Study design and rationale for IFCT- 2203 TAXIO: A study that aims to evaluate the effectiveness of a first-line chemotherapy regimen without etoposide, combined with durvalumab, for patients with extensive disease small cell lung cancer.

BACKGROUND: Studies have shown improvement in overall survival with anti-PD1/PD-L1 molecules in combination with cisplatin/carboplatin and etoposide as a first-line treatment for Small Cell Lung Cancer (SCLC). However, first-line efficacy remains limited and well below that observed in Non-Small Cell Lung Cancer (NSCLC). Etoposide may have a detrimental effect on lymphocyte activation, which could explain the limited benefit of immunotherapy in the first line and the lack of benefit in the second line for patients previously exposed to high levels of etoposide. METHODS: We initiated a multicenter, single-arm, open-label phase II study of a chemotherapy regimen with durvalumab, combined with carboplatin and paclitaxel for extensive disease SCLC. Eligible patients will receive durvalumab plus carboplatin and paclitaxel every 3 weeks for up to 4 cycles, followed by durvalumab every 4 weeks until progression or unacceptable toxicity. A total of 67 patients will be enrolled in this study, with a 12-month enrollment period and 36-month follow-up. The primary endpoint is Overall Survival (OS) rate at 12 months. Secondary endpoints are best response rate, OS, OS at 24- and 36 months, progression free survival (PFS), duration of response, quality of life and safety. RESULTS: This study aims to establish the efficacy of durvalumab combined with carboplatin and paclitaxel in patients with extensive disease Small Cell Lung Cancer. CLINICAL TRIAL REGISTRATION: EU CT: 2023-504670-38-00.

PPP3CB overexpression mediates EGFR TKI resistance in lung tumors via calcineurin/MEK/ERK signaling.

Despite initial high response rates to first-line EGFR TKI, all non-small-cell lung cancer (NSCLC) with EGFR-activating mutation will ultimately develop resistance to treatment. Identification of resistance mechanisms is critical to adapt treatment and improve patient outcomes. Here, we show that a PPP3CB transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of PPP3CB by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment.

Pursuit or discontinuation of anti-PD1 after 2 years of treatment in long-term responder patients with non-small cell lung cancer.

Background: The optimal duration of immune checkpoint inhibitor (ICI) treatment for patients with advanced non-small cell lung cancer (NSCLC) remains to be determined. Treatment durations in cornerstone phase 3 clinical trials vary between a fixed 2-year duration and pursuit until disease progression. Clinical practices may thus differ according to the attending physician. Objectives: Here we provide real-world data about treatment decisions at 2 years, with subsequent clinical outcomes. Design and Methods: This multicentric observational study included patients with advanced NSCLC whose disease was controlled after 2 years of pembrolizumab or nivolumab. The primary outcome was the decision to discontinue ICI treatment or not, along with factors motivating this decision. Secondary outcomes included progression-free survival (PFS) (according to treatment continuation or not) and adverse events. Results: A total of 91 patients were included, of which 60 (66%) had been pre-treated. The programmed death-ligand 1 expression level was ⩾50% in 43 patients (47%). In 61 patients (67%), ICI was continued after 2 years of treatment. This decision was significantly associated with the care center (p < 0.001) but neither with the tumor response at 2 years, as evaluated by CT scan or PET scan, nor with clinical status, immune-related adverse events, or previous locally treated oligo-progressive disease under ICI. Two years after the 2-year decision, PFS was 68.5%, [95% confidence interval (CI) (53.3-88.0)] in the 'ICI discontinuation' group and 64.1% [95% CI (51.9-79.2)] in the 'ICI pursuit' group; hazard ratio for relapse was 1.14 [95% CI (0.54-2.30), p = 0.77]. The overall survival rate at 24 months after discontinuation was 89.2% [95% CI (78.4-100)] for the 'discontinuation' group and 93.1% [95% CI (85.8-100)] for the 'pursuit' group. Given insufficient power, overall survival could not be compared. Conclusion: The decision to continue ICI or not after 2 years of treatment depends mainly on the care center and does not seem to impact survival. Larger, randomized data sets are required to confirm this result.

[The revolution of immuno-oncology therapy: specificities for the physicians]. / L'immunothérapie, une révolution en oncologie - Spécificités de l'immunothérapie pour le clinicien.

The use of immune checkpoint inhibitors has revolutionized the treatment and prognosis of many cancer patients. Associated with the raise of these new treatments, new side effects have been observed, requiring specific management. In addition, the tumor evolution and its monitoring under immunotherapy differ from conventional treatments, and require an adaptation of the radiological criteria for tumor lesions monitoring. Many other therapeutic targets exist and could potentially be associated with immune checkpoint inhibitors. Many challenges still need to be overcome in order to better understand and optimize the use of these new molecules.

TITLE: L'immunothérapie, une révolution en oncologie - Spécificités de l'immunothérapie pour le clinicien. ABSTRACT: L'utilisation des inhibiteurs de points de contrôle immunitaire a révolutionné la prise en charge et le pronostic de nombreux patients atteints de cancer. L'arrivée de ces nouveaux traitements s'est accompagnée de la découverte de nouveaux effets indésirables nécessitant des prises en charge spécifiques. De plus, l'évolution tumorale et sa surveillance sous immunothérapie est différente de celle sous traitements classiques, et ont nécessité une adaptation des critères radiologiques et du suivi des lésions tumorales. De nombreuses autres cibles thérapeutiques existent, et pourraient potentiellement être associées aux inhibiteurs des points de contrôle immunitaires. Il existe donc encore de nombreux défis à relever afin de mieux comprendre et d'optimiser l'utilisation de ces nouvelles molécules.

[The revolution of immuno-oncology therapy: review of immune checkpoint inhibitors efficacy]. / L'immunothérapie, une révolution en oncologie - Revue de l'efficacité des inhibiteurs de points de contrôle immunitaire.

Immunotherapy represents a major paradigm shift, as the treatment no longer directly targets tumor cells, but the patient him/herself, in order to restore an effective anti-tumor immunity. This article illustrates the growing place of immune checkpoint inhibitors in the available therapeutic options, by focusing on two cancers with poor outcome: metastatic melanoma and metastatic non-small cell lung cancer (NSCLC), against which Immune checkpoints inhibitors now occupy a central place. Many questions remain unresolved, such as the search for markers predicting a good response to treatment, which would allow the selection of responder patients. Numerous trials are in progress, evaluating the relevance of these new molecules at earlier stages of the disease (adjuvant and neoadjuvant strategies) and their place in combined strategies (associated with chemotherapy, targeted therapies, and other types of immunotherapy).

TITLE: L'immunothérapie, une révolution en oncologie - Revue de l'efficacité des inhibiteurs de points de contrôle immunitaire. ABSTRACT: L'immunothérapie anti-tumorale représente un changement de paradigme majeur où le traitement ne cible plus directement les cellules tumorales mais le patient lui-même, afin de restaurer une immunité anti-tumorale efficace. Parmi les différentes immunothérapies, les inhibiteurs de points de contrôle immunitaire occupent une place centrale dans les options thérapeutiques disponibles de deux cancers au pronostic particulièrement péjoratif: le mélanome malin et le cancer pulmonaire non à petites cellules métastatique. De nombreux essais sont en cours, évaluant la pertinence de ces molécules à des stades plus précoces de la maladie (stratégies adjuvantes ou d'induction) et leur place dans des stratégies combinatoires (associés à de la chimiothérapie, des thérapies ciblées, d'autres types d'immunothérapies, etc.).