Novel therapeutic strategies for rare mutations in non-small cell lung cancer.

Lung cancer is still the leading cause of cancer-related mortality. Over the past two decades, the management of non-small cell lung cancer (NSCLC) has undergone a significant revolution. Since the first identification of activating mutations in the epidermal growth factor receptor (EGFR) gene in 2004, several genetic aberrations, such as anaplastic lymphoma kinase rearrangements (ALK), neurotrophic tropomyosin receptor kinase (NTRK) and hepatocyte growth factor receptor (MET), have been found. With the development of gene sequencing technology, the development of targeted drugs for rare mutations, such as multikinase inhibitors, has provided new strategies for treating lung cancer patients with rare mutations. Patients who harbor this type of oncologic driver might acquire a greater survival benefit from the use of targeted therapy than from the use of chemotherapy and immunotherapy. To date, more new agents and regimens can achieve satisfactory results in patients with NSCLC. In this review, we focus on recent advances and highlight the new approval of molecular targeted therapy for NSCLC patients with rare oncologic drivers.

The cost-effectiveness of iruplinalkib versus alectinib in anaplastic lymphoma kinase-positive crizotinib-resistant advanced non-small-cell lung cancer patients in China.

Background: Iruplinalkib is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC), which is independently developed by a Chinese pharmaceutical company. This study examined the cost-effectiveness of iruplinalkib versus alectinib in the Chinese healthcare setting. Methods: A partitioned survival model was developed to project the economic and health outcomes. Efficacy was derived using unanchored matching-adjusted indirect comparison (MAIC). Cost and utility values were obtained from the literature and experts' opinions. Deterministic and probabilistic sensitivity analyses (PSA) were carried out to evaluate the model's robustness. Results: Treatment with iruplinalkib versus alectinib resulted in a gain of 0.843 quality-adjusted life years (QALYs) with incremental costs of $20,493.27, resulting in an incremental cost-effectiveness ratio (ICER) of $24,313.95/QALY. Parameters related to relative efficacy and drug costs were the main drivers of the model outcomes. From the PSA, iruplinalkib had a 90% probability of being cost-effective at a willingness-to-pay threshold of $37,863.56/QALY. Conclusion: Compared to alectinib, iruplinalkib is a cost-effective therapy for patients with ALK-positive crizotinib-resistant advanced NSCLC.

Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer.

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.

Two cases of inflammatory myofibroblastic tumor treated with targeted drugs: A case report.

INTRODUCTION: Inflammatory myofibroblastic tumor (IMT) is a rare invasive soft tissue tumor. Many IMTs are positive for anaplastic lymphoma kinase (ALK) with ALK gene fusion; other gene mutations have also been reported, which indicates a key role for genetic testing and the development of target therapy to optimize treatment strategies. PATIENT CONCERNS: We report 2 patients who obtained clinical benefits following targeted treatment with ensartinib. DIAGNOSIS: The first patient was diagnosed as IMT, with TFG-ROS1 fusion gene mutation. The second patient was IMT harboring the ALK-STRN fusion gene mutation. INTERVENTIONS: We performed gene testing for these 2 patients. According to the test result, both patients received ensartinib 225 mg QD as targeted therapy for a 30-day cycle. OUTCOMES: The first patient achieved partial remission and maintained a stable state for 14.7 months. The second patient was treated for 10 months and reached complete remission after 5 months and is currently still benefiting from treatment. Treatment-related side effects were mild in both patients. CONCLUSION: Our cases provided some new insights and approaches for the clinical diagnosis and treatment of IMT.

A multicenter, retrospective archive study of radiological and clinical features of ALK-positive non-small cell lung cancer patients and crizotinib efficacy.

To evaluate radiological and clinical features in metastatic anaplastic lymphoma kinase+ non-small cell lung cancer patients and crizotinib efficacy in different lines. This national, non-interventional, multicenter, retrospective archive screening study evaluated demographic, clinical, and radiological imaging features, and treatment approaches in patients treated between 2013-2017. Totally 367 patients (54.8% males, median age at diagnosis 54 years) were included. Of them, 45.4% were smokers, and 8.7% had a family history of lung cancer. On radiological findings, 55.9% of the tumors were located peripherally, 7.7% of the patients had cavitary lesions, and 42.9% presented with pleural effusion. Pleural effusion was higher in nonsmokers than in smokers (37.3% vs. 25.3%, P = .018). About 47.4% of cases developed distant metastases during treatment, most frequently to the brain (26.2%). Chemotherapy was the first line treatment in 55.0%. Objective response rate was 61.9% (complete response: 7.6%; partial response: 54.2%). The highest complete and partial response rates were observed in patients who received crizotinib as the 2nd line treatment. The median progression-free survival was 14 months (standard error: 1.4, 95% confidence interval: 11.2-16.8 months). Crizotinib treatment lines yielded similar progression-free survival (P = .078). The most frequent treatment-related adverse event was fatigue (14.7%). Adrenal gland metastasis was significantly higher in males and smokers, and pleural involvement and effusion were significantly higher in nonsmokers-a novel finding that has not been reported previously. The radiological and histological characteristics were consistent with the literature data, but several differences in clinical characteristics might be related to population characteristics.

Reclassification of a spindle cell sarcoma after identification of a TFG-ROS1 fusion: A case demonstrating the clinical benefit of next-generation sequencing in sarcoma.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal soft tissue sarcomas that often present diagnostic challenges due to their wide and varied morphology. A subset of IMTs have fusions involving ALK or ROS1. The role of next-generation sequencing (NGS) for classification of unselected sarcomas remains controversial. METHODS AND RESULTS: We report a case of a metastatic sarcoma in a 34-year-old female originally diagnosed as an unclassified spindle cell sarcoma with myofibroblastic differentiation and later reclassified as IMT after NGS revealed a TFG-ROS1 rearrangement. Histologically, the neoplasm had spindle cell morphology with a lobulated to focally infiltrative growth pattern with scant inflammatory cell infiltrate. Immunohistochemistry demonstrated focal desmin and variable smooth muscle actin staining but was negative for SOX10, S100, and CD34. Fluorescence in situ hybridization was negative for USP6 or ALK gene rearrangements. NGS revealed a TFG-ROS1 rearrangement and the patient was treated with crizotinib with clinical benefit. CONCLUSIONS: 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.

Spitz tumour with ALK rearrangement: A case report and literature review.

Spitz tumour with ALK rearrangement is a recently described entity and a rare tumour. The incidence of Spitz tumour was estimated at 3.63 per 100,000 persons in American paediatric population; while there is no data in Asian population. Here we reported a case of an eleven-year-old Asian boy who presented with a left shin nodule of two months' duration. The skin biopsy revealed a Spitz tumour with predominantly spindle cell morphology arranged in fascicles, vertically orientated nests and radial growth pattern. Junctional component, melanin pigment or Kamino bodies were not identified. Immunohistochemical study displayed homogenous cytoplasmic staining for ALK. Fluorescence in-situ hybridisation (FISH) analysis confirmed ALK rearrangement. Review of the literatures demonstrated that positive ALK immunohistochemistry may not correlate with ALK rearrangement. ALK-rearranged Spitz tumour confirmed with FISH analysis favour clinically benign behaviour despite atypical histomorphology or positive sentinel lymph node. Therefore, correlation of histomorphology, immunohistochemical stain and molecular study are important for the definitive diagnosis of this entity.

Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma.

Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

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.

Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations.

Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, particularly in women. EGFR mutations and anaplastic lymphoma kinase (ALK) fusions are major genetic alterations observed in NSLA, and NSLA with these alterations have been well studied and can be treated with targeted therapies. To provide insights into the molecular profile of NSLA without EGFR and ALK alterations (NENA), we selected 141 NSLA tissues and performed proteogenomic characterization, including whole genome sequencing (WGS), transcriptomic, methylation EPIC array, total proteomic, and phosphoproteomic analyses. Forty patients with NSLA harboring EGFR and ALK alterations and seven patients with NENA with microsatellite instability were excluded. Genome analysis revealed that TP53 (25%), KRAS (22%), and SETD2 (11%) mutations and ROS1 fusions (14%) were the most frequent genetic alterations in NENA patients. Proteogenomic impact analysis revealed that STK11 and ERBB2 somatic mutations had broad effects on cancer-associated genes in NENA. DNA copy number alteration analysis identified 22 prognostic proteins that influenced transcriptomic and proteomic changes. Gene set enrichment analysis revealed estrogen signaling as the key pathway activated in NENA. Increased estrogen signaling was associated with proteogenomic alterations, such as copy number deletions in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14. Finally, saracatinib, an Src inhibitor, was identified as a potential drug for targeting activated estrogen signaling in NENA and was experimentally validated in vitro. Collectively, this study enhanced our understanding of NENA NSLA by elucidating the proteogenomic landscape and proposed saracatinib as a potential treatment for this patient population that lacks effective targeted therapies. SIGNIFICANCE: The proteogenomic landscape in never-smoker lung cancer without known driver mutations reveals prognostic proteins and enhanced estrogen signaling that can be targeted as a potential therapeutic strategy to improve patient outcomes.

Prognostic importance of prognostic nutritional index and modified Glasgow prognostic score in advanced lung cancer with targetable mutation.

BACKGROUND: Inflammation and nutrition are important parameters that significantly affect survival in various malignancies. Prognostic nutritional index (PNI) and modified Glasgow prognostic score (mGPS) can reflect both inflammatory and nutritional conditions. Therefore, we aimed to evaluate the prognostic value of PNI and mGPS in patients who had the targetable mutation and also received targeted therapy. MATERIALS AND METHODS: Advanced lung cancer patients with EGFR mutation (mut) and ALK rearrangement were enrolled to study, retrospectively. PNI has with the following formula: 10 × serum albumin (g/dl) + 0.005 × peripheral lymphocyte count (per mm3) and threshold value was accepted as 50. Modified GPS was also calculated using albumin and CRP level and patients were scored as range 0 to 2. RESULTS: A total of 182 patients enrolled in the study. 132 and 50 of 182 patients had EGFR mut and ALK rearrangement, respectively. PFS was significantly longer in high PNI group in both the EGFR and ALK rearrangement-positive subgroups (P = 0.004 for EGFR mut-positive group; P = 0.017 for ALK rearrangement-positive group). Additionally, PFS was significantly shortened from mGPS 0 to 2 (P = < 0.001 for EGFR mut-positive group; P = 0.016 for ALK rearrangement-positive group). CONCLUSION: Both PNI and mGPS can be used as a reliable, inexpensive, and easily applicable prognostic index in the advanced lung cancer patients who had the targetable mutation and also received targeted therapy.

ALK-positive large B-cell lymphoma (ALK + LBCL) with aberrant CD3 expression.

ALK-positive ( +) large B cell lymphoma (ALK + LBCL) is a rare distinct subtype of diffuse large B cell lymphoma presenting with high stage and aggressive behavior. Although B cell markers such as CD20, CD19, and CD22 are generally negative, plasmacytic markers including CD138, CD38, and MUM1 are positive. T cell markers are negative with rare exceptions. We report an unusual case of ALK1 + LBCL in a 58-year-old man with partial expression of CD3 without other T cell antigen expression. The tissue was evaluated with flow cytometry, immunohistochemistry, fluorescent in situ hybridization, and gene rearrangement studies. Gene rearrangement studies for IGH and TCR gamma were performed. Flow cytometry did not demonstrate any abnormal lymphoid populations. Tissue sectioning shows a malignant plasmacytic large cell neoplasm which expresses CD45 but is negative for CD20, CD79a, and PAX5. Plasmacytic markers CD138 and MUM1 are positive with kappa light chain restriction. Strong granular cytoplasmic expression of ALK is present. FISH showing disrupted ALK supports the diagnosis while MYC, BCL6, and BCL2 are intact. Gene rearrangement studies show coexisting IGH and TCR gamma clones; however, the TCR peak was present within a polyclonal background suggesting the disputed cells are likely only a subset of the T cell population. ALK + LBCL can present with an ambiguous immunophenotype, which warrants the use of multiple B cell, T cell, and plasmacytic antibodies. CD3 expression in this entity is rare and of uncertain clinical significance, but warrants further study.

Navigating resistance to ALK inhibitors in the lorlatinib era: a comprehensive perspective on NSCLC.

INTRODUCTION: The emergence of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) has revolutionized targeted therapy. This dynamic landscape, featuring novel ALK inhibitors and combination therapies, necessitates a profound understanding of resistance mechanisms for effective treatment strategies. Recognizing two primary categories - on-target and off-target resistance - underscores the need for comprehensive assessment. AREAS COVERED: This review delves into the intricacies of resistance to ALK inhibitors, exploring complexities in identification and management. Molecular testing, pivotal for early detection and accurate diagnosis, forms the foundation for patient stratification and resistance management. The literature search methodology involved comprehensive exploration of Pubmed and Embase. The multifaceted perspective encompasses new therapeutic horizons, ongoing clinical trials, and their clinical implications post the recent approval of lorlatinib. EXPERT OPINION: Our expert opinion encapsulates the critical importance of understanding resistance mechanisms in the context of ALK inhibitors for shaping successful treatment approaches. With a focus on molecular testing and comprehensive assessment, this review contributes valuable insights to the evolving landscape of NSCLC therapy.

New Treatment Options for Patients With Oncogene-Addicted Non-Small Cell Lung Cancer Focusing on EGFR-Mutant Tumors.

Druggable oncogene-driven non-small cell lung cancer has led to innovative systemic treatment options, improving patients' outcome. This benefit is not only achieved in the metastatic setting but also in the postsurgical setting, such as in lung cancers harboring a common sensitizing EGFR mutation or ALK-rearrangement. To enhance the outcome of these patients, we need to understand the mechanisms of acquired resistance and evaluate the role of new drugs with novel mechanisms of action in the treatment landscape. In this chapter, we review treatment strategies of EGFR-mutant tumors in all stages, the mechanisms of acquired strategies, and novel therapies in this subset.

Anaplastic lymphoma kinase-positive pulmonary inflammatory myofibroblastic tumour: a case report.

BACKGROUND: Pulmonary inflammatory myofibroblastic tumour (IMT) is a rare condition that usually presents in young individuals and is associated with anaplastic lymphoma kinase (ALK)-translocation. CASE PRESENTATION: We report a case of an 18-year-old Caucasian man with ALK-translocated pulmonary IMT treated with multimodality therapy. The patient presented with breathlessness and was found to have a collapsed left lung. Further investigations revealed an ALK-translocated pulmonary IMT. This is usually treated with an ALK-inhibitor but patient declined after discussing potential side-effects and had repeated rigid bronchoscopic interventions for local disease control. Due to persistent local recurrence, patient received radical external beam radiotherapy (EBRT) with pulse steroids, and one year later started on Ibuprofen, a non-steroidal anti-inflammatory agent (NSAID). Following multimodality treatment, he developed a complete response. He remains treatment-free for the past seven years. Eleven years on from his diagnosis, he remains in remission with a ECOG performance status of zero. CONCLUSIONS: Achieving long-term local control in pulmonary IMT can be challenging. Multimodality treatment is sometimes needed but the overall outlook remains good.

Development of crizotinib-associated renal cyst in a non-small cell lung cancer patient with ALK fusion: a case report and review of the literature.

BACKGROUND: Crizotinib, an oral first-generation tyrosine kinase inhibitor (TKI), is superior to systemic chemotherapy for the treatment of non-small cell lung cancer (NSCLC) with positive rearrangement of anaplastic lymphoma kinase (ALK). However, an increased incidence of renal and hepatic cysts has been reported in the patients on crizotinib treatment. CASE PRESENTATION: Here, we describe a case of a 71-year-old Chinese women developed multiple cystic lesions in kidney and liver during crizotinib treatment for the primary and metastatic NSCLC. The renal and hepatic cysts were noted by CT scan 3 months after crizotinib treatment, which were spontaneously and significantly regressed after stopping crizotinib. CONCLUSIONS: Based on literature review and our experience in this case report, we concluded that crizotinib-associated renal cyst (CARCs) has features of malignancy and abscess in radiographic imaging, and thus, pathological confirmation is necessary to avoid inappropriate treatment decision. In addition, to benefit the patients with progress-free survival (PFS), switching from crizotinib to alectinib is recommended for the treatment of NSCLC patients who developed CARCs.