Maldonado, Fabien

The NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of NSCLC. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines, with a focus on systemic therapy options for the treatment of patients with nonmetastatic NSCLC and the corresponding molecular testing considerations.

Thymomas and thymic carcinomas are rare mediastinal tumors that originate in the thymus. Patients with thymoma may experience symptoms associated with autoimmune paraneoplastic diseases (such as myasthenia gravis), which typically do not occur in patients with thymic carcinoma. The NCCN Guidelines for Thymomas and Thymic Carcinomas provide guidance for the diagnosis, treatment, and surveillance of patients with thymoma and thymic carcinoma. Involvement of a multidisciplinary team with experience treating thymomas and thymic carcinomas is highly recommended.

Introduction Bronchoscopic lung volume reduction with endobronchial valves (EBV) is an effective procedure for patient with severe emphysema to improve lung function, exercise tolerance, dyspnoea and quality of life. Optimisation of patient and treatment lobe selection is essential for successful EBV outcomes. While clinical selection criteria are rigorous, many centres use a multidisciplinary team and rely on previous clinical experience for the selection process. To aid objective clinical decision making, we present a mathematical model to facilitate patient and target lobe selection. Methods A multidisciplinary team reviewed quantitative high-resolution computed tomography (HRCT) analysis from 119 patients to select candidates for EBV and to select a treatment lobe. Two logistic regression models, (1) candidacy for EBV placement and (2) target-lobe selection, were developed based on the normalised distributions of the four quantitative HRCT variables (fissure completeness score, per cent of voxel density with HU < −910 and HU < −950, and lobar volumes) across all five lung lobes. An external cohort of 50 patients (25 candidates and 25 non-candidates) was used to validate the prediction model. Results Performance measures of the training cohort demonstrated an area under the curve (AUC) of 0.91, accuracy of 81%, sensitivity of 93% and specificity of 78% compared with the multidisciplinary teams’ target lobe selection. The validation cohort demonstrated an AUC of 0.89, accuracy of 84%, sensitivity of 88% and specificity of 83% compared with the multidisciplinary team decision making. Conclusions Endobronchial valve lung volume reduction remains a potent palliative measure to improve quality of life in patients with hyperinflated emphysema. Our model for target lobe selection harnesses the multidisciplinary experience at a tertiary care centre to objectively select candidates and target lobes to assist clinicians’ decision making. Future studies investigating prediction of lobar collapse and functional improvement after target lobe selection using our model are needed.

Abstract Rationale Stereotactic body radiation therapy (SBRT) represents an effective therapeutic strategy for early-stage non–small cell lung cancer (NSCLC); however, local and systemic recurrences represent ongoing challenges. Computed tomography (CT) radiomics-based risk models can potentially be used to predict the risk of local recurrence on pretreatment CT scans. Objective Development of a radiomics model to predict local recurrence after SBRT in patients with NSCLC. Methods This single-institution study includes a retrospective case-control training set (20 patients with local recurrence and 40 control subjects) and an independent validation set (198 consecutive cases) of patients with early-stage NSCLC treated with SBRT. Tumors were semiautomatically segmented, and 102 quantitative radiomic features, including texture, landscape, spatial, nodule shape, and nodule surface features, were extracted. These features were included in three separate multivariable models to predict the risk of recurrence on the basis of pre-SBRT, post-SBRT, and the difference between the pre-SBRT and post-SBRT scans (Delta model). The pre-SBRT model was subsequently validated in an independent validation set. Results Thirteen independent variables were selected for the models using the Boruta algorithm. The sensitivity, specificity, and area under the curve of the pre-SBRT, post-SBRT, and Delta models were 85%, 90%, and 0.91; 85%, 92.5%, and 0.92; and 85%, 92.5%, and 0.94, respectively. The pre-SBRT model was validated in the independent validation set (area under the curve, 0.89; confidence interval, 0.83–0.92), because this model was believed to be the most useful to assist in individualized treatment planning. Conclusions Radiomic analysis facilitated the development of three high-performing models predicting local recurrence using either pre-SBRT CT, post-SBRT CT, or the change between these two. We successfully validated the most clinically relevant model, the pre-SBRT model. Although this model needs further validation, it may facilitate individualized surveillance, treatment planning, and selection of adjuvant therapy.

8634 Background: Patients with unresectable non-small cell lung cancer (NSCLC) with an inadequate response to immune checkpoint inhibitors (ICI) have limited therapeutic options and expected median overall survival (mOS) of 11.6 to 14.5m (PMID: 35658002 ). The immunosuppressive tumor microenvironment and the lack of a specific T cell response underpin inadequate clinical response. CAN-2409 is a replication-defective adenovirus encoding the HSV-tk gene. Transduced cells activate orally delivered valacyclovir, resulting in immunogenic cell death, and in situ immunization against the patient’s tumor antigens, eliciting a specific immune response against the injected tumor and uninjected metastases. Methods: NCT04495153 is an open-label, phase 2 clinical trial of CAN-2409 + valacyclovir in combination with continued ICI in patients with non-resectable, stage III/IV NSCLC, refractory or resistant to anti-PD-(L)1. Patients were enrolled in 2 cohorts (C) depending on disease status at enrolment: C1, stable disease or C2, progressive disease. Two doses of CAN-2409 (5x1011vp) were given 5-7w apart via bronchoscopic or percutaneous injection into lung tumor, disease-positive lymph node, or peripheral metastasis, each followed by oral prodrug. Patients were assessed for safety, immunologic biomarkers, and OS. Results: As of 16Jan2024, 73 patients were treated (safety population: ≥1 dose of CAN-2409) and 44 were evaluable per protocol (received 2 doses of CAN-2409+ valacyclovir and 12-week CT scan). Baseline treated pt median age was 67 [43-88] yrs, 44% female, 68% on aPD(L)1 alone and 32% aPD(L)1 + pemetrexed regimen. We observed no dose-limiting toxicities or ≥grade 4 treatment-related AEs. mOS of the evaluable population was estimated as 22.0m (95% CI: 14.3m, NA; median follow up (mFU) time of 18.2m). In C2 (n = 38) mOS was 20.6 (mFU 19.2.m) and in C1 (n = 6) was N.A. (mFU 15.2m). mOS in the safety population (n = 73) was 14.3.m (mFU16.8m). 64% of evaluable patients had systemic clinical response with shrinkage of both injected and uninjected lesions. We found a significant correlation between increases in T cell populations after the second injection of CAN-2409 (circulating memory and effector memory CD4+ and CD8+T cells, CD4+ Ki67+IFNg+ and CD4+granzymeB+ T cells, CD8+granzymeB+Ki67+ T cells, T regulatory cells) and subsequent OS (R2 between 0.181 and 0.354 and p = 0.043 and 0.004). Conclusions: Experimental treatment with CAN-2409+valacyclovir in NSCLC pts following an inadequate response to ICI is well tolerated and results in the induction of a cytotoxic and memory circulating T cell response associated with shrinkage of injected and uninjected lesions and a raised tail of the survival curve. mOS of the evaluable population was estimated as 22.0m, markedly longer than the expected mOS of 11.6-14.5m. Clinical trial information: NCT04495153 .

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term “malignant” is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

TPS9162 Background: Immune checkpoint inhibitors (ICI) are a standard of care (SOC) treatment that have improved outcomes for patients (pts) with non-small cell lung cancer (NSCLC). However, most pts progress, signaling a need for combination approaches to further improve outcomes. CAN-2409 is a replication-defective adenoviral construct encoding the herpes simplex virus thymidine kinase (HSV-tk) gene that is injected intratumorally followed by 2 weeks of prodrug (valacyclovir or acyclovir). HSV-tk converts the prodrug in the tumor microenvironment into a toxic metabolite, resulting in immunogenic cell death, while the adenoviral proteins provide a strong pro-inflammatory signal. Together, this leads to in situ vaccination against the patient’s own tumor. As a result, CD8+ cytotoxic T cells are educated on how to recognize and kill tumor cells in both the injected tumor and the uninjected metastases. A completed neoadjuvant phase I trial in resectable NSCLC demonstrated safety and immune stimulation (Predina et al 2021), warranting further investigation of CAN-2409 + prodrug as a therapy that can lead to improved long-term outcomes for pts with NSCLC who have a suboptimal response to ICI. Methods: LuTK02 (NCT04495153) is an open-label, multi-arm, phase II clinical trial to evaluate CAN-2409 + prodrug added to SOC ICI (anti-PD-(L)1) therapy in pts with stage III/IV NSCLC presenting with inadequate response (as defined below) to ICI. Cohort 1 includes pts with nonresponding but stable disease ≥18 weeks after starting ICI; cohort 2 includes pts with progressive disease ≥18 weeks after starting ICI. Key eligibility criteria include RECIST-evaluable disease; an injectable lesion (via bronchoscopy or US/IR guidance); ability to continue ICI for the treatment period; no change of ICI or prior interruptions of > 4 weeks within 6 months of enrollment; and no focal therapy at > 3 sites of disease within 12 months prior to enrollment. Key exclusion criteria include a history of ICI immune-related adverse events and known alterations in EGFR, ALK, or ROS1. Eligible patients receive 2 injections of CAN-2409 approximately 6 weeks apart followed by prodrug for 14 days. After treatment of ~40 evaluable pts in cohort 2 with two injections of CAN-2409, the protocol has been amended to include a new cohort (n~20) of pts treated with three injections of CAN-2409 approximately 4 weeks apart, each followed by prodrug for 14 days, to further define the optimal therapeutic regimen. Primary endpoints are overall response and/or disease control rate per RECIST 1.1 criteria and safety of CAN-2409 + prodrug. Secondary endpoints include duration of response, PFS, OS, and biomarker studies. Exploratory endpoints include evaluation of effects in non-injected lesions, changes in non-target (per RECIST) lesions, tumor growth trajectory, and viral shedding. Clinical trial information: NCT04495153 .