ALK Translocation Research Articles

Clinical Outcomes of Maintenance Durvalumab After Definitive Concurrent Chemoradiotherapy in Unresectable Locally Advanced Stage III NSCLC According to EGFR and ALK Status: Korean Cancer Study Group LU-22-18

IntroductionThe role of maintenance durvalumab after definitive concurrent chemoradiotherapy (CCRT) in unresectable locally advanced NSCLC with EGFR mutation or ALK translocation remains unclear. We compared the effectiveness of durvalumab maintenance therapy in groups with EGFR/ALK wild-type versus those with EGFR or ALK mutations. MethodsIn this retrospective multicenter observational study, patients with locally advanced NSCLC without progression after CCRT followed by maintenance durvalumab and available molecular test results (EGFR and ALK) were eligible. The primary objective was to compare progression-free survival (PFS) between EGFR/ALK wild-type and EGFR or ALK mutant NSCLC. Secondary objectives include overall survival according to EGFR or ALK mutation and programmed death-ligand 1 (PD-L1) expression. ResultsAmong 339 patients, 279 had wild-type EGFR/ALK, 41 had EGFR mutations and 19 had ALK translocations. The median age was 68 years with 276 male individuals (81.4%) and 63 female individuals (18.6%), 165 (49.3%) had adenocarcinoma, 149 (44.5%) had squamous cell carcinoma, and 21 (6.3%) had other histologic types, 120 (35.4%) had stage IIIA, 168 (49.6%) stage IIIB, and 51 (15.0%) had stage IIIC. Most of the patients (n = 288, 85%) achieved partial response to CCRT, two (0.6%) had a complete response, and 49 patients (14.4%) had stable disease. Excluding four patients with unknown PD-L1 tumor proportion score (TPS), 16 (4.8%) had a PD-L1 TPS of 0, 168 (50.1%) had 1 to 49, and 151 (45.1%) had 50 or higher. The median PFS was 21.4 months (95% confidence interval [CI]: 17.3–25.3) for the EGFR/ALK wild-type group and 21.0 months (95% CI: 15.7–not available [NA]) for the EGFR or ALK mutant group with no significant difference (p = 0.74). Significant differences occurred in PFS on the basis of PD-L1 expression with values of 13.6 (95% CI: 10.5–NA), 18.7 (95% CI: 15.1–26.9), and 24.7 (95% CI: 20.7–NA) months for TPS of 0, 1–49, and 50 or higher, respectively (p = 0.02). ConclusionsDurvalumab maintenance therapy after definitive CCRT in unresectable locally advanced NSCLC patients with EGFR or ALK mutation demonstrates comparable clinical outcomes to those with wild-type EGFR/ALK when PD-L1 expression is present.

Family history of cancer and lung cancer: Utility of big data and artificial intelligence for exploring the role of genetic risk

ObjectivesLung Cancer (LC) is a multifactorial disease for which the role of genetic susceptibility has become increasingly relevant. Our aim was to use artificial intelligence (AI) to analyze differences between patients with LC based on family history of cancer (FHC). Materials and methodsFrom August 2016 to June 2020 clinical information was obtained from Thoracic Tumors Registry (TTR), a nationwide database sponsored by the Spanish Lung Cancer Group. In addition to descriptive statistical analysis, an AI-assisted analysis was performed. The German Technical Information Library supported the merging of data from the electronic medical records and database of the TTR. The results of the AI-assisted analysis were reported using Knowledge Graph, Unified Schema and descriptive and predictive analyses. ResultsAnalyses were performed in two phases: first, conventional statistical analysis including 11,684 patients of those 5,806 had FHC. Median overall survival (OS) for the global population was 23 months (CI 95 %: 21.39–24.61) in patients with FHC versus 21 months (CI 95 %: 19.53–22.48) in patients without FHC (NFHC), p < 0.001. The second AI-assisted analysis included 5,788 patients of those 939 had FHC. 58.48 % of women with FHC had LC. 9.53 % of patients had an EGFR or HER2 mutation or ALK translocation and at least one relative with cancer. A family history of LC was associated with an increased risk of smoking-related LC. Non-smokers with a family history of LC were more likely to have an EGFR mutation in NSCLC. In Bayesian network analysis, 55 % of patients with a family history of LC and never-smokers had an EGFR mutation. ConclusionIn our population, the incidence of LC in patients with a FHC is higher in women and younger patients. FHC is a risk factor and predictor of LC development, especially in people ≤ 50 years. These results were confirmed by conventional statistics and AI-assisted analysis.

Concomitant ALK translocation and EGFR C797S mutation as resistance mechanisms to osimertinib in an EGFR-mutant NSCLC patient

Concomitant ALK translocation and EGFR C797S mutation as resistance mechanisms to osimertinib in an EGFR-mutant NSCLC patient

Gene Expression Profile of Benign, Intermediate, and Malignant Spitz and Spitzoid Melanocytic Lesions.

Spitz and Spitzoid lesions represent one of the most challenging melanocytic neoplasms in dermatopathology. Nosologic classification has been more recently improved by the discovery of novel molecular drivers, particularly translocations. In the current study, we aimed to use an unbiased approach to explore the gene expression profile of a group of melanocytic Spitz and Spitzoid melanocytic lesions ranging from benign lesions to melanoma, including intermediate lesions such as SPARK nevi and atypical Spitz tumors/melanocytomas. Using unsupervised analysis of gene expression data, we found some distinct hierarchical clusters of lesions, including groups characterized by ALK and NTRK translocations. Few non-ALK translocated tumors demonstrated increased ALK expression, confirmed by immunohistochemistry. Spitz tumors with overlapping features of dysplastic nevi, so-called SPARK nevi, appear to have a common gene expression profile by hierarchical clustering. Finally, weighted gene correlation network analysis identified gene modules variably regulated in subtypes of these cases. Thus, gene expression profiling of Spitz and Spitzoid lesions represents a viable instrument for the characterization of these lesions.

Peripheral T-cell lymphomas expressing CD30 and CD15 expand the spectrum of anaplastic large cell lymphoma, ALK-negative.

Peripheral T-cell lymphomas (PTCL) are morphologically and biologically heterogeneous and a subset expresses CD30, including anaplastic large cell lymphomas (ALCL) and a minority of PTCL, not otherwise specified (PTCL, NOS). ALCL with ALK translocations (ALCL, ALK+) are readily identified by routine diagnostic methods, but differentiating ALCL without ALK translocation (ALCL, ALK-) and PTCL, NOS expressing CD30 (PTCL CD30+) can be challenging. Furthermore, rare PTCL co-express CD30 and CD15 (PTCL CD30+CD15+); some resemble ALCL, ALK- while others resemble classic Hodgkin lymphoma. To explore the relationship between PTCL CD30+CD15+ and ALCL, ALK-, we analysed 19 cases of PTCL with CD30 expression, previously diagnosed as ALCL, ALK- (nine cases) and PTCL CD30+CD15+ (10 cases) for DUSP22/IRF4 rearrangements, coding RNA expression and selected transcriptome analysis using the NanoString nCounter gene expression analysis platform. Unsupervised clustering showed no clear segregation between ALCL, ALK- and PTCL CD30+CD15+. Three cases previously classified as PTCL CD30+CD15+ showed DUSP22/IRF4 rearrangements, favouring a diagnosis of ALCL, ALK-. Our results suggest that cases previously designated PTCL CD30+CD15+, likely fall within the spectrum of ALCL, ALK-; additionally, a subset of ALCL, ALK- with DUSP22/IRF4 rearrangement expresses CD15, consistent with previous reports and expands the immunophenotypic spectrum of this lymphoma subgroup.

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution.

Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying ALK and ROS1 translocations, biallelic BRCA1/2 inactivation and/or homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.

Successful Conversion Surgery after Ceritinib Monotherapy in a Patient with Advanced Inflammatory Myofibroblastic Tumor Harboring SQSTM1-ALK fusion

Abstract Inflammatory myofibroblastic tumor (IMT) is an intermediate malignant neoplasm, and approximately 50% of patients are anaplastic lymphoma kinase positive (ALK+). Given this unique trait, ALK tyrosine kinase inhibitors (TKIs), initially developed for ALK+ nonsmall cell lung carcinoma, were expected to be effective. Subsequently, crizotinib, a first-generation ALK-TKI, was approved by the U. S. Food and Drug Administration, and other generations of ALK-TKIs have since been tested for their efficacy. In this study, we report a case of unresectable IMT who showed a partial response to ceritinib, a second-generation ALK-TKI, allowing conversion surgery to be performed. Furthermore, the patient was found to have a rare ALK translocation, sequestosome 1 (5)-ALK (20), detected by next-generation sequencing. In conclusion, this case presents real-world evidence to establish the role of ceritinib as a first-line treatment for ALK+ IMT, which can contribute to further studies on ALK+ IMT.

Analytical and Clinical Validation of a Highly Sensitive NGS-Based ctDNA Assay with Real-World Concordance in Non-Small Cell Lung Cancer.

There have been needs to improve the sensitivity of liquid biopsy. This report aims to report the analytical and clinical validation of a next-generation sequencing (NGS)-based circulating tumor DNA (ctDNA) assay. Analytical validation was conducted in vitro by evaluating the limit of detection (LOD), precision, and specificity for various genomic aberrations. The real-world performance in non-small cell lung cancer (NSCLC) was assessed by comparing the results of AlphaLiquid100 to the tissue-based results. The LODs with 30 ng input DNA were 0.11%, 0.11%, 0.06%, 0.21%, and 2.13 copies for detecting single nucleotide variants, insertions, deletions, fusions, and copy number alterations (CNA), respectively. Quantitatively, single nucleotide variants/insertions and deletions, fusions, and CNAs showed a good correlation (R2=0.91, 0.40, and 0.65; y=0.95, 1.06, and 1.19) to the manufacturer's values, and per-base specificities for all types of variants were near 100%. In real-world NSCLC (n=122), key actionable mutations in NSCLC were detected in 60.7% (74/122) with the ctDNA assay. Comparative analysis against the NGS-based tissue results for all key mutations showed positive percent agreement (PPA) of 85.3%. For individual genes, the PPA was as high as 95.7% for epidermal growth factor receptor (EGFR) mutations and 83.3% for ALK translocations. AlphaLiquid100 detected drug-sensitive EGFR mutation at a variant allele frequency as low as 0.02% and also identified an EGFR mutation in a case where tissue sample missed. Blood samples collected post-targeted therapies revealed additional acquired mutations. The AlphaLiquid100 ctDNA assay demonstrates robust analytical validity, offering clinically important information for NSCLC patients.

Abdominal inflammatory myofibroblastic tumour: Clinicopathological and molecular analysis of 20 cases, highlighting potential therapeutic targets.

Inflammatory myofibroblastic tumour (IMT) is a rare mesenchymal neoplasm of intermediate malignant potential, occurring at any age and at multiple sites. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of IMT, typically involving the abdomen. Most IMTs harbour kinase gene fusions, especially involving ALK and ROS1, but 20-30% of IMTs show no detectable translocations. The aim of this study is to further delineate clinicopathological and molecular characteristics of abdominal IMT and discover potential new therapeutic targets. In 20 IMTs, including four EIMS, RNA fusion analysis was performed, followed by multiplex DNA analysis if no ALK or ROS1 fusion was detected. Fourteen IMTs (70.0%) had an ALK translocation and the fusion partner was identified in 11, including a RRBP1::ALK fusion, not previously described in classical (non-EIMS) IMT. RANBP2::ALK fusion was demonstrated in all EIMS. One IMT had a ROS1 fusion. In all ALK/ROS1 translocation-negative IMTs mutations or fusions - as yet unreported in primary IMT - were found in genes related to the receptor tyrosine kinase (RTK)/PI3K/AKT pathway. Three of four patients with EIMS died of disease [mean survival 8 months (4-15 months)], whereas only one of 14 classical IMT patients succumbed to disease [mean follow-up time 52 months (2-204 months); P < 0.01]. This study shows the wide clinical spectrum of abdominal IMTs and affirms the poor prognosis of EIMS, raising discussion about its status as IMT subtype. Furthermore, the newly detected alterations of the RTK/PI3K/AKT pathway expand the molecular landscape of IMTs and provide potential therapeutic targets.

Comparison of Clinical and Genetic Characteristics Between Younger and Older Lung Cancer Patients

IntroductionThe aim of this study was to analyze the clinical and genetic characteristics of young lung cancer cases, and to compare them with those of older cases. MethodsWe used the Thoracic Tumors Registry (TTR) as a data source representative of lung cancer cases diagnosed in Spain, and included all cases registered until 9/01/2023 which had information on age at diagnosis or the data needed to calculate it. We performed a descriptive statistical analysis and fitted logistic regressions to analyze how different characteristics influenced being a younger lung cancer patient. ResultsA total of 26,336 subjects were included. Lung cancer cases <50 years old had a higher probability of being women (OR: 1.38; 95% CI: 1.21–1.57), being in stage III or IV (OR: 1.32; 95% CI: 1.08–1.62), not having comorbidities (OR: 5.21; 95% CI: 4.59–5.91), presenting with symptoms at diagnosis (OR: 1.53; 95% CI: 1.29–1.81), and having ALK translocation (OR: 7.61; 95% CI: 1.25–46.32) and HER2 mutation (OR: 5.71; 95% CI: 1.34–24.33), compared with subjects ≥50 years. Among subjects <35 years old (n=61), our study observed a higher proportion of women (59.0% vs. 26.6%; p<0.001), never smokers (45.8% vs. 10.3%; p<0.001), no comorbidities (21.3% vs. 74.0%; p<0.001); ALK translocation (33.3% vs. 4.4%; p<0.001) and ROS1 mutation (14.3% vs. 2.3%; p=0.01), compared with subjects ≥35 years. ConclusionsLung cancer displays differences by age at diagnosis which may have important implications for its clinical management.

P11.02.B DO GENOMIC ALTERATIONS INFLUENCE THE DEVELOPMENT OF BRAIN METASTASES IN ADVANCED AND METASTATIC NON-SMALL CELL LUNG CANCER?

Abstract BACKGROUND Lung cancer is the most common cause of cancer deaths worldwide. Development of brain metastases (BM) in patients with advanced (Stage III) and metastatic (Stage IV) non-small cell lung cancer (NSCLC) is linked with poor prognosis. Identifying mutations associated with BM development could influence screening and determine targeted treatment paradigms. We aimed to establish BM prevalence and incidence in patients with advanced and metastatic NSCLC, stratified by genomic alterations. MATERIAL AND METHODS A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines (PROSPERO ID CRD42022315915). Three databases were searched, and articles published between January 2000-May 2022 included (Search date 30th April 2022). Prevalence at diagnosis, and incidence of new BM per year were obtained, including patients with EGFR, ALK, KRAS, ROS1, RET, MET, and other genomic alterations. Pooled incidence rates were calculated using random effects models. RESULTS Of 960 articles identified, 65 were included in the study (24,784 patients). Pooled BM prevalence at diagnosis was 28.6% (45 studies, 95% Confidence Interval [CI] 26.1-31.0), and highest in patients with ALK (34.9%) and RET translocations (32.2%). With a median follow-up of 24 months, the per-year incidence of new BM was 12.5% in the wild-type group (14 studies, 95% CI 10.9-15.9). Incidence in the subgroups with different genomic alterations was 15.6% in the EGFR group (16 studies, 95% CI 11.4-21.2), 17.0% in the ALK group (6 studies, 95% CI 11.3-25.8), 9.8% in the KRAS group (4 studies, 95% CI 5.5-17.5), 12.5% in the ROS1 group (3 studies, 95% CI 5.7-27.6), and 11.8% in the RET group (2 studies, 95% CI 8.0-17.5). At the end of the follow-up period, a median of 55.0% of patients had BM (IQR 44.2-67.8). CONCLUSION This is the first study to show prevalence, and incidence of BM development in advanced and metastatic NSCLC, stratified by genomic alterations. Our data indicates a higher prevalence and incidence of BM in patients with targetable genomic alterations. This supports brain imaging at staging and follow-up, underlining the need for NSCLC therapies with brain penetrance and efficacy.

The use of brigatinib in the treatment of ALK-positive NSCLC in the progression of crizotinib

non-small cell lung cancer, ALK translocation, brigatinib, resistance

Analysis and therapeutic targeting of the IL-1R pathway in anaplastic large cell lymphoma

AbstractAnaplastic large cell lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings to both anaplastic lymphoma kinase positive (ALK+) and primary cutaneous (pC) ALK− ALCLs and identified an unexpected role of the interleukin-1R (IL-1R) inflammatory pathway in supporting the viability of pC ALK− ALCL. Importantly, this pathway is activated by IL-1α in an autocrine manner, which is essential for the induction and maintenance of protumorigenic inflammatory responses in pC-ALCL cell lines and primary cases. Hyperactivation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC-ALCL lines we analyze and is regulated by the nonproteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation and enhances the sensitivity of JAK inhibitors in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor, pacritinib, exhibited strong activities against pC ALK− ALCL, where the IL-1R pathway is hyperactivated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC-ALCL and provided opportunities for developing novel therapeutic strategies.

Immune phenotype-driven treatment outcome of IO-only versus chemo-IO in PD-L1-high, first-line, advanced non-small cell lung cancer (NSCLC).

e21179 Background: PD-L1 tumor proportion score (TPS) is the only biomarker for clinical decision-making regarding immunotherapy (IO) in advanced NSCLC. Currently, there is uncertainty when selecting treatment options between IO monotherapy (IO-only) and in combination with chemotherapy (Chemo-IO) when solely based on PD-L1, in patients with PD-L1 TPS ≥ 50%. Here, we explored a novel biomarker, immune phenotype as assessed by artificial intelligence (AI)-powered spatial tumor infiltrating lymphocytes (TIL) analysis to provide additional information in determining first-line treatment for advanced NSCLC, using a real-world dataset. Methods: A total of 349 whole-slide images (WSIs) of H&amp;E-stained slides for advanced/metastatic NSCLC patients without actionable EGFR mutation and ALK translocation treated with IO-only or Chemo-IO as their first-line were retrospectively collected from Samsung Medical Center. An AI-powered spatial TIL analyzer, Lunit SCOPE IO classified inflamed immune phenotype (IIP, the proportion of inflamed area ≥ 33.3% in tumor microenvironment) versus non-inflamed IP (non-IIP). PD-L1 TPS was assessed based on PD-L1 pharmDx 22C3 staining. Progression-free survival (PFS) was measured by the investigators per RECIST v1.1. Results: In the analysis set, all IO-only group (n = 84) had TPS ≥ 50%, but Chemo-IO group (n = 265) consisted of 21.1%, 29.8%, and 49.1% of TPS ≥ 50%, 1-49%, and &lt; 1%, respectively. Proportions of squamous cell carcinoma were not significantly different between IO-only and Chemo-IO (32.1% vs 27.5%, p = 0.5008). Proportions of IIP were significantly correlated with the TPS group, as they were 33.6%, 19.0%, and 13.1% in TPS ≥ 50%, 1-49%, and &lt; 1%, respectively (p = 0.0002). In the merged dataset (n = 349), PFS was significantly increased in IIP (22.6%) compared to non-IIP (median PFS [mPFS] 14.6 vs 6.0 m, 6-m PFS rate 72.1% vs 49.9%, hazard ratio [HR, 95% confidence interval] 0.57 [0.39-0.82], p = 0.0014). In TPS ≥ 50% group, IIP was significantly correlated with favorable PFS in IO-only group (IIP vs non-IIP; mPFS 14.6 vs 4.6 m, 6-m rate 65.5 vs 45.2%, HR 0.55 [0.31-0.98], p = 0.0375), however, it was not statistically different in Chemo-IO (n = 56, mPFS not reached [NR] vs 8.3 m, 6-m rate 88.5 vs 65.3%, HR 0.45 [0.15-1.33], p = 0.1185). Interestingly, in the subgroup of TPS ≥ 50% with IIP (n = 47), PFS was not significantly different based on treatment regimen (Chemo-IO vs IO-only, mPFS NR vs 14.6 m, 6-m rate 88.5 vs 65.5%, HR 0.52 [0.17-1.59], p = 0.2263), but Chemo-IO was significantly superior to IO-only in TPS ≥ 50% with non-IIP group (n = 93, mPFS 8.3 vs 4.6 m, 6-m rate 65.3 vs 45.2%, HR 0.53 [0.30-0.94], p = 0.0255). Conclusions: Immune Phenotype based on AI-powered spatial TIL analysis may provide complementary information for clinical decision-making between IO-only and Chemo-IO in advanced NSCLC patients with TPS ≥ 50%.

Sustained Improvement in the Management of Patients with Non-Small-Cell Lung Cancer (NSCLC) Harboring ALK Translocation: Where Are We Running?

ALK translocation amounts to around 3-7% of all NSCLCs. The clinical features of ALK+ NSCLC are an adenocarcinoma histology, younger age, limited smoking history, and brain metastases. The activity of chemotherapy and immunotherapy is modest in ALK+ disease. Several randomized trials have proven that ALK inhibitors (ALK-Is) have greater efficacy with respect to platinum-based chemotherapy and that second/third generation ALK-Is are better than crizotinib in terms of improvements in median progression-free survival and brain metastases management. Unfortunately, most patients develop acquired resistance to ALK-Is that is mediated by on- and off-target mechanisms. Translational and clinical research are continuing to develop new drugs and/or combinations in order to raise the bar and further improve the results attained up to now. This review summarizes first-line randomized clinical trials of several ALK-Is and the management of brain metastases with a focus on ALK-I resistance mechanisms. The last section addresses future developments and challenges.

Lung adenocarcinoma with neuroendocrine differentiation: Molecular markers testing and treatment outcomes

Among the histologic types of lung cancer, adenocarcinoma is the most common. Moreover, lung adenocarcinoma with neuroendocrine differentiation (LANED) is a rare histologic character. So far, the clinical significance remains unclear. We searched for the patients diagnosed with LANED from the electronic pathology database between January 2000 and June 2020 in a tertiary hospital. The tumor specimens were reviewed by a pathologist to confirm the diagnosis. EGFR mutation, ALK translocation, as well as programmed death ligand 1 (PD-L1) and rearranged during transfection (RET) expression were tested in the specimens of LANED. The clinical data were also collected and analyzed. A total of 10 patients diagnosed with LANED were included. Most were male (80%) and ever smokers (70%). The median age was 71.5 years old. At diagnosis, most had tumors harboring no EGFR mutation (70%), negative ALK translocation (88.9%), and without PD-L1 expression (90%). All specimens tested by immunohistochemical staining for RET expression (n=9) showed positive results. Among the 10 patients, five underwent operation (stage I, n=4; stage II, n=1). The patient with stage II disease had recurrence 11 months later. For patients with advanced stages (stage III, n=1; stage IV, n=4), the treatment modalities varied and the overall survival ranged from 11.0 to 46.7 months. LANED might be associated with a high proportion of RET expression, whereas EGFR mutation, ALK alteration, and PD-L1 expression were uncommon. Further large-scale prospective studies on molecular testing profile and clinical significance of LANED are warranted.

New update to the guidelines on testing predictive biomarkers in non-small-cell lung cancer: a National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

Non-small cell lung cancer (NSCLC) presents the greatest number of identified therapeutic targets, some of which have therapeutic utility. Currently, detecting EGFR, BRAF, KRAS and MET mutations, ALK, ROS1, NTRK and RET translocations, and PD-L1 expression in these patients is considered essential. The use of next-generation sequencing facilitates precise molecular diagnosis and allows the detection of other emerging mutations, such as the HER2 mutation and predictive biomarkers for immunotherapy responses. In this consensus, a group of experts in the diagnosis and treatment of NSCLC selected by the Spanish Society of Pathology and the Spanish Society of Medical Oncology have evaluated currently available information and propose a series of recommendations to optimize the detection and use of biomarkers in daily clinical practice.

Identification of ALK-positive patients with advanced NSCLC and real-world clinical experience with crizotinib in Spain (IDEALK study)

ObjectivesTo determine the incidence of ALK translocations in patients with advanced/metastatic NSCLC in Spain, to describe the clinical characteristics of these patients, and to evaluate the effectiveness and safety of treatment with crizotinib in a real-world setting. MethodsThis is an observational prospective and retrospective cohort study to determine the incidence of ALK translocations and to analyze the effectiveness and safety of crizotinib in a real-world setting. Patient characteristics, treatment patterns, time to best overall response, duration of treatment, objective response rates (ORR), rates of adverse events (AE), progression free survival (PFS) and overall survival (OS) were evaluated in the ALK study cohort of patients treated with crizotinib (prospective and retrospective). ALK incidence and quality of life (QoL) questionnaires were measured from patients included in the prospective cohort. ResultsThe incidence of ALK translocations was 5.5 % (31 of 559 patients). Compared with ALK-negative patients, ALK-positive patients were significantly younger, predominantly female, and non-smokers. In the crizotinib effectiveness and safety study, 91 patients (42 prospective, 49 retrospective) with ALK-positive NSCLC (43.9 % in first-line, 56.1 % in second or more lines) were included. The ORR was 59.3 % and the median duration of response was 13.5 months (IQR, 5.3–26.2). The median PFS was 15.8 months (95 % CI, 11.8–22.3) and the median OS was 46.5 months, with 53 patients (58.2 %) still alive at data cut-off date. Frequently reported AEs included elevated transaminases, gastrointestinal disorders, and asthenia. Most patients (76.5 %) reported improved or stable scores for global QoL during treatment. ConclusionsThe observed incidence of ALK translocations in NSCLC patients is aligned with published reports. This analysis of the real-world clinical experience in Spain confirms the therapeutic benefit and safety of crizotinib in advanced/metastatic ALK-positive NSCLC. Clinicaltrials.gov: NCT02679170.

EP08.02-092 Coexistence of a Novel NBAS-ALK, EML4-ALK Double-Fusion in a Lung Adenocarcinoma Patient With LM and Response to Ensartinib

ALK gene rearrangement accounts for approximately 5%-7% in non-small cell lung cancer (NSCLC), and usually demonstrate a response to ALK tyrosine kinase inhibitors (TKIs). However, a recent study showed that the presence of nonreciprocal/reciprocal ALK translocation was predictive for shorter PFS and greater risk of brain metastases (BM) in patients with ALK-rearranged NSCLC. Herein, we report that, for the first time, one NSCLC patient with the coexistence of a novel NBAS-ALK, EML4-ALK double-fusion responds to ensartinib after disease progression on sequential crizotinib, alectinib, ceritinib, and then chemotherapy.

1022P A phase II study of KN046 (a bispecific anti-PD-L1/CTLA-4) in patients with metastatic non-small cell lung cancer (NSCLC) who failed first line treatment

KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD1 and CTLA-4 interaction with CD80/CD86. In the phase II study, promising anti-tumor activity was seen with KN046 in subjects with non-small cell lung cancer (NSCLC). Here, we reported the efficacy and safety results of KN046 in second line treatment of advanced NSCLC from Cohort A and B in this study. This is an open-label, multi-center, multiple cohorts, single arm study to evaluate the efficacy, safety and tolerability of KN046 in NSCLC. Subjects with NSCLC who had failed from first line platinum-based doublet chemotherapy without PD-(L)1 immune checkpoint blockade were enrolled. Subjects with EGFR mutation and/or ALK translocation will be excluded. All subjects enrolled will receive KN046 3 mg/kg (Cohort A) and 5 mg/kg (Cohort B) Q2W IV administration, respectively. Primary endpoint was objective response rate (ORR) per RECIST version 1.1 by BICR. Between May 16, 2019 and April 30, 2020, 64 subjects with metastatic NSCLC who failed first line treatment were enrolled. At the data cutoff of August 31, 2021, the median follow-up was 21.6 months (95% CI, 20.3, 23.2). Among all 64 subjects, the ORR was 14.1% (9/64, 95% CI, 6.64, 25.02%), median progression-free survival (mPFS) was 3.7 months (95% CI, 2.9, 5.5) and median overall survival (mOS) was 18.4 months (95% CI, 12.9, 21.9). Furthermore, the ORR was 17.1% (7/41, 95% CI, 7.15, 32.06%), mPFS was 3.7 months (95% CI, 2.76, 5.45) and mOS was 19.8 months (95% CI, 13.04, 23.36) in non-squamous NSCLC (n=41). And in squamous NSCLC (n=20), the ORR was 10.0% (2/20, 95% CI, 1.23, 31.70%), mPFS was 7.4 months (95% CI, 1.81, 14.39) and mOS was 12.9months (95% CI, 8.97, -). 27(42.2%) out of the 64 subjects had experienced treatment-related adverse event (TRAE) at grade 3 or higher levels. The most common TRAEs of grade 3 or higher were infusion reaction (7/64 [10.9%]), hepatic dysfunction (3/64 [4.7%]), pneumonia (2/64 [3.1%]), etc. The bispecific antibody, KN046 was well tolerated and effective as second line treatment of advanced NSCLC. KN046 showed promising OS benefit in both squamous and non-squamous NSCLC.