; 95% CI 60.9–89.9) and 62.5% ( ROS1: n = 10/16; 95% CI 35.4–84.8). Efficacy outcomes are shown in the Table. The most common adverse events were pyrexia (50.5%), vomiting (40.7%) and anemia (40.7%). Conclusions: Entrectinib continued to yield rapid and durable responses in pediatric patients with extracranial solid or primary CNS tumors harboring an NTRK or ROS1 fusion. The safety profile of entrectinib was in line with previous reports. Clinical trial information: NCT02650401 / NCT04589845 / NCT02568267 . [Table: see text]

Efficacy and safety of PD-1 inhibitors plus metronomic oral vinorelbine in elderly pre-treated patients with metastatic non-small-cell lung cancer.

e20556 Background: The subsequent therapy of elderly non-small cell lung cancer (NSCLC) without driver oncogene has always been a challenge due to the poor performance status and multiple comorbidities, especially in those who acquired resistance to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade. Metronomic chemotherapy (MCT) is the frequent administration of chemotherapy drugs at lower doses each time which shows a better safety profile, antitumor angiogenesis, and immune modulatory effects compared with traditional chemotherapy. Here we designed an observational study to evaluate the efficacy and safety of PD-1 inhibitors plus metronomic oral vinorelbine(mOV) in elderly pre-treated metastatic NSCLC. Methods: Patients aged 65 years and above who had been histologically or cytologically confirmed unresectable stage III and IV NSCLC were recruited for this study. All the pts had no EGFR mutation, ALK fusions, or ROS1 fusions and received at least one systematic treatment. Pts received PD-1 inhibitors combined with mOV (30mg, TIW1, day 1-3-5 per week) for 6 cycles, followed by PD-1 inhibitors maintenance until disease progression or intolerable toxicities. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: From May 2020 to June 2023, 23 pts were enrolled in the study. The median age was 70 with 18(78%) males. Median follow-up time was 22.8 months (range 3.9months-41.9months). The median PFS was 5.13 months (95%Cl: 3.1 months-7.1 months) and the median OS was 28.1 months (95%Cl: (15.2 months-NA). The ORR and DCR were 13% (95%C1: 1.44%-27.6%) and 69.6% (95%Cl: 49.2%-89.9%), respectively. The PFS (p = 0.459, HR = 0.671 95%CI 0.233-1.932) and OS (p = 0.483, HR = 1.607 95%CI 0.426-6.056) were similar between those pts who previously received immunotherapy (N = 16, 69.5%) and not. PD-L1 TPS didn’t affect the patient’s PFS (<1% vs≥1%, p = 0.078, HR = 2.648 95%CI 0.895-7.835 ) and OS(<1% vs≥1%, p = 0.306, HR = 2.202 95%CI 0.485-9.989). Adverse events (AEs) of any grade were observed in 20(86.9%) pts of which grade III-IV AEs occurred in 4 (17.4%) pts. These grade III-IV events consisted of interstitial pneumonia, pulmonary infection, leukopenia, and neutropenia. Immune-related adverse events (irAEs) occurred in 4 (17.4%) pts, of which grade III irAEs occurred in 2 (8.7%) patients with interstitial pneumonia. No grade 4 irAEs and grade 5 adverse events even occurred. Conclusions: The regimen of PD-1 inhibitors plus mOV for the subsequent therapy showed good overall survival benefits and safety in elderly patients with metastatic NSCLC without driver oncogene which suggests it is worth further exploration.

Clinical impact of the rapid genomic screening platform for non-small cell lung cancer in Asia-Pacific (LC-SCRUM-AP).

8637 Background: In 2013, a lung cancer genomic screening project (LC-SCRUM-Asia) started in Japan and expanded to other Asia-Pacific countries in October 2022 (LC-SCRUM-AP). The objective of this study is to clarify the characteristics of genomic profile in Asia-Pacific countries outside of Japan and to elucidate the clinical significance of rapid genomic screening. Methods: To shorten the turnaround time (TAT), a central laboratory was set in each participating country. Samples are analyzed by a multi-gene PCR assay and a rapid next-generation sequencing assay. Clinical, pathological and genomic data are stocked as a clinical-genomic database in each participating country, which is combined with Japanese database and the integrated clinical-genomic database of the Asia-Pacific region was established. Results: A multi-gene PCR assay data was available in 7879 samples from 4 Asia-Pacific countries (Taiwan/Thailand/Malaysia/Japan = 126/65/30/7658 pts). The rates of driver alterations in never-smokers with non-squamous histology were similar in the 4 Asia-Pacific countries: 83%, 80%, 89% and 75% in Taiwan, Thailand, Malaysia, and Japan, respectively. The pattern of genomic profile was also similar among these 4 countries. The median TAT was 4 days and 5 days in Japanese cohort and Taiwan/Thailand/Malaysia cohort, respectively. In Taiwan/Thailand/Malaysia cohort (n = 221), the genomic analysis successful rate was 99.5%. The rates of genomic alterations detected: EGFR (35%) of which ex20ins (6%), KRAS (10%) of which G12C (4%), ALK fusions (6%), ROS1 fusions (4%), RETfusions (0.5%), HER2ex20ins (4%), MET ex14skip (3%), BRAF V600E (1.5%), and NTRK3 fusions (0.5%). Oncogenic driver alterations were detected in 149 pts, of which 102 (68%) pts received targeted therapies approved in each country. 14 patients were enrolled into clinical trials of the investigational drugs, of which 5 were for targeting rare driver alterations. Conclusions: LC-SCRUM-AP is the first international genomic screening platform established in the Asia-Pacific region, which enables the efficient detection of rare driver alterations with a short TAT, contributing to the high implementation rate of targeted therapies. The similar pattern of genomic profile in the 4 Asia-Pacific countries indicates the utility of this screening platform as the basis for the clinical trials for NSCLC with rare driver alterations. We plan to further expand the number of institutions and participating countries.

Lung cancer in females from nonsmoker families in India: Observations and inferences in 5 years.

e20610 Background: Incidence in lung cancer in last two decades has been changing drastically in terms of gender, age, smoking behaviour of patients, stage at presentation, histopathology, genetic abnormalities, operability at presentation and survival. More perplexing is the increase in its occurrence in females from non smoker families, mitigating the sole importance of the traditional risk factors of tobacco and smoking in the recent times. This highlights the need to investigate other risk factors like radon exposure from indoor pollution where females stay most of the time, exposure to arsenic and other chemicals in daily life, particle pollution, physical inactivity and inflammatory diseases of airways. Methods: It was an observational study of patients who were diagnosed and treated at a high volume cancer centre in Karnataka state of India. 89 never smoker female patients under 50 years of age from non smoker families with no obvious exposure to second hand or third hand smoke were enrolled from October, 2018 to June, 2023. It was a longitudinal prospective cohort study where the demographic data, symptoms with duration, histopathology including genetic abnormalities, treatment details and survival were noted. Results: 89 never smoker females from non smoker families with ages ranging from 36 to 50 years had a median age of 46 years. About 70% of the ladies were from houses closely associated with farm in past or present. 55% of them had overweight and obese body habitus. Most common presenting symptom was dry cough with median duration of about 3 months in about 89%. Other symptoms were pleuritic chest pain(39%), breathlessness (19%), generalized body ache(9%) and jaundice(2%). Stage of disease was IV(69%), IIIC(12.3%), IIIB(11.2%), IIIA(5.6%) and II in just one patient. Most common sites of metastasis were contralateral lung(45%), bone(20%), liver(20%), adrenal glands(10%) and brain (15%). Most common histopathology was adenocarcinoma(87.6%), adenosquamous carcinoma(7.8%), squamous cell carcinoma(3.3%), large cell neuroendocrine carcinoma in just one patient. EGFR was mutated in 56(62.9%) with deletion 19( 33%) and L858R(21%) being the most common abnormalities. ALK rearrangements and ROS1 fusion were seen in about 9(3.3%) and 3(3.3%) patients respectively. Surgery was done in only 3 patients and chemoradiation after neoadjuvant chemotherapy was given in 8(8.9%) patients. Median overall survival was about 42 months in stage IV patients. Conclusions: Changing demographic profile of lung cancer warrants more research into the other causes of lung cancer. More stage IV disease highlights the emphasis on prevention and screening for the disease.