Airway replacement using stented aortic matrices: Long-term follow-up and results of the TRITON-01 study in 35 adult patients.

Over the past 25 years, we have demonstrated the feasibility of airway bioengineering using stented aortic matrices experimentally then in a first-in-human trial (n = 13). The present TRITON-01 study analyzed all the patients who had airway replacement at our center to confirm that this innovative approach can be now used as usual care. For each patient, the following data were prospectively collected: postoperative mortality and morbidity, late airway complications, stent removal and status at last follow-up on November 2, 2021. From October 2009 to October 2021, 35 patients had airway replacement for malignant (n = 29) or benign (n = 6) lesions. The 30-day postoperative mortality and morbidity rates were 2.9% (n = 1/35) and 22.9% (n = 8/35) respectively. At a median follow-up of 29.5 months (range 1-133 months), 27 patients were alive. There have been no deaths directly related to the implanted bioprosthesis. Eighteen patients (52.9%) had stent-related granulomas requiring a bronchoscopic treatment. Ten among 35 patients (28.6%) achieved a stent free survival. The actuarial 2- and 5-year survival rates (Kaplan-Meier estimates) were respectively 88% and 75%. The TRITON-01 study confirmed that airway replacement using stented aortic matrices can be proposed as usual care at our center. Clinicaltrials.gov Identifier: NCT04263129.

Adoptive cell therapies in thoracic malignancies.

Immunotherapy has gained great interest in thoracic malignancies in the last decade, first in non-small cell lung cancer (NSCLC), but also more recently in small-cell lung cancer (SCLC) and malignant pleural mesothelioma (MPM). However, while 15-20% of patients will greatly benefit from immune checkpoint blockers (ICBs), a vast majority will rapidly exhibit resistance. Reasons for this are multiple: non-immunogenic tumors, immunosuppressive tumor microenvironment or defects in immune cells trafficking to the tumor sites being some of the most frequent. Current progress in adoptive cell therapies could offer a way to overcome these hurdles and bring effective immune cells to the tumor site. In this review, we discuss advantages, limits and future perspectives of adoptive cell therapy (ACT) in thoracic malignancies from lymphokine-activated killer cells (LAK), cytokine-induced killer cells (CIK), natural killer cells (NK), dendritic cells (DC) vaccines and tumor-infiltrating lymphocytes (TILs) to TCR engineering and CARs. Trials are still in their early phases, and while there may still be many limitations to overcome, a combination of these different approaches with ICBs, chemotherapy and/or radiotherapy could vastly improve the way we treat thoracic cancers.

Anti-PD-(L)1 for KRAS-mutant advanced non-small-cell lung cancers: a meta-analysis of randomized-controlled trials.

PURPOSE: The most frequent mutation in advanced non-small-cell lung cancer (NSCLC), Kirsten rat-sarcoma viral oncogene (KRAS) is found in 20-25% of these patients' tumors. While phase III trials on therapies targeting KRAS, especially KRASG12C, are ongoing, the clinical efficacy of anti-programmed death protein-1 (PD-1) or its ligand (PD-L1) against KRAS-mutant NSCLCs remains a topic of debate. METHODS: This meta-analysis examined randomized-trial data comparing first- or second-line anti-PD-(L)1 with or without chemotherapy vs. chemotherapy alone for advanced KRAS-mutant NSCLCs. Outcome measures included overall survival (OS) and progression-free survival (PFS). Analyses were computed using the Cochrane method of collaboration for meta-analyses, with Review Manager software (RevMan version 5.3; Oxford, UK). RESULTS: We analyzed 3 first-line trials (IMpower-150, Keynote-189 and Keynote-042) and 3 second-line trials (Oak, Poplar and CheckMate-057) that included 1313 NSCLCs (386 KRAS-mutant and 927 KRAS wild-type tumors). For KRAS-mutant NSCLCs, anti-PD-(L)1 with or without chemotherapy was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.59 [0.49-0.72]; p < 0.00001) and PFS (0.58 [0.43-0.78]; p = 0.0003) compared to chemotherapy alone. OS benefited in both first- and second-line trials. OS for patients with KRAS-mutant NSCLCs was significantly longer than that for those with KRAS wild-type tumors (p = 0.001). CONCLUSIONS: Anti-PD-(L)1 with or without chemotherapy seemed to achieve longer OS and PFS than chemotherapy alone for patients with KRAS-mutant and wild-type KRAS advanced NSCLCs, with an even greater OS benefit for the former.

Feasibility of Bioengineered Tracheal and Bronchial Reconstruction Using Stented Aortic Matrices.

Importance: Airway transplantation could be an option for patients with proximal lung tumor or with end-stage tracheobronchial disease. New methods for airway transplantation remain highly controversial. Objective: To establish the feasibility of airway bioengineering using a technique based on the implantation of stented aortic matrices. Design, Setting, and Participants: Uncontrolled single-center cohort study including 20 patients with end-stage tracheal lesions or with proximal lung tumors requiring a pneumonectomy. The study was conducted in Paris, France, from October 2009 through February 2017; final follow-up for all patients occurred on November 2, 2017. Exposures: Radical resection of the lesions was performed using standard surgical techniques. After resection, airway reconstruction was performed using a human cryopreserved (-80°C) aortic allograft, which was not matched by the ABO and leukocyte antigen systems. To prevent airway collapse, a custom-made stent was inserted into the allograft. In patients with proximal lung tumors, the lung-sparing intervention of bronchial transplantation was used. Main Outcomes and Measures: The primary outcome was 90-day mortality. The secondary outcome was 90-day morbidity. Results: Twenty patients were included in the study (mean age, 54.9 years; age range, 24-79 years; 13 men [65%]). Thirteen patients underwent tracheal (n = 5), bronchial (n = 7), or carinal (n = 1) transplantation. Airway transplantation was not performed in 7 patients for the following reasons: medical contraindication (n = 1), unavoidable pneumonectomy (n = 1), exploratory thoracotomy only (n = 2), and a lobectomy or bilobectomy was possible (n = 3). Among the 20 patients initially included, the overall 90-day mortality rate was 5% (1 patient underwent a carinal transplantation and died). No mortality at 90 days was observed among patients who underwent tracheal or bronchial reconstruction. Among the 13 patients who underwent airway transplantation, major 90-day morbidity events occurred in 4 (30.8%) and included laryngeal edema, acute lung edema, acute respiratory distress syndrome, and atrial fibrillation. There was no adverse event directly related to the surgical technique. Stent removal was performed at a postoperative mean of 18.2 months. At a median follow-up of 3 years 11 months, 10 of the 13 patients (76.9%) were alive. Of these 10 patients, 8 (80%) breathed normally through newly formed airways after stent removal. Regeneration of epithelium and de novo generation of cartilage were observed within aortic matrices from recipient cells. Conclusions and Relevance: In this uncontrolled study, airway bioengineering using stented aortic matrices demonstrated feasibility for complex tracheal and bronchial reconstruction. Further research is needed to assess efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT01331863.

Fluorine 18 fluorodeoxyglucose PET/CT volume-based indices in locally advanced non-small cell lung cancer: prediction of residual viable tumor after induction chemotherapy.

PURPOSE: To study whether volume-based indices of fluorine 18 fluorodeoxyglucose positron emission tomographic (PET)/computed tomographic (CT) imaging is an accurate tool to predict the amount of residual viable tumor after induction chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This study was approved by institutional review board with waivers of informed consent. Twenty-two patients with locally advanced NSCLC underwent surgery after induction chemotherapy. All had pre- and posttreatment FDG PET/CT scans. CT largest diameter, CT volume, maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumor volume (TV), and total lesion glycolysis of primary tumor were calculated. Changes in tumor measurements were determined by dividing follow-up by baseline measurement (ratio index). Amounts of residual viable tumor, necrosis, fibrous tissue, inflammatory infiltrate, and Ki-67 proliferative index were estimated on resected tumor. Correlations between imaging indices and histologic parameters were estimated by using Spearman correlation coefficients or Mann-Whitney tests. RESULTS: No baseline or posttreatment indices correlated with percentage of residual viable tumor. TV ratio was the only index that correlated with percentage of residual viable tumor (r = 0.61 [95% confidence interval: 0.24, 0.81]; P = .003). Conversely, SUVmax and SUVmean ratios were only indices correlated with Ki-67 (r = 0.62 [95% confidence interval: 0.24, 0.82]; P = .003; and r = 0.60 [95% confidence interval: 0.21, 0.81]; P = .004, respectively). Total lesion glycolysis ratio was moderately correlated with residual viable tumor (r = 0.53 [95% confidence interval: 0.13, 0.78]; P = .01) and with Ki-67 (r = 0.57 [95% confidence interval: 0.18, 0.80]; P = .006). No ratios were correlated with presence of inflammatory infiltrate or foamy macrophages. CONCLUSION: TV and total lesion glycolysis ratios were the only indices correlated with residual viable tumor after induction chemotherapy in locally advanced NSCLC.

First-line concomitant EGFR-TKI + chemotherapy versus EGFR-TKI alone for advanced EGFR-mutated NSCLC: a meta-analysis of randomized phase III trials.

INTRODUCTION: A tyrosine-kinase inhibitor (TKI) is indicated as a first-line treatment for patients with non-small-cell lung cancer (NSCLC) harboring an epidermal growth-factor - receptor (EGFR) mutation. Chemotherapy (ChT) given in combination with an EGFR-TKI in this setting is of interest. METHODS: We conducted a meta-analysis of phase III randomized trials comparing EGFR-TKI + ChT vs. EGFR-TKI alone as first-line therapy for advanced NSCLC harboring an activating EGFR mutation. RESULTS: Three studies evaluated gefitinib + ChT (NEJ009, GAP-Brain, and Noronha et al.) and another evaluated osimertinib + ChT (FLAURA-2). Those four eligible studies included 1413 patients with non-squamous NSCLCs, 826 (58%) with an exon-19 deletion (ex19del) and 541 (38%) with EGFRL858R. The EGFR-TKI + ChT combination was significantly associated with prolonged PFS (hazard ratio [HR]: 0.52 [95% confidence interval (CI): 0.45-0.59]; p < 0.0001) and OS (HR: 0.69 [0.52-0.93]; p = 0.01). PFS was particularly improved for patients with brain metastases (HR: 0.41[0.33-0.51]; p < 0.00001). CONCLUSIONS: For patients with untreated, advanced, EGFR-mutated NSCLCs, the EGFR-TKI + ChT combination, compared to EGFR-TKI alone, was associated with significantly prolonged PFS and OS. However, further studies are needed to identify which patients will benefit the most from the combination. REGISTRATION: PROSPERO CRD42024508055.

Prognostic implications of volume-based measurements on FDG PET/CT in stage III non-small-cell lung cancer after induction chemotherapy.

PURPOSE: We sought to determine whether metabolic volume-based measurements on FDG PET/CT scans could provide additional information for predicting outcome in patients with stage III non-small-cell lung cancer (NSCLC) treated with induction chemotherapy. METHODS: Included in the study were 32 patients with stage III NSCLC who were treated with induction platinum-based chemotherapy followed in 21 by surgery. All patients had an FDG PET/CT scan before and after the induction chemotherapy. Tumours were delineated using adaptive threshold methods. The SUVmax, SUVpeak, SUVmean, tumour volume (TV), total lesion glycolysis (TLG), and volume and largest diameter on the CT images (CTV and CTD, respectively) were calculated. Index ratios of the primary tumour were calculated by dividing the follow-up measurements by the baseline measurements. The prognostic value of each parameter for event-free survival (EFS) was determined using Cox regression models. RESULTS: The median follow-up time was 19 months (range 6-43 months). Baseline PET and CT parameters were not significant prognostic factors. After induction therapy, only SUVmax, SUVpeak, SUVmean, TV, TLG and CTV were prognostic factors for EFS, in contrast to CTD. Of the index ratios, only TV and TLG ratios were prognostic factors for EFS. Patients with a TLG ratio <0.48 had a longer EFS than those with a TLG ratio >0.48 (13.9 vs. 9.2 months, p = 0.04). After adjustment for the effect of surgical treatment, all the parameters significantly correlated with EFS remained significant. CONCLUSION: SUV, metabolic volume-based indices, and CTV after induction chemotherapy give independent prognostic information in stage III NSCLC. However, changes in metabolic TV and TLG under induction treatment provide more accurate prognostic information than SUV alone, and CTD and CTV.

[Postoperative radiotherapy in non-small cell lung cancer stage IIIA - N2: Focus and perspectives]. / La radiothérapie postopératoire dans les cancers non à petites cellules de stade IIIA ­ N2 : mise au point et perspectives.

Patients with resectable stage IIIA - N2 lung cancer represent a very heterogeneous population with variable risks of postoperative recurrence depending on the type of N2 involvement (unisite N2, multisite N2, bulky N2, extra-capsular rupture, incomplete resection…). This heterogeneity associated with the difficulty of carrying out prospective randomized studies with sufficient power in stages IIIA - 2, results in the absence of clear and consensual recommendations (except for stages IIIA - N2 resectable R0, since LungART and PORT-C studies). The objective of this article is to make an update on the place of postoperative radiotherapy in the management of stages IIIA - N2 following the publication of two recent randomized trials (PORT-C and LungART) but also compare them fort a better understanding of the current issues raised by these first published results. Indeed, these two trials do not find any benefit in terms of progression free survival and overall survival of postoperative radiotherapy but exploratory analyzes from these two studies seem to show a potential benefit of postoperative in some pN2 populations at high risk of locoregional recurrence (N2 multisite, N2 bulky…). In addition, the advent of immunotherapy (atezolizumab or pembrolizumab) and targeted therapies (osimertinib) in the adjuvant situation are redebating the place of a possible indication for postoperative radiotherapy in stage IIIA - 2.

Total Metabolic Tumor Volume on 18F-FDG PET/CT Is a Useful Prognostic Biomarker for Patients with Extensive Small-Cell Lung Cancer Undergoing First-Line Chemo-Immunotherapy.

Background: We aimed to evaluate the prognostic value of imaging biomarkers on 18F-FDG PET/CT in extensive-stage small-cell lung cancer (ES-SCLC) patients undergoing first-line chemo-immunotherapy. Methods: In this multicenter and retrospective study, we considered two cohorts, depending on the type of first-line therapy: chemo-immunotherapy (CIT) versus chemotherapy alone (CT). All patients underwent baseline 18-FDG PET/CT before therapy between June 2016 and September 2021. We evaluated clinical, biological, and PET parameters, and used cutoffs from previously published studies or predictiveness curves to assess the association with progression-free survival (PFS) or overall survival (OS) with Cox prediction models. Results: Sixty-eight patients were included (CIT: CT) (36: 32 patients). The median PFS was 5.9:6.5 months, while the median OS was 12.1:9.8 months. dNLR (the derived neutrophils/(leucocytes-neutrophils) ratio) was an independent predictor of short PFS and OS in the two cohorts (p < 0.05). High total metabolic tumor volume (TMTVhigh if > 241 cm3) correlated with outcomes, but only in the CIT cohort (PFS for TMTVhigh in multivariable analysis: HR 2.5; 95%CI 1.1-5.9). Conclusion: Baseline 18F-FDG PET/CT using TMTV could help to predict worse outcomes for ES-SCLC patients undergoing first-line CIT. This suggests that baseline TMTV may be used to identify patients that are unlikely to benefit from CIT.

Preliminary results in tracheal replacement using stented aortic matrices for primary extensive tracheal cancer.

Objective: Recent studies have demonstrated the feasibility and favorable long-term results of tracheobronchial replacement using stented cryopreserved aortic allografts. We propose to investigate the outcomes of this emerging technique in the subgroup of patients with extensive tracheal cancer. Methods: This study was based on 13 patients with primary extensive tracheal cancer extracted from the prospective registry TRITON-01 (ClinicalTrials.gov Identifier: NCT04263129), which included 40 patients in total. We analyzed early and late outcomes in this subset of patients. Results: From March 2019 to September 2022, 13 patients were included in the study. There were 9 female and 4 male patients, with a mean age of 53.9 years [36-71 years]. They had tracheal replacement for extended adenoid cystic carcinoma (n = 11), squamous cell carcinoma (n = 1), and mucoepidermoid carcinoma (n = 1). A venovenous extracorporeal membrane oxygenation was used in the 6 last cases. The mean length of resection was 81 mm [50-120 mm]. There was no 30-day postoperative mortality. A complete resection (R0) was achieved in 11 patients. The main late complications consisted of tracheal granulomas related to the stent and requiring repeated bronchoscopies (n = 9), pneumonia (n = 3), airway infection (n = 1), bronchoesophageal fistula (n = 1), mechanical stent obstruction requiring change (n = 2), and mediastinitis treated by antibiotics, drainage, and omentoplasty (n = 1). With a maximal follow-up of 3 years and 7 months, cancer recurrence was observed in 2 patients. All patients were alive at last follow-up except 2 (84.6%). Conclusions: Airway replacement using stented CAA represents a feasible and promising solution for extensive tracheal cancer.

Successful sequential tyrosine kinase inhibitors to overcome a rare compound of EGFR exon 18-18 and EGFR amplification: A case report.

Background: New mutational detection techniques like next-generation sequencing have resulted in an increased number of cases with uncommon mutation and compound mutations [3%-14% of all epidermal growth factor receptor (EGFR) mutations]. In rare exon 18 mutations (3%-6%), G719X and E709X represent the majority, but CMut associating these exon 18 points mutations are even rarer, making the understanding of the impact of epidermal growth factor receptor tyrosine kinase inhibitors still limited. Three generations of EGFR tyrosine kinase inhibitors (TKIs) are available to target EGFR mutations, but according to the types of mutations, the sensitivity to TKI is different. Afatinib, osimertinib, and neratinib have showed some effectiveness in single exon 18, but no report has precisely described their efficiency and acquired mechanism of resistance in a CMut of exon 18-18 (G719A and E709A). Case presentation: We report a case of a 26-year-old woman with bilateral advanced adenocarcinoma of the lung harboring a compound mutation associating G719A and E709A in exon 18, who developed an EGFR amplification as resistance mechanism to osimertinib. She presented a significant clinical and morphological response under sequential TKIs treatment (afatinib, osimertinib, and then neratinib). Conclusion: A non-small cell lung cancer (NSCLC) with rare compound mutation exon 18-exon 18 (G719A and E709A) and EGFR amplification can be overcome with adapted sequential second- and third-generation TKIs. This report has potential implications in guiding decisions for the treatment of these rare EGFR mutations.

Immune Checkpoint Inhibitors for Patients Aged ≥ 75 Years with Advanced Cancer in First- and Second-Line Settings: A Meta-Analysis.

BACKGROUND: The impact of aging on the effectiveness of immune checkpoint inhibitors (ICIs) remains controversial, and little is known on the subject in adults aged ≥ 75 years. OBJECTIVE: The objective of this comprehensive meta-analysis was to assess the efficacy of ICIs in patients aged ≥ 75 years. METHODS: We performed a meta-analysis of published randomized controlled trials concerning ICIs (as monotherapy or in combination) versus standard therapy in patients with advanced solid tumors between January 2010 and January 2020. We compared overall survival between older (aged ≥ 75 years) and younger (< 75 years) patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) were collected and pooled. The secondary endpoint focused on the impact of the use of ICIs in first- and second-line settings. RESULTS: In total, 15 phase III studies evaluating anti-programmed cell death 1 (anti-PD-1) (nivolumab or pembrolizumab), anti-programmed cell death ligand 1 (anti-PD-L1) (atezolizumab or avelumab), or anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) (ipilimumab) therapies were included. Enrolled patients had non-small-cell lung cancer, renal cell carcinoma, melanoma, head and neck squamous cell carcinoma, or gastric cancer. Eight studies assessed treatment in the first-line setting and seven in the second-line setting. The median age was 64 years, with 906 patients aged ≥ 75 years (552 in first line, 354 in second line) and 8741 were aged < 75 years (4992 in first line, 3749 in second line). In the first-line setting, HRs for death were 0.78 (95% CI 0.61-0.99) in patients aged ≥ 75 years versus 0.84 (95% CI 0.71-1.00) in those aged < 75 years. In the second-line setting, HRs for death were 1.02 (95% CI 0.77-1.36) in patients aged ≥ 75 years versus 0.68 (95% CI 0.61-0.75) in those aged < 75 years, with a statistically significant difference observed between subgroups (p = 0.009 for interaction). CONCLUSIONS: ICIs appear to be effective in patients aged ≥ 75 years. However, the survival benefit is mainly observed in first-line treatment and remains unclear in the second-line setting.

First-line immune-checkpoint inhibitor plus chemotherapy versus chemotherapy alone for extensive-stage small-cell lung cancer: a meta-analysis.

INTRODUCTION: Platin-based chemotherapy (CT) has long been the first-line standard-of-care for patients with extensive-stage small-cell lung cancer (ES-SCLC). Adding immune-checkpoint inhibitor(s) to CT (ICI+CT) in this setting is an option of interest, although its benefit is apparently modest. METHODS: This meta-analysis was conducted on randomized trials comparing first-line ICI+CT versus CT alone for ES-SCLC. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), response at 12 months and adverse events (AEs). Subgroup analyses were computed according to the immunotherapy used, performance status (PS), age, platinum salt, liver metastases and brain metastases at diagnosis. RESULTS: The literature search identified one randomized phase II (ECOG-ACRIN-5161) and four phase III trials (CASPIAN, IMPOWER-133, KEYNOTE-604 and Reck et al. 2016) that included 2775 patients (66% males, 95% smokers, median age: 64 years, PS = 0 or 1). ICI+CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS [0.82 (0.75-0.89); p < 0.00001] and PFS [0.81 (0.75-0.87); p < 0.00001], with OS benefits for anti-PD-L1 [0.73 (0.63-0.85); p < 0.0001] or anti-PD-1 [0.76 (0.63-0.93); p < 0.006] but not for anti-CTLA-4 [0.90 (0.80-1.01), p = 0.07]. ORRs for ICI+CT or CT alone were comparable [odds ratio 1.12 (0.97-1.00); p = 0.12], but responses at 12 months favored ICI+CT [4.16 (2.81-6.17), p < 0.00001]. Serious grade-3/4 AEs were more frequent with ICI+CT [odds ratio 1.18 (1.02-1.37); p = 0.03]. Compared with CT, no ICI+CT benefit was found for ES-SCLC with brain metastases at diagnosis [HR 1.14 (0.87-1.50); p = 0.34]. CONCLUSIONS: First-line ICI+CT appears to be superior to CT alone for ES-SCLC except for patients with brain metastases at diagnosis.

First-line angiogenesis inhibitor plus erlotinib versus erlotinib alone for advanced non-small-cell lung cancer harboring an EGFR mutation.

PURPOSE: Erlotinib is indicated as first-line treatment for patients with non-small-cell lung cancer (NSCLC) harboring an epidermal growth-factor-receptor (EGFR) mutation. Addition of a vascular endothelial growth factor (VEGF) inhibitor (anti-VEGF) in combination with the tyrosine-kinase inhibitor erlotinib in this setting is controversial. METHODS: We conducted a meta-analysis of randomized trials comparing anti-VEGF plus erlotinib vs erlotinib alone as first-line therapy for advanced NSCLC harboring an EGFR mutation. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and median duration of response (DOR). A fixed-effect model was used. RESULTS: Four studies evaluated bevacizumab + erlotinib (ARTEMIS, NEJ026, J025667, Stinchcombe et al.), and another evaluated ramucirumab + erlotinib (RELAY). These five eligible studies included 1230 non-squamous NSCLC patients, 654 (53.2%) with exon 19 deletion (ex19del) and 568 (46.8%) with EGFRL858R. Patients were predominantly women (63%), Asians (85%) and non-smokers (60%); the median age was 64 years. The combination (anti-VEGF + erlotinib) was significantly associated with prolonged PFS (hazards ratio [HR] 0.59 [95% confidence interval (CI) 0.51-0.69]; p < 0.00001). The combination achieved significantly longer median DOR (p < 0.005). Based on interim analyses, OS (HR 0.90 [0.68-1.19]; p = 0.45) and ORR (odds ratio 1.19 [95% CI 0.91-1.55]; p = 0.21 were comparable. CONCLUSIONS: For patients with untreated, advanced, EGFR-mutation-harboring NSCLCs, the anti-VEGF + erlotinib combination, compared to erlotinib alone, was associated with significantly prolonged PFS but mature data for OS are needed to confirm the benefit of this strategy.

First-line PD-1/PD-L1 inhibitor plus chemotherapy vs chemotherapy alone for negative or < 1% PD-L1-expressing metastatic non-small-cell lung cancers.

AIMS: Single-agent anti-PD-1/PD-L1 clinical efficacy against < 1% PD-L1-expressing non-small-cell lung cancers (NSCLCs) is controversial. METHODS: This meta-analysis examined randomized-trial data comparing first-line PD-1/PD-L1-inhibitor + chemotherapy (CT) vs CT alone for advanced < 1% PD-L1 NSCLCs. Outcome measures included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). RESULTS: IMpower (atezolizumab + CT), Keynote (pembrolizumab + CT) and CheckMate (nivolumab + CT) trials included 2037 NSCLCs (1246 PD-L1-negative; 791 < 1% PD-L1 expression). Anti-PD-1/PD-L1 + CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.75 [0.63-0.89]; p = 0.0008) and PFS (0.72 [0.65-0.80]; p < 0.0001), and higher ORR (odds ratio 2.06 [1.50-2.83]; p < 0.0001). CONCLUSIONS: First-line anti-PD-1/PD-L1 + CT combination appears superior to CT alone for advanced, < 1% PD-L1-expressing NSCLCs for OS, PFS and ORR.

Budget Impact Analysis of Fixed Dose Versus Weight-Based Dosing Regimen of Nivolumab and Pembrolizumab in the Treatment of Non-Small Cell Lung Cancer.

In 2018, dosing regimens of the two most prescribed immune check point inhibitors (ICI), nivolumab (Opdivo®) and pembrolizumab (Keytruda®), in the treatment of lung cancer were changed from weight-based dosing to fixed dosing. The aim of this study was to compare the economic impact of this change in our university hospital group and then across Ile-de-France, the most inhabited French region. A budget impact analysis (BIA) has been performed on the French public health insurance data. The duration of treatment and the weight of the patients were calculated using data from the patients treated at our health facility and from clinical studies. The cost of treatment was calculated at the local level of our health facility and then for Ile-de-France. Our model demonstrates an additional cost of €550,115 in our hospital and €9,704,778 in Ile-de-France for a fixed dose prescription in 2018. In 2019, the BIA concluded an additional cost, according to the respective low and high assumptions, of €556,969 and €756,544 locally and € 10,201,027 to €14,486,141 for Ile-de-France for an equivalent efficacy between the two different drug dosing regimens of nivolumab and pembrolizumab. The adoption of the fixed dose regimen would lead, according to the least expensive hypothesis, to an additional cost of 26% for the ICI. These results encourage reflection on the strict adoption of this dosage modification. The option of maintaining the free choice between a prescription adapted to weight or in a fixed dose seems a relevant option and should be considered.

Development, validation and clinical impact of a prediction model for 6-month mortality in older cancer patients: the GRADE.

BACKGROUND: To develop, validate, and assess the clinical impact of a clinical score to predict a 6-month mortality risk among older cancer patients. RESULTS: The mean age was 81.2 ± 6.1 years (women: 54%, various cancers, metastatic cancer: 45%). The score, namely the GRADE, included two geriatric variables (unintentional weight loss, impaired mobility), two oncological variables (cancer site, cancer extension), and exclusively supportive care. Up to a 14% risk of early death, the decision curves suggest that cancer treatment should be instated. CONCLUSION: We have developed and validated a simple score, easy to implement in daily oncological practice, to predict early death among older cancer patients which could guide oncologists in their treatment decisions. METHODS: 603 outpatients prospectively included in the Physical Frailty in Elderly Cancer patients cohort study. We created a multivariate prediction model by evaluating the strength of the individual components of the Geriatric Assessment regarding risk of death at 6 months. Each component was evaluated by univariate analysis and the significant variables (P ≤ 0.20) were carried on as covariates in the multivariate cox proportion hazard analysis. The beta coefficients from the model were used to build a point-based scoring system. Clinical impact was assessed using decision curves.

[Efficacy of weekly epoetin Beta in the treatment of chemotherapy-induced anemia in solid tumors]. / Efficacité de l'époétine bêta hebdomadaire dans l'anémie des tumeurs solides sous chimiothérapie.

OBJECTIVE: The aim of the study was to assess the efficacy and safety of epoetin beta once-weekly in anemic patients with solid tumors treated with chemotherapy. METHOD: Prospective, open-label, multicenter, single-arm study of epoetin beta 30 000 I.U. once-weekly in anemic patients with solid tumors receiving chemotherapy (n = 365). RESULTS: Epoetin beta increased mean haemoglobin (Hb) levels from 10.3 +/- 0.9 g/dL at baseline to 12.3+/-2.0 g/dL at week 12. The response rate was achieved in 61% (CI 95%: 55-68) of the patients. The mean Hb level increased was 1.8 g/dL (CI 95%: 1.5-2,0); in lung cancer patients (n = 102) Hb increase was 2.7 g/dL. Treatment with epoetin beta was well tolerated; only 1.4 % patients had thrombotic events. CONCLUSION: Epoetin beta (30 000 I.U. once weekly) increased Hb levels and was well-tolerated to correct anemia in patients with solid tumors treated with chemotherapy.

Monitoring anti-PD-1-based immunotherapy in non-small cell lung cancer with FDG PET: introduction of iPERCIST.

BACKGROUND: Immunotherapy represents a new therapeutic approach in non-small cell lung carcinoma (NSCLC) with the potential for prolonged benefits. Because of the systemic nature and heterogeneity of tumoral diseases, as well as the immune restoration process induced by immunotherapy, the assessment of therapeutic efficacy is challenging, and the role of FDG PET is not well established. We evaluated the potential of FDG PET to monitor NSCLC patients treated with a checkpoint inhibitor. RESULTS: This was a retrospective analysis of 28 NSCLC patients treated with nivolumab, a programmed cell death 1 (PD-1) blocker. All patients underwent a PET scan before treatment (SCAN-1) and another scan 2 months later (SCAN-2). Disease progression was assessed by immune PET Response Criteria in Solid Tumors (iPERCIST), which was adapted from PERCIST; and the immune Response Evaluation Criteria in Solid Tumors (iRECIST). iPERCIST is a dual-time-point evaluation of "unconfirmed progressive metabolic disease" (UPMD) status at SCAN-2. UPMD at SCAN-2 was re-evaluated after 4 weeks with SCAN-3 to confirm PMD. Patients with complete/partial metabolic response (CMR or PMR) or stable metabolic disease (SMD) at SCAN-2 or -3 were considered responders. Patients with UPMD confirmed at SCAN-3 were considered non-responders. The Kaplan-Meier method was used to estimate survival. At SCAN-2, we found 9/28 cases of PMR, 4/28 cases of SMD, 2/28 cases of CMR, and 13/28 cases of UPMD. Four of the 13 UPMD patients were classified as responders at SCAN-3 (PMR n = 1, SMD n = 3). The remaining nine UPMD patients were classified as non-responders due to clinical degradation, and treatment was stopped. The median follow-up was 16.7 months [3.6-32.2]. Responders continued treatment for a mean of 10.7 months [3.8-26.3]. Overall survival was longer for responders than that for non-responders (19.9 vs. 3.6 months, log rank p = 0.0003). The 1-year survival rates were 94% for responders and 11% for non-responders. A comparison with iRECIST showed reclassification in 39% (11/28) of patients with relevant additional prognostic information. CONCLUSIONS: iPERCIST dual-time-point evaluation might be a powerful tool for evaluating anti-PD-1-based immunotherapy, with the ability to identify patients who can benefit most from treatment. The prognostic value of iPERCIST criteria should be confirmed in large prospective multicentric studies.