BACKGROUND:The treatment landscape for metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) is rapidly evolving, with the development of specific targeted therapies. The bispecific antibody amivantamab is the new standard of care for this population but real-world safety and efficacy data are lacking. METHODS:This is a multicenter, retrospective, observational study conducted on advanced NSCLC patients harboring EGFRex20ins who were included within the ATLAS Italian real-world registry between January and December 2024. Clinical-pathological features, treatment effectiveness, and safety outcomes were retrospectively collected and analyzed. RESULTS:A total of 119 advanced NSCLC patients harboring EGFRex20ins mutations were included. Seventy-six (63.9%) and 24 (20.2%) received first-line platinum-based chemotherapy with or without immunotherapy, respectively. Overall 64 of 119 patients received single agent amivantamab in the subsequent lines. Treatment-related adverse events (TRAEs) of any grade and grade 3-4 were reported in 68.8% and 10.9%, respectively, including skin rash (56%, G3 9.4%), asthenia (9%), peripheral edema (8%), and infusion-related reactions (9.4%, G3 1.5%). Dose interruptions, reductions, and discontinuations due to TRAEs occurred in 20.3%, 12.5%, and 3.1% patients, respectively. The objective response rate was 37.5%, the DCR was 66.2%, the median progression-free survival (mPFS) was 9.6 months, and the median overall survival was 16.9 months under amivantamab. Among the 23 patients with brain metastasis, 13% achieved a partial intracranial (ic) response and 43.5% a stable disease. The ic mPFS was 11.6 months. CONCLUSION:This data confirms the efficacy and safety profile of amivantamab observed in the CHRYSALIS trial, showing a meaningful clinical benefit in a heavily pretreated real-world population.

BACKGROUND:Immunotherapy represented a turning point for treating extensive small-cell lung cancer (ES-SCLC). Although, many issues remain debated.METHODS:A group of Italian medical and radiation oncologists with expertise in managing patients with ES-SCLC developed a list of statements divided in six areas of interest. The Delphi method was used to assess the consensus on the defined list of statements.RESULTS:32 statements were included in the final list to be voted by the Delphi panel, and 26 reached a consensus on the agreement. A prompt involvement of a multidisciplinary team is a priority to provide an integrated treatment strategy. First-line recommended treatment is immunotherapy in combination with platinum-based chemotherapy and etoposide for four cycles followed by maintenance immunotherapy.CONCLUSIONS:While awaiting new data from clinical trials and real-world studies, these recommendations can represent a useful tool to guide the management of ES-SCLC patients in daily practice.

The WHO Classification of Tumors, Thoracic Tumors, 5th edition, has outlined the use of TTF-1 and ΔNP63/P40 to discriminate between adenocarcinoma and squamous cell carcinoma. In 2015, the first description of a rare non-small cell lung carcinoma featuring co-expression of glandular and squamous differentiation within most of the same individual tumor cells was reported on, with ultrastructural and molecular demonstration of such a biphenotypic differentiation. We herein describe an additional case of this rare tumor entity, which is confirmed to be an aggressive neoplasm despite potential targets of therapy.

Supplementary Figure 1. "Phase 2-Eligible" Population. Supplementary Figure 2. ALKA-372-001 and STARTRK-1 Dosing Regimens.

DOC- 25K, Supplementary Tables 1-6

INTRODUCTION:Immune-checkpoint inhibitors (IO) have significantly improved outcomes of patients with non-oncogene-addicted non-small cell lung cancer (NSCLC), becoming the first-line agents for advanced disease. However, resistance remains a significant clinical challenge, limiting their effectiveness.AREAS COVERED:Hereby, we addressed standard and innovative therapeutic approaches for NSCLC patients experiencing progression after IO treatment, discussing the emerging resistance mechanisms and the ongoing efforts to overcome them. In order to provide a complete overview of the matter, we performed a comprehensive literature search across prominent databases, including PubMed, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library, and a research of the main ongoing studies on clinicaltrials.gov.EXPERT OPINION:The dynamics of progression to IO, especially in terms of time to treatment failure and burden of progressive disease, should guide the best subsequent management, together with patient clinical conditions. Long-responders to IO might benefit from continuation of IO beyond-progression, in combination with other treatments. Patients who experience early progression should be treated with salvage CT in case of preserved clinical conditions. Finally, patients who respond to IO for a considerable timeframe and who later present oligo-progression could be treated with a multimodal approach in order to maximize the benefit of immunotherapy.

ROS1 tyrosine kinase inhibitors (TKIs) were found to provide a substantial clinical benefit for patients with advanced ROS1-positive (ROS1+) NSCLC. Nevertheless, TKI resistance inevitably develops with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to entrectinib. Hereby, we report the case of a patient with ROS1+ NSCLC in which F2004V-acquired mutation was detected on a site of disease progression, after entrectinib and crizotinib failure. A subsequent treatment with next-generation TKI repotrectinib led to disease response, providing the first clinical evidence of activity of repotrectinib against F2004V resistance mutation.

Abstract Cancer immunotherapy, largely represented by immune checkpoint inhibitors (ICI), has led to substantial changes in preclinical cancer research and clinical oncology practice over the past decade. However, the efficacy and toxicity profiles of ICIs remain highly variable among patients, with only a fraction achieving a significant benefit. New combination therapeutic strategies are being investigated, and the search for novel predictive biomarkers is ongoing, mainly focusing on tumor- and host-intrinsic components. Less attention has been directed to all the external, potentially modifiable factors that compose the exposome, including diet and lifestyle, infections, vaccinations, and concomitant medications, that could affect the immune system response and its activity against cancer cells. We hereby provide a review of the available clinical evidence elucidating the impact of host-extrinsic factors on ICI response and toxicity.

Background: Osimertinib represents the standard of care for the treatment of advanced non -small -cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor ( EGFR ) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. Patients and methods: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression -free survival (mPFS), and overall survival were estimated by the Kaplan - Meier method. Results: Eighty-six patients harboring uEGFR and treated with osimertinib were identi fi ed. Patients with ' major ' uEGFR, that is, G719X, L861X, and S768I mutations ( n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer ' minor ' mutations ( n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation ( n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Ampli fi cation of EGFR or MET , TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. Conclusion: The ARTICUNO study con fi rms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon e common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

This study sought to evaluate the real-world clinical outcomes of chemo-immunotherapy (CT-IT) with cis/carboplatin, pemetrexed and pembrolizumab for the first-line (1L) treatment of advanced lung adenocarcinoma (LUAC) patients in Italy.

Liquid biopsy recently gained widespread attention as a noninvasive alternative/complementary technique to tissue biopsy in patients with cancer. As technological advances have improved both feasibility and turnaround time, liquid biopsy has expanded tumor molecular analysis with acknowledgement of both spatial and temporal heterogeneity, overcoming many limitations of traditional tissue biopsy. Because of its diagnostic, prognostic, and predictive value, liquid biopsy has been extensively studied also in metastatic colorectal cancer. Indeed, as personalized medicine establishes its role in cancer treatment, genetic biomarkers unveiling the emergence of early resistance are needed. Among the wide variety of tumor analytes amenable to collection, circulating DNA and circulating tumor cells are the most adopted approaches, and both carry clinical relevance in colorectal cancer. However, few studies focused on comparing feasibility between these two approaches. In this review, we discuss the potential implications of liquid biopsy in metastatic colorectal cancer, assessing the advantages and drawbacks of circulating DNA and circulating tumor cells, and highlighting the most relevant trials for clinical practice.

Background: The potential added value of liquid biopsy (LB) is not well determined in the case of small cell lung cancer (SCLC), an aggressive tumor that can occur either de novo or from the histologic transformation of non-small cell lung cancer (NSCLC). Methods: A systematic review of studies adopting LB in patients with SCLC have been performed to assess the clinical utility of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs). Results: After a screening of 728 records, 62 studies (32 evaluating CTCs, 27 ctDNA, and 3 both) met predetermined eligibility criteria. Only four studies evaluated LB in the diagnostic setting for SCLC, while its prognostic significance was evaluated in 38 studies and prominently supported by both ctDNA and CTCs. A meta-analysis of 11 studies as for CTCs enumeration showed an HR for overall survival of 2.63 (1.71–4.05), with a potential publication bias. The feasibility of tumor genomic profiling and the predictive role of LB in terms of response/resistance to chemotherapy was assessed in 11 and 24 studies, respectively, with greater consistency for those regarding ctDNA. Intriguingly, several case reports suggest that LB can indirectly capture the transition to SCLC in NSCLC treated with EGFR tyrosine kinase inhibitors. Conclusions: While dedicated trials are needed, LB holds potential clinical roles in both de novo and transformed SCLC. CtDNA analysis appears the most valuable and practicable tool for both disease monitoring and genomic profiling.

Neuregulin 1 (NRG1) gene fusions are oncogenic drivers in multiple cancer types. NRG1 fusion proteins bind to HER3 and signal through HER2/HER3 heterodimers, leading to increased downstream signaling and tumor growth. Clinical responses to agents that target this pathway have been reported. Zenocutuzumab (Zeno, MCLA-128) is a HER2/HER3 bispecific antibody that binds to or ‘docks’ onto the more abundant cell surface HER2 protein, potently blocking NRG1 fusion protein binding and preventing HER2/HER3 dimerization.

Unresectable malignant pleural mesothelioma (MPM) is an aggressive disease with a 5-year survival rate of approximately 10%. Recent data suggest that MPM is an immunologically active tumor, in which checkpoint inhibition through the blockade of the anti-cytotoxic T lymphocyte antigen-4 (-CTLA-4) or anti-programmed cell death 1 (PD-1) could play a major therapeutic role. Initially, clinical trials evaluated immune checkpoint inhibitors (ICIs) in the salvage setting after platinum-based chemotherapy with mixed results in terms of efficacy. More recently, the combination of the anti-CTLA-4 agent ipilimumab plus the anti-PD-1 agent nivolumab was tested in the front-line setting, and reported a superior survival as compared to platinum/pemetrexed. While other clinical trials ore ongoing in order to investigate ICIs for MPM, it seems now evident that we have entered a new "era" for the treatment of MPM. In the future, a few issues need to be solved with regard to the use of ICIs for MPM. Among them, there is the identification of biomarkers of sensitivity to immunotherapy that may help enrich the patient population who could benefit the most from treatment, while avoiding for some other patients the potential occurrence of immune-related side effects from therapies that are anticipated to be ineffective.

Background Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure. Case presentation We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15–20. Conclusions This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.

Les fusions NRG1 sont des anomalies oncogéniques retrouvées dans différents types de cancers solides, en particulier les cancers du poumon non à petites cellules (CBNPC) et les cancers du pancréas KRAS sauvage. La protéine de fusion NRG1 active HER3 conduisant à l’hétérodimérisation d’HER3 avec HER2 et à la promotion de la croissance tumorale. Une efficacité clinique des anticorps anti-HER3 et des inhibiteurs de tyrosine kinase d’HER2 a été rapportée dans les tumeurs NRG1-positives. Le MCLA-128 est un anticorps bispécifique qui bloque la liaison NRG1-HER3 ainsi que la dimérisation HER2/HER3. Il a montré une activité préclinique robuste dans des modèles tumoraux NRG1- positifs. Sur la base de ces données, un essai basket propose d’évaluer l’efficacité du MCLA-128 chez des patients atteints de tumeurs présentant des fusions de NRG1. Il s’agit d’une étude internationale, ouverte, non contrôlée, multicentrique de phase II « basket » évaluant l’efficacité du MCLA-128 chez des patients ayant des cancers solides avancées avec fusion NRG1. Le critère d’éligibilité principal est cancer avancé avec fusion de NRG1 en échec du traitement standard recommandé. Le diagnostic moléculaire de la fusion NRG1 est effectué soit localement avec confirmation centralisée post-hoc, soit centralisé. Trois cohortes de patients seront évaluées : cancer du pancréas (n = 25), CBNPC (n = 25), tout autres tumeurs solides avec fusion NRG1 (n = 40). Le critère de jugement principal pour les 3 cohortes est le taux de réponse objective selon l’investigateur (RECIST v1.1). Les critères d’efficacité secondaires sont la durée de réponse, la survie sans progression et la survie globale. Les patients éligibles recevront le MCLA-128 à une dose fixe de 750 mg en perfusion IV de 2 heures, toutes les 2 semaines, en cycles de 4 semaines. L’étude recrute activement des patients en Amérique du Nord, Europe et Asie.

This study was conducted in the setting of advanced Non-small-cell lung cancer in older patients. It is a multicenter retrospective analysis on very old persons that explores the efficacy and the safety of anti-programmed cell death protein 1 therapy. Older patients seem to tolerate immunotherapy as well as younger patients with comparable efficacy. This is a relevant message for everyday clinical practice. Introduction: Non-small-cell lung cancer (NSCLC) is predominantly a disease of the elderly population. Over the past few years, immunotherapy with monoclonal antibodies named checkpoint inhibitors (ICIs) greatly improved the clinical management of a significant proportion of patients with metastatic NSCLC. However, pivotal trials excluded older patients, although, given the favorable clinical profile of ICIs, this treatment may be revealed to be a most valuable option also for these patients. To this aim, a multicenter retrospective analysis was performed on patients aged >= 75 years with NSCLC treated with anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy. Material and Methods: Inclusion criteria were: diagnosis of locally advanced or metastatic NSCLC (stage IIIB or IV, according to the American Joint Committee on Cancer (AJCC) classification system, version 8.0); age >= 75 years; treatment with anti-PD-1/PD-L1 monoclonal antibodies in first or subsequent lines of treatment; absence of epidermal growth factor receptor-activating mutations or anaplastic lymphoma kinase and ROS-1 rearrangements. The primary endpoints of the study were the efficacy, in terms of overall response rate, progression-free survival, and overall survival, and safety, by means of evaluations of the incidence of immune-related adverse events. Results: Eighty-six patients were considered for the final analysis; 71 (82.6%) were male. The mean age was 78.5 years (range, 75-86 years; SD, 3.12 years). Of the 86 patients, 69 (80.2%) of patients had a performance status of 0 or 1. The overall median progression-free survival was 5.6 months (range 1-36 months; SD, 7.5 months,) whereas the median overall survival was 10.1 months (range, 1.7-34.8 months; SD, 8 months). At the Cox regression analysis, the only parameter significantly associated with survival was the smoking status (P =.008). No difference in survival was found between patients younger and older than 80 years. Conclusions: In the present real-world retrospective cohort, efficacy and toxicity profiles of ICIs in older patients with advanced NSCLC were comparable with those observed in younger patients enrolled in clinical trials. (C) 2020 Elsevier Inc. All rights reserved.