Use of non-small cell lung cancer multicellular tumor spheroids to study the impact of chemotherapy.

BACKGROUND: Lung cancers represent the main cause of cancer related-death worldwide. Recently, immunotherapy alone or in combination with chemotherapy has deeply impacted the therapeutic care leading to an improved overall survival. However, relapse will finally occur, with no efficient second line treatment so far. New therapies development based on the comprehension of resistance mechanisms is necessary. However, the difficulties to obtain tumor samples before and after first line treatment hamper to clearly understand the consequence of these molecules on tumor cells and also to identify adapted second line therapies. METHODS: To overcome this difficulty, we developed multicellular tumor spheroids (MCTS) using characterized Non-Small Cell Lung Cancer (NSCLC) cell lines, monocytes from healthy donors and fibroblasts. MCTS were treated with carboplatin-paclitaxel or -gemcitabine combinations according to clinical administration schedules. The treatments impact was studied using cell viability assay, histological analyses, 3'RNA sequencing, real-time PCR, flow cytometry and confocal microscopy. RESULTS: We showed that treatments induced a decrease in cell viability and strong modifications in the transcriptomic profile notably at the level of pathways involved in DNA damage repair and cell cycle. Interestingly, we also observed a modification of genes expression considered as hallmarks of response to immune check point inhibitors and immunogenicity, particularly an increase in CD274 gene expression, coding for PD-L1. This result was validated at the protein level and shown to be restricted to tumor cells on MCTS containing fibroblasts and macrophages. This increase was also observed in an additional cell line, expressing low basal CD274 level. CONCLUSIONS: This study shows that MCTS are interesting models to study the impact of first line therapies using conditions close to clinical practice and also to identify more adapted second line or concomitant therapies for lung cancer treatment.

LEAP-014: first-line lenvatinib + pembrolizumab + chemotherapy in advanced/metastatic esophageal squamous cell carcinoma.

Treatment options for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) are improving. Current guidelines recommend first-line pembrolizumab plus chemotherapy for patients with unresectable or metastatic ESCC, which has led to improvements in survival outcomes. Antiangiogenic therapy combined with immune checkpoint inhibitors can act synergistically to convert the immunosuppressive tumor microenvironment to an immune supportive microenvironment, thus enhancing antitumor immune responses. In preclinical models, the antiangiogenic agent lenvatinib combined with an anti-PD-1 agent showed synergistic antitumor activity. We describe the design and rationale for the randomized, open-label, phase III LEAP-014 study of lenvatinib in combination with pembrolizumab plus chemotherapy in patients with advanced or metastatic ESCC. Overall survival and progression-free survival are the dual primary end points.Clinical Trial Registration: NCT04949256 (ClinicalTrials.gov).

[Box: see text].

[National survey of Advanced Practice Nurses in oncology-haematology: Evaluation of activity and continuing education]. / Enquête nationale auprès des infirmiers en pratique avancée mention oncologie-hématologie : évaluation de l'activité et de la formation continue.

INTRODUCTION: The number of Advanced Practice Nurses (APNs) has significantly increased in France since 2019, with the number of graduates expected to reach 1700 by the end of 2023, up from approximately 60. Fifteen percent of them specialize in oncology-hematology (APN-OH). Data on their activities, access to continuing education, and expectations are limited. METHODS: We conducted an observational study among practicing APN-OHs in France. A questionnaire was distributed from June to September 2023. RESULTS: Of the 55 responding APN-OHs, 78.3% worked in Cancer Centers or within University Hospital Centers. Their primary motivation for becoming APN-OH was to enhance their nursing practice and deepen their medical knowledge, with teaching and research interests remaining marginal. Their level of responsibility generally aligned with their expectations and the medical staff was perceived as supportive. The main challenges were of logistical and material nature. The heterogeneity in APN-OH training was seen as a limiting factor in the attractiveness of the profession. The most significant gaps in their education revolved around the lack of practical cases. CONCLUSION: This study highlights that the primary concern of APN-OHs is to strengthen their practical training. Medical personnel are perceived as supportive, but challenges related to working conditions and education persist. It is essential to consider these factors to support the deployment of APN-OHs across the country and improve ongoing education.

Second-line treatment outcomes after first-line chemotherapy plus immunotherapy in Extensive-Stage small cell lung cancer (ES-SCLC) patients: A large French multicenter study.

INTRODUCTION: Chemotherapy combined with immunotherapy (CT-IO) is the standard treatment for patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC). This study evaluates the effectiveness of second-line (2L) following CT-IO. PATIENTS AND METHODS: All patients from 10 centers who received a 2L after a first-line CT-IO were included. They were divided into 3 groups: platinum-based, lurbinectedin or others (topotecan, CAV, taxanes). We assessed overall survival (OS) and 2L progression-free survival (2L-PFS) according to treatment and platinum free-interval (PFI) < or ≥ 90 days. RESULTS: Among 82 patients included, median age was 67.0 years, 29.3 % had a Performans Status ≥ 2, 36.6 % had brain progression, 69.5 % were considered "platine-sensitive" and 30.5 % "platine-resistant" (PFI ≥ or < 90 days, respectively). As 2L, 37/82 patients (45.1 %) received platinum-doublet, 21/82 (25.6 %) lurbinectedin and 24/82 (29.3 %) others. Patients with a PFI ≥ 90 days received mainly platinum-based rechallenge (34/57, 59.6 %). With a median follow-up of 18.5 months, the median OS was 5.0 months (95 %CI, 1.5-7.9) / 6.8 months (95 %CI, 5.5-8.7) for platinum-resistant / sensitive, respectively (log rank p = 0.017). The median 2L-PFS was 1.9 months (95 %CI, 1.2-4.7) / 3.9 months (95 %CI, 2.9-6.0) for platinum-resistant / sensitive, respectively. Median OS was 8.1 (95 %CI, 6.3-12.9) / 4.9 (95 %CI, 3.7-6.8) / 5.1 months (95 %CI, 2.5-7.8) with platinum rechallenge / lurbinectedin / others, respectively (p = 0.017). Median 2L-PFS was 4.6 (95 %CI, 3.9-7.2) / 2.7 (95 %CI, 1.6-3.9) / 2.2 months (95 %CI, 1.5-4.1) with platinum rechallenge / lurbinectedin / others, respectively (p = 0.025). DISCUSSION: Platinum-based rechallenge after a first-line CT-IO showed promising results despite particularly unfavorable characteristics within our real-word population. Lurbinectedin when used after IO demonstrated as low efficacy as other platinum-free regimens.

Prognostic Impact of TP53 Mutations in Metastatic Nonsquamous Non-small-cell Lung Cancer.

BACKGROUND: The prognostic impact of TP53 mutations in advanced or metastatic nonsquamous non-small-cell lung cancer (nsNSCLC) patients treated with chemotherapy and/or immune checkpoint inhibitors (ICI) remains unclear. MATERIALS AND METHODS: We retrospectively collected data from patients with nsNSCLC treated in the first line from January 2018 to May 2021. The patient was separated into 2 groups according to their TP53 mutation status (wt vs. mut). Survival was estimated through the Kaplan-Meier method and compared by log-rank test. RESULTS: Of 220 patients included, 126 were in the mutTP53 group, and 94 were in the wtTP53wt group. Median OS (mOS) was not significantly different between the mutTP53 and wtTP53 groups [17.5 months (95% confidence interval (CI), 11.3-21.5) vs. 9.5 months (95% CI, 7.4-14.2), (P = .051)]. In subgroup analyses, the mutTP53 group treated with ICI had a significantly improved mOS compared to the wtTP53 group [(24.7 months (95% CI, 20.8-not reach) vs. 12.0 months (95% CI, 4.7-not reach), (P = .017)] and mPFS [(9.6 months (95% CI, 5.8-not reach) vs. 3.2 months (95% CI, 1.3-13.8) (P = .048)]. There was no difference in terms of mOS and mPFS between the mutTP53 and the wtTP53 group treated by chemotherapy alone or combined with ICI. CONCLUSION: TP53 mutation had no survival impact in the overall population, but is associated with better outcomes with ICI alone. These results suggest that patients with TP53 mutations could be treated with ICI alone, and wild-type patients could benefit from the addition of chemotherapy.