ALK inhibitors in ALK-positive NSCLC with central nervous system metastases

In anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer, brain metastases occur in 22–33% of cases at diagnosis and could reach up to 70% after crizotinib failure. Next-generation ALK inhibitors (ngALKi) have superior intracranial activity and prolonged responses compared with crizotinib and chemotherapy, as was shown in treatment-naïve or crizotinib pre-treated patients, irrespective of prior brain irradiation. Nevertheless, central nervous system relapse is also seen with ngALKi. Tailored treatment is necessary to obtain long-term survival without detrimental effects on cognition. Possible options include profiling secondary mutations to select sequential ngALKi, stereotactic radiotherapy and/or surgery, with the aim to avoid/deter whole brain irradiation

Blocking light in compact Riemannian manifolds

We study compact Riemannian manifolds for which the light between any pair of points is blocked by finitely many point shades. Compact flat Riemannian manifolds are known to have this finite blocking property. We conjecture that amongst compact Riemannian manifolds this finite blocking property characterizes the flat metrics. Using entropy considerations, we verify this conjecture amongst metrics with nonpositive sectional curvatures. Using the same approach, K. Burns and E. Gutkin have independently obtained this result. Additionally, we show that compact quotients of Euclidean buildings have the finite blocking property. On the positive curvature side, we conjecture that compact Riemannian manifolds with the same blocking properties as compact rank one symmetric spaces are necessarily isometric to a compact rank one symmetric space. We include some results providing evidence for this conjecture.Comment: 19 page

Boussinesq/Boussinesq systems for internal waves with a free surface, and the KdV approximation

We study here some asymptotic models for the propagation of internal and surface waves in a two-fluid system. We focus on the so-called long wave regime for one dimensional waves, and consider the case of a flat bottom. Starting from the classical Boussinesq/Boussinesq system, we introduce a new family of equivalent symmetric hyperbolic systems. We study the well-posedness of such systems, and the asymptotic convergence of their solutions towards solutions of the full Euler system. Then, we provide a rigorous justification of the so-called KdV approximation, stating that any bounded solution of the full Euler system can be decomposed into four propagating waves, each of them being well approximated by the solutions of uncoupled Korteweg-de Vries equations. Our method also applies for models with the rigid lid assumption, and the precise behavior of the KdV approximations depending on the depth and density ratios is discussed for both rigid lid and free surface configurations. The fact that we obtain {\it simultaneously} the four KdV equations allows us to study extensively the influence of the rigid lid assumption on the evolution of the interface, and therefore its domain of validity. Finally, solutions of the Boussinesq/Boussinesq systems and the KdV approximation are rigorously compared and numerically computed.Comment: To appear in M2A

Randomized open-label controlled study of cancer vaccine OSE2101 versus chemotherapy in HLA-A2-positive patients with advanced non-small-cell lung cancer with resistance to immunotherapy: ATALANTE-1

Cancer vaccine; Immunotherapy resistance; Quality of lifeVacuna contra el cáncer; Resistencia a la inmunoterapia; Calidad de vidavacuna contra el càncer; Resistència a la immunoteràpia; Qualitat de vidaBackground Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients. Patients and methods ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks. Results Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002). Conclusions In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.This work was supported by OSE Immunotherapeutics (no grant number)

455 Pegasus Lung, a platform study of SAR444245 (THOR-707, a pegylated recombinant non-alpha IL-2) with anti-cancer agents in patients with non-small cell lung cancer (NSCLC) and mesothelioma

BackgroundSAR444245 (THOR-707) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. In animal models, SAR444245 showed anti-tumor benefits, but with no severe side effects, both as single agent and when combined with anti-PD1 comparing with historical data from aldesleukin. The HAMMER trial, which is the FIH study shows preliminary encouraging clinical results: initial efficacy and safety profile with SAR444245 monotherapy and in combination with pembrolizumab support a non-alpha preferential activity, validating preclinical models. The Pegasus Lung Ph2 study will evaluate the clinical benefit of SAR444245 in combination with other anticancer therapies for the treatment of patients with lung cancer or pleural mesotheliomaMethodsThe Pegasus Lung (NCT04914897) will enroll approximately 354 patients in 6 separate cohorts concurrently or sequentially. In cohorts A1 & A2, patients with first line (L) NSCLC will receive SAR444245 + pembrolizumab. In cohort A3, patients with 1L non-squamous NSCLC will receive SAR444245 + pembrolizumab + pemetrexed + carboplatin/cisplatin. In cohort B1 & B2 patients with 2/3L NSCLC who have progressed on a checkpoint inhibitor (CPI)-based therapy will receive SAR444245 + pembrolizumab, or SAR444245 + pembrolizumab + nab-paclitaxel. In cohort C patients with 2/3L CPI naïve mesothelioma will receive SAR444245 + pembrolizumab. SAR444245 is administered IV at a dose of 24 ug/kg Q3W in an outpatient setting until disease progression or completion of 35 cycles. Pembrolizumab is administered at a dose of 200 mg Q3W until PD or completion of 35 cycles. The study primary objective is to determine the antitumor activity of SAR444245 in combination with other anticancer therapies. Secondary objectives include confirmation of dose and safety profile, assess other indicators of antitumor activity, and assess the pharmacokinetic profile and immunogenicity of SAR444245. The study will be conducted in the US, Australia, France, Italy, Japan, Poland, South Korea, Spain, and Taiwan.AcknowledgementsThe Pegasus Lung study is sponsored by Sanofi.Trial RegistrationNCT04914897Ethics ApprovalThis study has been approved by applicable ethics committees or institutional review boards. All participants gave informed consent before taking part.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal

Lincp21-RNA as Predictive Response Marker for Preoperative Chemoradiotherapy in Rectal Cancer

Preoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (RC) patients, but its use in non-responders can be associated with increased toxicities and resection delay. LincRNA-p21 is a long non-coding RNA involved in the p53 pathway and angiogenesis regulation. We aimed to study whether lincRNA-p21 expression levels can act as a predictive biomarker for neoadjuvant CRT response. We analyzed RNAs from pretreatment biopsies from 70 RC patients treated with preoperative CRT. Pathological response was classified according to the tumor regression grade (TRG) Dworak classification. LincRNA-p21 expression was determined by RTqPCR. The results showed that lincRNA-p21 was upregulated in stage III tumors (p = 0.007) and in tumors with the worst response regarding TRG (p = 0.027) and downstaging (p = 0.016). ROC curve analysis showed that lincRNA-p21 expression had the capacity to distinguish a complete response from others (AUC:0.696; p = 0.014). LincRNA-p21 was shown as an independent marker of preoperative CRT response (p = 0.047) and for time to relapse (TTR) (p = 0.048). In conclusion, lincRNA-p21 is a marker of advanced disease, worse response to neoadjuvant CRT, and shorter TTR in locally advanced RC patients. The study of lincRNA-p21 may be of value in the individualization of pre-operative CRT in RC

On the Korteweg-de Vries approximation for uneven bottoms

In this paper we focus on the water waves problem for uneven bottoms on a two-dimensionnal domain. Starting from the symmetric Boussinesq systems derived in [Chazel, Influence of topography on long water waves, 2007], we recover the uncoupled Korteweg-de Vries (KdV) approximation justified by Schneider and Wayne for flat bottoms, and by Iguchi in the context of bottoms tending to zero at infinity at a substantial rate. The goal of this paper is to investigate the validity of this approximation for more general bathymetries. We exhibit two kinds of topography for which this approximation diverges from the Boussinesq solutions. A topographically modified KdV approximation is then proposed to deal with such bathymetries. Finally, all the models involved are numerically computed and compared

Electrochemotherapy in radiotherapy-resistant epidural spinal cord compression in metastatic cancer patients

Objective: To report efficacy and safety of percutaneous electrochemotherapy (ECT) in patients with radiotherapy-resistant metastatic epidural spinal cord compression (MESCC). Material/ methods: This retrospective study analyzed all consecutive patients treated with bleomycin-based ECT between February-2020 and September-2022 in a single tertiary referral cancer center. Changes in pain were evaluated with the Numerical Rating Score (NRS), in neurological deficit with the Neurological Deficit Scale, and changes in epidural spinal cord compression were evaluated with the epidural spinal cord compression scale (ESCCS) using an MRI. Results: Forty consecutive solid tumour patients with previously radiated MESCC and no effective systemic treatment options were eligible. With a median follow-up of 5.1 months [1-19.1], toxicities were temporary acute radicular pain (25%), prolonged radicular hypoesthesia (10%), and paraplegia (7.5%). At 1 month, pain was significantly improved over baseline (median NRS: 1.0 [0-8] versus 7.0 [1.0-10], P < .001) and neurological benefits were considered as marked (28%), moderate (28%), stable (38%), or worse (8%). Three-month follow-up (21 patients) confirmed improved over baseline (median NRS: 2.0 [0-8] versus 6.0 [1.0-10], P < .001) and neurological benefits were considered as marked (38%), moderate (19%), stable (33.5%), and worse (9.5%). One-month post-treatment MRI (35 patients) demonstrated complete response in 46% of patients by ESCCS, partial response in 31%, stable disease in 23%, and no patients with progressive disease. Three-month post-treatment MRI (21 patients) demonstrated complete response in 28.5%, partial response in 38%, stable disease in 24%, and progressive disease in 9.5%. Conclusions: This study provides the first evidence that ECT can rescue radiotherapy-resistant MESCC