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Treatment of metastatic non-small-cell lung cancers (NSCLCs) has long been based on cytotoxic chemotherapy. Immune checkpoint inhibitors (ICIs), notably monoclonal antibodies directed against programmed cell death protein-1 (PD-1) or its ligand (PD-L1), have transformed therapeutic standards in thoracic oncology. These ICIs are now the reference first-line therapy, and numerous phase III trials have established their efficacy in treatment-naïve patients. First-line pembrolizumab monotherapy was validated for patients with ≥ 50% of tumor cells expressing PD-L1 and, in the USA, for patients with ≥ 1% PD-L1 positivity. More recently, cemiplimab as monotherapy was also validated for patients whose tumors expressed ≥ 50% PD-L1. Several ICIs (pembrolizumab, atezolizumab, nivolumab, and recently durvalumab) in combination with chemotherapy achieved overall survival gains among “all comers”, compared with chemotherapy alone. The results were more contrasting for paired immunotherapies combining anti-PD-L1 and anti-cytotoxic T-lymphocyte antigen-4 agents, with the benefit/risk balance not yet fully established. Recently, nivolumab–ipilimumab and two chemotherapy cycles limited patient exposure to chemotherapy and obtained positive results compared with the latter alone. However, those phase III trials included selected patients in good general condition and without active brain metastases. Little is known about immunotherapy and combination immunotherapy–chemotherapy efficacies in never-smokers or patients with tumors harboring an epidermal growth factor receptor ( EGFR ) mutation or anaplastic lymphoma kinase ( ALK ) translocation. In this review, we report our analysis of the main results available on first-line ICI use, as monotherapy or combined or in combination with chemotherapy, to treat metastatic NSCLCs in general and also for specific populations: the elderly, never-smokers, patients with brain metastases, and those with an EGFR mutation or ALK translocation.

The response to immunotherapy has been little investigated in overweight and obese cancer patients. We evaluated the relationships between BMI, toxicity, and survival in patients treated by immunotherapy for metastatic cancer. We included metastatic cancer patients treated by immunotherapy between January 2017 and June 2020 at the Centre Léon Bérard. In total, 272 patients were included: 64% men and 36% women, with a median age of 61.4 years. BMI ≥ 25 in 34.2% and 50% had non-small cell lung cancer (n = 136). Most received monotherapy, with nivolumab in 41.9% and pembrolizumab in 37.9%. Toxicity, mostly dysthyroiditis, occurred in 41%. Median overall survival (OS), estimated by Kaplan–Meier analysis, was significantly longer for patients with a BMI ≥ 25 than for those with a BMI < 25 (24.8 versus 13.7 months HR = 0.63; 95% CI 0.44–0.92, p = 0.015), and for patients experiencing toxicity than for those without toxicity (NR versus 7.8 months, HR = 0.22; 95% CI 0.15–0.33, p < 0.001). Adjusted OS was associated with toxicity, and the occurrence of toxicity was associated with sex and histological features but not with BMI. Thus, being overweight and experiencing toxicity was associated with longer overall survival in patients treated by immunotherapy. More attention should be paid to body composition in the care of cancer patients.

Tumor genomic profiling has a dramatic impact on the selection of targeted treatment and for the identification of resistance mechanisms at the time of progression. Solid tissue biopsies are sometimes challenging, and liquid biopsies are used as a non-invasive alternative when tissue is limiting. The clinical relevance of tumor genotyping through analysis of ctDNA is now widely recognized at all steps of the clinical evaluation process in metastatic non-small cell lung cancer (NSCLC) patients. ctDNA analysis through liquid biopsy has recently gained increasing attention as well in the management of early and locally advanced, not oncogene-addicted, NSCLC. Its potential applications in early disease detection and the response evaluation to radical treatments are promising. The aim of this review is to summarize the landscape of liquid biopsies in clinical practice and also to provide an overview of the potential perspectives of development focusing on early detection and screening, the assessment of minimal residual disease, and its potential role in predicting response to immunotherapy. In addition to available studies demonstrating the clinical relevance of liquid biopsies, there is a need for standardization and well-designed clinical trials to demonstrate its clinical utility.

Introduction: Compared with docetaxel, the phase-III trial, ULTIMATE, showed a significant improvement of progression-free survival (PFS) with paclitaxel–bevacizumab combination (PB) as second- or third-line treatment in advanced non-small cell lung cancer (NSCLC). With the increase of immunotherapy treatment in first-line settings, the optimal treatment after first-line failure must be redefined. Methods: This multicentric retrospective study identified all advanced NSCLC patients treated with PB as second-line therapy and beyond. The main efficacy outcomes assessed were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS). The adverse events were reported according to Common Terminology Criteria for Adverse Events (CTCAE). Results: From January 2010 to February 2020, 314 patients in 16 centers received the PB combination. Most patients were male (55%), with a median age of 60 years (19–82), 95% had adenocarcinoma, 27% had a performance status ⩾2, 45% had brain metastases at the time of inclusion. They mostly received the PB combination either in second (20%) or in third-line (39%), and 28% were treated just after ICI failure. ORR and DCR were 40% and 77%, respectively; median PFS and OS were 5.7 [interquartile range (IQR): 3.2–9.6] and 10.8 [IQR: 5.3–19.6] months, respectively. All grade adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued monotherapy (mostly with bevacizumab) alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compared with those not previously treated with ICI (ICI−): 7.0 [IQR: 4.2–11.0] versus 5.2 [IQR: 2.9–8.8] months, p = 0.01, without statistically significant difference for OS between these two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment and performance status of 0–1. Only a performance status of 0–1 was associated with superior OS. Conclusion: PB combination as second-line treatment or beyond for advanced non-squamous NSCLC had acceptable toxicity and a clinically relevant efficacy and is an option as salvage treatment for these patients, more particularly after ICI progression.

Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D ( ROS1 -positive). Patients ≥18 years of age with stage IIIB/IV, ROS1 -positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1 -positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 . Results from this single-arm cohort of the BFAST trial showed that the clinical efficacy of entrectinib in patients with ROS1 -positive NSCLC, selected using liquid biopsies, is consistent with that seen in previous reports where patients were selected using tissue-based testing methods.

Background Durvalumab, an anti-PD-L1 immune checkpoint inhibitor, after radio-chemotherapy (RCT) has changed the management of locally advanced non-small cell lung cancer (LA NSCLC). A series of retrospective studies have investigated different cut-off of lymphocyte count (LyC) and neutrophil-to-lymphocyte ratio (NLR) to predict survival in LA NSCLC. None of these studies has validated their threshold in an independent group of patients. We wanted to assess the OS prognostic value of NLR and LyC in patients with LA NSCLC treated by RCT and durvalumab, with threshold determination and their validation in an external cohort. Methods Patients were enrolled in four institutions between Oct. 2017 and Jan. 2022. Pre durvalumab LyC, neutrophils count (NC) and NLR were collected. To define NLR and LyC cut-off value predicting survival event, time dependent Receiver Operating Characteristics (ROC) curves was performed. Survival outcomes were estimated by the Kaplan-Meier method and differences were compared using univariate and multivariate Cox proportional hazard models. Results We included 76 patients in the training set and 85 in the test set. The best cut off were 2,94 for NLR and 0,61 G/l for LyC to predict OS in the training set. For patients with NLR > 2,94, univariate analysis showed no significant deterioration in OS in either the training set ( p  = 0,066) or the test set ( p  = 0,12). Patients with LyC > 0,61 G/L, in univariate analysis, had longer OS in training set ( p  = 0,030) and in test set ( p  = 0,0062). This OS increase was not found in multivariate analysis ( p  = 0,057) in training set but was confirmed in test set (0,039). Conclusion LyC > 0,61 G/l is associated with longer OS for LA NSCLC patient’s treated with RCT and durvalumab in univariate analysis. In this context, a particular expectation for organs at risk sparing during RT to avoid lymphopenia seems important. Trial registration Retrospectively registered.

Introduction: Rearranged during transfection (RET) gene fusions are rare genetic drivers in non-small cell lung cancer (NSCLC). Selective RET-inhibitors such as selpercatinib have shown therapeutic activity in early clinical trials; however, their efficacy in the real-world setting is unknown. Methods: A retrospective efficacy and safety analysis was performed on data from RET fusion-positive NSCLC patients who participated in a selpercatinib access program (named patient protocol) between August 2019 and January 2021. Results: Data from 50 patients with RET fusion-positive advanced NSCLC treated with selpercatinib at 27 centers in 12 countries was analyzed. Most patients were Non-Asian (90%), female (60%), never-smokers (74%), with a median age of 65 years (range, 38–89). 32% of the patients had known brain metastasis at the time of selpercatinib treatment. Overall, 13 patients were treatment-naïve, while 37 were pretreated with a median of three lines of therapy (range, 1–8). The objective response rate (ORR) was 68% [95% confidence interval (CI), 53–81] in the overall population. The disease control rate was 92%. The median progression-free survival was 15.6 months (95% CI, 8.8–22.4) after a median follow-up of 9 months. In patients with measurable brain metastases (n = 8) intracranial ORR reached 100%. In total, 88% of patients experienced treatment-related adverse events (TRAEs), a large majority of them being grade 1 or 2. The most common grade ⩾ 3 TRAEs were increased liver enzyme levels (in 10% of patients), prolonged QTc time (4%), abdominal pain (4%), hypertension (4%), and fatigue/asthenia (4%). None of patients discontinued selpercatinib treatment for safety reasons. No new safety concerns were observed, nor where there any treatment-related death. Conclusions: In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated.

The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is an effective first-line therapy for patients with common mutation-positive non-small cell lung cancer (NSCLC). However, almost all patients become resistant to treatment. In some patients, emergence of tertiary mutations is implicated as a resistance mechanism. This study describes patients with NSCLC who acquired the rare mutations, L718Q or G724S, following EGFR TKI treatment. This was a retrospective, observational study undertaken in France from Feb-Nov 2021, in patients with mutation-positive NSCLC with an acquired L718Q or G724S mutation. Primary objectives were description of tumor characteristics, progression, and progression under treatment. Nine eligible patients were identified. Acquired resistance to initial EGFR TKI treatment was associated with T790M emergence in six patients, who then received osimertinib monotherapy. Overall, eight patients received osimertinib monotherapy treatment at some point (average treatment duration: 18.3 months). Following the emergence of L718Q or G724S, patients received chemotherapy (n = 4; two of whom subsequently received afatinib), nivolumab (n = 2), afatinib (n = 2), or immunochemotherapy (n = 1). In the four patients who received afatinib after identification of L718Q or G724S, 2 achieved a partial response, one had stable disease and one had progressive disease. Treatment duration was 1.6-31.7 months. In patients with controlled disease (n = 3), progression-free survival was 6.1-31.7 months. Two of these patients had previously received osimertinib. Currently, there is no consensus regarding the treatment of mutation-positive NSCLC following emergence of the osimertinib resistance mutations, L718Q or G724S. Afatinib appears to be a promising treatment option in this setting.

Purpose The integration of palliative care (PC) into oncological management is recommended well before the end of life. It improves quality of life and symptom control and reduces the aggressiveness of end-of-life care. However, its appropriate timing is still debated. Entry into an early-phase clinical trial (ECT) represents hopes for the patient when standard treatments have failed. It is an opportune moment to integrate PC to preserve the patient’s general health status. The objective of this study was to evaluate the motives for acceptance or refusal of early PC management in patients included in an ECT. Methods Patients eligible to enter an ECT were identified and concomitant PC was proposed. All patients received exploratory interviews conducted by a researcher. Their contents were analyzed in a double-blind thematic analysis with a self-determination model. Results Motives for acceptance (PC acceptors: n  = 27) were both intrinsic (e.g., pain relief, psychological support, anticipation of the future) and extrinsic (e.g., trust in the medical profession, for a relative, to support the advance of research). Motives for refusal (PC refusers: n  = 3) were solely intrinsic (e.g., PC associated with death, negative representation of psychological support, no need for additional care, claim of independence). Conclusions The motives of acceptors and refusers are not internalized in the same way and call for different autonomy needs. Acceptors and refusers are influenced by opposite representations of PC and a different perception of mixed management.

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal–epithelial transition (MET) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48–91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47–69), whereas it was 68% (95% CI, 50–82) in treatment-naïve and 50% (95% CI, 35–65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7–14.3), whereas it was 10.6 months (95% CI, 5.5–15.7) in first-line and 9.1 months (95% CI, 3.1–15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2–23.1). In patients with measurable brain metastases (n = 11), the intracranial ORR was 46% (95% CI, 17–77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting.