Nationwide Audit of Postoperative Mortality and Complications After Digestive Cancer Surgery: Will New Legal Thresholds be Sufficient?

BACKGROUND: French policymakers recently chose to regulate high-risk digestive cancer surgery (DCS). A minimum of five cases per year should be performed for each of the following types of curative cancer surgery: esophagus/esogastric junction (ECS), stomach (GCS), liver (LCS, metastasis included), pancreas (PCS), and rectum (RCS). This study aimed to evaluate the hypothetical beneficial effects of the new legal minimal volume thresholds on the rates of 90-day postoperative mortality (90POM) for each high-risk DCS. METHODS: This nationwide observational population-based cohort study used data extracted from the French National Health Insurance Database from 1 January 2015-31 December 2017. Mixed-effects logistic regression models were performed to estimate the independent effect of hospital volume. RESULTS: During the study period, 61,169 patients (57.1 % male, age 69.7 ±12.2 years) underwent high-risk DCS including ECS (n = 4060), GCS (n = 5572), PCS (n = 8598), LCS (n = 10,988), and RCS (n = 31,951), with 90POM of 6.6 %, 6.9 %, 6.0 %, 5.2 %, and 2.9 %, respectively. For hospitals fulfilling the new criteria, 90POM was lower after adjustment only for LCS (odds ratio [OR],15.2; 95 % confidence interval [CI], 9.5-23.2) vs OR, 7.6; 95 % CI, 5.2-11.0; p < 0.0001) and PCS (OR, 3.6; 95 % CI, 1.7-7.6 vs OR, 2.1; 95 % CI, 1.0-4.4; p<0.0001). With higher thresholds, all DCSs showed a lower adjusted risk of 90POM (e.g., OR, 0.38; 95 % CI, 0.28-0.51) for PCS of 40 or higher. CONCLUSION: Based on retrospective data, thresholds higher than those promulgated would better improve the safety of high-risk DCS. New policies aiming to further centralize high-risk DCS should be considered, associated with a clear clinical pathway of care for patients to improve accessibility to complex health care in France.

Multicentric development and evaluation of [18F]FDG PET/CT and CT radiomic models to predict regional and/or distant recurrence in early-stage non-small cell lung cancer treated by stereotactic body radiation therapy.

PURPOSE: To develop machine learning models to predict regional and/or distant recurrence in patients with early-stage non-small cell lung cancer (ES-NSCLC) after stereotactic body radiation therapy (SBRT) using [18F]FDG PET/CT and CT radiomics combined with clinical and dosimetric parameters. METHODS: We retrospectively collected 464 patients (60% for training and 40% for testing) from University Hospital of Liège and 63 patients from University Hospital of Brest (external testing set) with ES-NSCLC treated with SBRT between 2010 and 2020 and who had undergone pretreatment [18F]FDG PET/CT and planning CT. Radiomic features were extracted using the PyRadiomics toolbox®. The ComBat harmonization method was applied to reduce the batch effect between centers. Clinical, radiomic, and combined models were trained and tested using a neural network approach to predict regional and/or distant recurrence. RESULTS: In the training (n = 273) and testing sets (n = 191 and n = 63), the clinical model achieved moderate performances to predict regional and/or distant recurrence with C-statistics from 0.53 to 0.59 (95% CI, 0.41, 0.67). The radiomic (original_firstorder_Entropy, original_gldm_LowGrayLevelEmphasis and original_glcm_DifferenceAverage) model achieved higher predictive ability in the training set and kept the same performance in the testing sets, with C-statistics from 0.70 to 0.78 (95% CI, 0.63, 0.88) while the combined model performs moderately well with C-statistics from 0.50 to 0.62 (95% CI, 0.37, 0.69). CONCLUSION: Radiomic features extracted from pre-SBRT analog and digital [18F]FDG PET/CT outperform clinical parameters in the prediction of regional and/or distant recurrence and to discuss an adjuvant systemic treatment in ES-NSCLC. Prospective validation of our models should now be carried out.

Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer. METHODS: In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0-2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m2 from day 1 to day 3]) or oral topotecan (2·3 mg/m2 from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02738346. FINDINGS: Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0-37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9-5·5 vs 2·7 months, 2·3-3·2; stratified hazard ratio 0·57, 90% CI 0·41-0·73; p=0·0041). The most frequent grade 3-4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group. INTERPRETATION: Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer. FUNDING: Amgen and the French Lung Cancer Group (Groupe Français de Pneumo-Cancérologie).

Uncommon MET mutational landscape in a non-small cell lung cancer patient treated with crizotinib: Case report.

Background: MET exon 14 (METex14) skipping mutations are oncogenic drivers observed in approximately 3-4% of non-small cell lung cancers (NSCLC). Several distinct genetic alterations leading to METex14 have been reported but clinical significances of rare mutations are not well defined as well as outcomes of patients upon MET inhibitors (METi). Case presentation: This report presents the case of a patient with metastatic NSCLC harboring an uncommon MET mutational landscape including notably a novel METex14 mutation (R1022L). Dramatic but transient efficacy was observed under crizotinib, due to early occurrence of acquired both on- and off-target mechanisms of resistance such as MET D1246H mutation and wild-type KRAS amplification. Conclusion: Our case provides additional data on MET rare oncogenic variants and their sensitivity to METi. Systematic assessment of post-tyrosine kinase inhibitor tumor sample remains critical to identify on- and off-target mechanisms that may represent therapeutically targetable drivers in resistant patients.

Coupling imaging mass cytometry with Alcian blue histochemical staining for a single-slide approach.

Imaging mass cytometry (IMC) is a metal mass spectrometry-based method allowing highly multiplex immunophenotyping of cells within tissue samples. However, some limitations of IMC are its 1-µm resolution and its time and costs of analysis limiting respectively the detailed histopathological analysis of IMC-produced images and its application to small selected tissue regions of interest (ROI) of one to few square millimeters. Coupling on a single-tissue section, IMC and histopathological analyses could permit a better selection of the ROI for IMC analysis as well as co-analysis of immunophenotyping and histopathological data until the single-cell level. The development of this method is the aim of the present study in which we point to the feasibility of applying the IMC process to tissue sections previously Alcian blue-stained and digitalized before IMC tissue destructive analyses. This method could help to improve the process of IMC in terms of ROI selection, time of analysis, and the confrontation between histopathological and immunophenotypic data of cells.

Identification of CT radiomic features robust to acquisition and segmentation variations for improved prediction of radiotherapy-treated lung cancer patient recurrence.

The primary objective of the present study was to identify a subset of radiomic features extracted from primary tumor imaged by computed tomography of early-stage non-small cell lung cancer patients, which remain unaffected by variations in segmentation quality and in computed tomography image acquisition protocol. The robustness of these features to segmentation variations was assessed by analyzing the correlation of feature values extracted from lesion volumes delineated by two annotators. The robustness to variations in acquisition protocol was evaluated by examining the correlation of features extracted from high-dose and low-dose computed tomography scans, both of which were acquired for each patient as part of the stereotactic body radiotherapy planning process. Among 106 radiomic features considered, 21 were identified as robust. An analysis including univariate and multivariate assessments was subsequently conducted to estimate the predictive performance of these robust features on the outcome of early-stage non-small cell lung cancer patients treated with stereotactic body radiation therapy. The univariate predictive analysis revealed that robust features demonstrated superior predictive potential compared to non-robust features. The multivariate analysis indicated that linear regression models built with robust features displayed greater generalization capabilities by outperforming other models in predicting the outcomes of an external validation dataset.

Case Report: Coronaro-bronchial fistula vascularizing a squamous cell lung cancer.

Coronary fistulas are rare, having been described for the first time by Krauss in 1865 in postmortem. They are commonly asymptomatic and can be caused by congenital or acquired malformations. We present the case of a 65-year-old patient who was treated for squamous cell lung cancer with chemoimmunotherapy and presented with angina. The coronary angiography showed a coronaro-bronchial fistula that arises from a branch of the right coronary artery and is associated with lung cancer.

Incidence of venous thromboembolism and association with PD-L1 expression in advanced non-small cell lung cancer patients treated with first-line chemo-immunotherapy.

Background: Venous thromboembolism (VTE) is a serious complication in non-small cell lung cancer (NSCLC) patients. The use of thromboprophylactic therapy is subject to an accurate assessment of the VTE risk depending on patients, tumor characteristics and type of systemic antineoplastic treatments. However, little is known concerning the risk of VTE in patients suffering from an advanced NSCLC treated with first-line chemo-immunotherapy and the impact of tumor biomarkers such as PD-L1 expression. Methods: We performed a retrospective, observational, single-centre study in a cohort of advanced NSCLC patients treated with first-line chemo-immunotherapy. The primary endpoint was the incidence of VTE. Secondary endpoints were the cumulative incidence of VTE, the impact of PD-L1 on VTE occurrence, overall survival, the rate of VTE recurrence under anticoagulant treatment and the rate of bleeding complications. Results: 109 patients were included, of whom 21 (19.3%) presented a VTE event during a median follow-up of 13 months. VTE incidence at 3, 6 and 12 months was 12.1%, 15.1% and 17.5% respectively. 61% were pulmonary embolisms, 9.5% were isolated deep vein thrombosis and 14.3% were central venous catheter-related thrombosis. Our study did not show a significant impact of PD-L1 on VTE occurrence. Overall survival at 6, 12 and 24 months was 81.9%, 74.4% and 70.3% respectively. Four patients developed a recurrent VTE under anticoagulation therapy 3 to 5 months after the first VTE event. One patient suffered from a major bleeding complication while under anticoagulation therapy, leading to death. Conclusion: VTE is a common complication in advanced NSCLC patients treated with concomitant chemo-immunotherapy. In our study, 19.3% of patients developed a VTE during a median follow-up of 13 months. PD-L1 did not appear to be associated with VTE occurrence. We recorded high VTE recurrence rates despite anticoagulant treatment. Further investigations are needed to determine if high PD-L1 expression is associated with VTE.

Safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination in stage IV non-small-cell lung cancer: An open-label phase II trial (VinMetAtezo).

OBJECTIVE: To evaluate the safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination for stage IV non-small-cell lung cancer. METHODS: This was a multicenter, open-label, single-arm Phase II study performed in patients with advanced NSCLC without activating EGFR mutation or ALK rearrangement who progressed after first-line platinum-doublet chemotherapy. Combination treatment was atezolizumab (1200 mg IV day 1, every 3 weeks) and oral vinorelbine (40 mg, 3 times by week). The primary outcome was progression-free survival (PFS) during the 4-month follow-up from the first dose of treatment. Statistical analysis was based on the exact single-stage Phase II design defined by A'Hern. Based on literature data, the Phase III trial threshold was set at 36 successes in 71 patients. RESULTS: 71 patients were analyzed (median age, 64 years; male, 66.2%; ex-smokers/active smokers, 85.9%; ECOG performance status 0-1, 90.2%; non-squamous NSCLC, 83.1%; PD-L1 ≥ 50%, 4.4%). After a median follow-up of 8.1 months from treatment initiation, 4-month PFS rate was 32% (95% CI, 22-44), i.e. 23 successes out 71 patients. OS rate was 73.2% at 4 months and 24.3% at 24 months. Median PFS and OS were 2.2 (95% CI, 1.5-3.0) months and 7.9 (95% CI, 4.8-11.4) months, respectively. Overall response rate and disease control rate at 4 months were 11% (95% CI, 5-21) and 32% (95% CI, 22-44), respectively. No safety signal was evidenced. CONCLUSION: Metronomic oral vinorelbine-atezolizumab in the second-line setting did not achieve the predefined PFS threshold. No new safety signal was reported for vinorelbine-atezolizumab combination.

Venous thrombotic events and impact on outcomes in patients treated with first-line single-agent pembrolizumab in PD-L1 ≥ 50% advanced non small cell lung cancer.

BACKGROUND: Few data are available on the impact of venous thrombotic events (VTE) in patients with metastatic non-small cell lung cancer (mNSCLC) treated with immunotherapy. METHODS: This is a secondary analysis of the ESKEYP study, a national, retrospective, multicenter study that consecutively included all PD-L1 ≥ 50% mNSCLC patients who initiated first-line treatment with pembrolizumab monotherapy. From May 2017 to November 2019, 845 patients were included (from availability of pembrolizumab in this indication in France to the authorization of the combination with chemotherapy). Impact of VTE and patient characteristics were analyzed. RESULTS: Of the 748 patients (88.5%) with available data, the incidence of VTE was 14.8% (111/748). At pembrolizumab initiation, Khorana score was ≥ 2 for 55.0% (61/111) of them. Recurrence of VTE was reported for 4 of the 111 patients and 5 had bleeding complications. Patients with VTE were significantly younger, had more frequently long-term corticosteroids treatment and more often liver metastases. Progression-free survival (PFS) was significantly shorter in patients with VTE compared to patients without VTE: 6.1 (95% CI 4.1-9.0) months vs. 8.3 (6.9-10.3) months (p = 0.03). VTE did not significantly impact overall survival (OS): 15.2 (10.0-24.7) months with VTE and 22.6 (18.4-29.8) months without VTE (p = 0.07). In multivariate analysis for PFS and OS, HRs for VTE were 1.3 (0.99-1.71), p = 0.06 and 1.32 (0.99-1.76), p = 0.05. CONCLUSION: The incidence of VTE appears to be as high with in first-line immunotherapy as with chemotherapy in patients with mNSCLC, with in patient with VTE, a no significant trend for lower PFS and OS in multivariate analysis. more marked impact on PFS than on OS.

Real-life second-line epirubicin-paclitaxel regimen as treatment of relapsed small-cell lung cancer: EpiTax study.

BACKGROUND: Few therapeutic options are approved as second-line treatment after failure of platinum-based chemotherapy for patients with extensive-stage small-cell lung cancer (ES-SCLC). Topotecan widespread use remains challenged by the risk of severe toxicities in a pretreated population. Little is known about the efficacy and safety of epirubicin-paclitaxel doublet in second-line and beyond and especially cerebral outcomes. METHODS: EpiTax is a retrospective multicenter observational real-life study. We evaluated the efficacy of epirubicin 90 mg/m2 combined with paclitaxel 175 mg/m2 every 3 weeks in SCLC patients after failure of at least one line of platinum-based chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), intracranial control rate (ICR), and safety. RESULTS: A total of 29 patients were included. The median of previous systemic therapy lines was 2 (1-4). Eleven patients received the treatment in the second line. Characteristics of patients were a median age of 60 years (45-77), 65.5% of males with 72.4% of PS 0-1. Fifteen patients had a history of brain metastases. Median PFS and OS achieved 11.0 (95% CI, 8.1-16.3) and 23 (95% CI, 14.1-29.6) weeks, respectively. ORR was 34.5% and DCR was 55.2%. ICR was 3/15 (20%). Grade 3-4 adverse events were mainly hematological and concerned 7 patients. No case of febrile neutropenia or toxic death was reported. CONCLUSION: Epirubicin-paclitaxel association highlighted promising efficacy with PFS and OS of 11 and 23 weeks, respectively, ORR of 34.5%, and a tolerable safety profile. This doublet could represent another valuable therapeutic option for ES-SCLC patients treated in the second line and beyond.

Predictors of three-month mortality and severe chemotherapy-related adverse events in patients aged 70 years and older with metastatic non-small-cell lung cancer: A secondary analysis of ESOGIA-GFPC-GECP 08-02 study.

INTRODUCTION: Predictors for mortality and toxicity in older patients with cancer are mainly studied in cohorts with various cancers at different stages. This study aims to identify predictive geriatric factors (PGFs) for early death and severe chemotherapy related adverse events (CRAEs) in patients aged ≥70 years with metastatic non-small-cell lung cancer (mNSCLC). MATERIAL AND METHODS: This is a secondary analysis of the multicenter, randomized, phase 3 ESOGIA trial that compared, for patients ≥70 years with mNSCLC, a treatment algorithm based on performance status and age to another algorithm based on geriatric assessment. To identify PGFs of three-month mortality and grade 3, 4, or 5 CRAEs, multivariate Cox models and logistic models, adjusted for treatment group and center, and stratified by randomization arm, were constructed. RESULTS: Among 494 included patients, 145 (29.4%) had died at three months and 344 (69.6%) had severe chemotherapy toxicity. For three-month mortality, multivariate analyses retained mobility (Test Get up and Go), instrumental activity of daily living (IADL) dependence and weight loss as PGFs. The combined effect of IADL ≤2/4 and weight loss ≥3 kg was strongly associated with three-month mortality (adjusted hazard ratio: 5.71 [95% confidence interval [CI]: 2.64-12.32]). For chemotherapy toxicity, Charlson Comorbidity Index ≥2 was independently associated with grade3, 4, or 5 CRAEs (adjusted odds ratio [95% CI]: 1.94 [1.06-3.56]). DISCUSSION: Mobility, IADL dependence, and weight loss were predictive of three-month mortality in a population aged ≥70 years treated for mNSCLC, while comorbidities were independently associated with severe chemotherapy toxicity.

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29).

Background: Pembrolizumab combined with chemotherapy is now first-line standard of care in advanced non-small cell lung cancer. This real-life study aimed to assess efficacy and safety of carboplatin-pemetrexed plus pembrolizumab in advanced non-squamous non-small cell lung cancer. Methods: CAP29 is a retrospective, observational, multicenter real-life study conducted in 6 French centers. We evaluated efficacy of first-line setting chemotherapy plus pembrolizumab (November 2019 to September 2020) in advanced (stage III-IV) non-squamous non-small cell lung cancer patients without targetable alterations. Primary endpoint was progression-free survival. Secondary endpoints were overall survival, objective response rate and safety. Results: With a median follow-up of 4.5 months (0 to 22 months), a total of 121 patients were included. Baseline characteristics were: median age of 59.8 years with 7.4% ≥75 years, 58.7% of males, 91.8% PS 0-1, 87.6% of stage IV with ≥3 metastatic sites in 62% of cases. Patients had brain and liver metastases in 24% and 15.7% of cases, respectively. PD-L1 was <1% (44.6%), 1-49% (28.1%) and ≥50% (21.5%). Median progression-free survival and overall survival achieved 9 and 20.6 months, respectively. Objective response rate was 63.7% with 7 prolonged complete responses. Survival benefit seemed to be correlated with PD-L1 expression. Brain and liver metastases were not statistically associated with decreased overall survival. Most common adverse events were asthenia (76%), anemia (61.2%), nausea (53.7%), decreased appetite (37.2%) and liver cytolysis (34.7%). Renal and hepatic disorders were the main causes of pemetrexed discontinuation. Grade 3-4 adverse events concerned 17.5% of patients. Two treatment-related deaths were reported. Conclusions: First-line pembrolizumab plus chemotherapy confirmed real-life efficacy for patients with advanced non-squamous non-small cell lung cancer. With median progression-free survival and overall survival of 9.0 and 20.6 months, respectively and no new safety signal, our real-life data are very close to results provided by clinical trials, confirming the benefit and the manageable toxicity profile of this combination.

Atezolizumab with or without bevacizumab and platinum-pemetrexed in patients with stage IIIB/IV non-squamous non-small cell lung cancer with EGFR mutation, ALK rearrangement or ROS1 fusion progressing after targeted therapies: A multicentre phase II open-label non-randomised study GFPC 06-2018.

BACKGROUND: Previous reports showed limited efficacy of immune checkpoint inhibitors as single-agent treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation or ALK/ROS1 fusion. We aimed at evaluating the efficacy and safety of immune checkpoint inhibitor combined with chemotherapy and bevacizumab (when eligible) in this patient subgroup. METHODS: We conducted a French national open-label multicentre non-randomised non-comparative phase II study in patients with stage IIIB/IV NSCLC, oncogenic addiction (EGFR mutation or ALK/ROS1 fusion), with disease progression after tyrosine kinase inhibitor and no prior chemotherapy. Patients received platinum, pemetrexed, atezolizumab, bevacizumab (PPAB cohort) or, if not eligible to bevacizumab, platinum-pemetrexed-atezolizumab (PPA cohort). The primary end-point was the objective response rate (RECIST v1.1) after 12 weeks, evaluated by blind independent central review. RESULTS: 71 patients were included in PPAB cohort and 78 in PPA cohort (mean age, 60.4/66.1 years; women 69.0%/51.3%; EGFR mutation, 87.3%/89.7%; ALK rearrangement, 12.7%/5.1%; ROS1 fusion, 0%/6.4%, respectively). After 12 weeks, objective response rate was 58.2% (90% confidence interval [CI], 47.4-68.4) in PPAB cohort and 46.5% (90% CI, 36.3-56.9) in PPA cohort. Median progression-free survival and overall survival were 7.3 (95% CI 6.9-9.0) months and 17.2 (95% CI 13.7-NA) months in PPAB cohort and 7.2 (95% CI 5.7-9.2) months and 16.8 (95% CI 13.5-NA) months in PPA cohort, respectively. Grade 3-4 adverse events occurred in 69.1% of patients in PPAB cohort and 51.4% in PPA cohort; Grade 3-4 atezolizumab-related adverse events occurred in 27.9% and 15.3%, respectively. CONCLUSION: Combination approach with atezolizumab with or without bevacizumab and platinum-pemetrexed achieved promising activity in metastatic EGFR-mutated or ALK/ROS1-rearranged NSCLC after tyrosine kinase inhibitor failure, with acceptable safety profile.

Multi-Omics Approaches for the Prediction of Clinical Endpoints after Immunotherapy in Non-Small Cell Lung Cancer: A Comprehensive Review.

Immune checkpoint inhibitors (ICI) have revolutionized the management of locally advanced and advanced non-small lung cancer (NSCLC). With an improvement in the overall survival (OS) as both first- and second-line treatments, ICIs, and especially programmed-death 1 (PD-1) and programmed-death ligands 1 (PD-L1), changed the landscape of thoracic oncology. The PD-L1 level of expression is commonly accepted as the most used biomarker, with both prognostic and predictive values. However, even in a low expression level of PD-L1, response rates remain significant while a significant number of patients will experience hyperprogression or adverse events. The dentification of such subtypes is thus of paramount importance. While several studies focused mainly on the prediction of the PD-L1 expression status, others aimed directly at the development of prediction/prognostic models. The response to ICIs depends on a complex physiopathological cascade, intricating multiple mechanisms from the molecular to the macroscopic level. With the high-throughput extraction of features, omics approaches aim for the most comprehensive assessment of each patient. In this article, we will review the place of the different biomarkers (clinical, biological, genomics, transcriptomics, proteomics and radiomics), their clinical implementation and discuss the most recent trends projecting on the future steps in prediction modeling in NSCLC patients treated with ICI.

Narrative Review of Synergistics Effects of Combining Immunotherapy and Stereotactic Radiation Therapy.

Stereotactic radiotherapy (SRT) has become an attractive treatment modality in full bloom in recent years by presenting itself as a safe, noninvasive alternative to surgery to control primary or secondary malignancies. Although the focus has been on local tumor control as the therapeutic goal of stereotactic radiotherapy, rare but intriguing observations of abscopal (or out-of-field) effects have highlighted the exciting possibility of activating antitumor immunity using high-dose radiation. Furthermore, immunotherapy has revolutionized the treatment of several types of cancers in recent years. However, resistance to immunotherapy often develops. These observations have led researchers to combine immunotherapy with SRT in an attempt to improve outcomes. The benefits of this combination would come from the stimulation and suppression of various immune pathways. Thus, in this review, we will first discuss the immunomodulation induced by SRT with the promising results of preclinical studies on the changes in the immune balance observed after SRT. Then, we will discuss the opportunities and risks of the combination of SRT and immunotherapy with the preclinical and clinical data available in the literature. Furthermore, we will see that many perspectives are conceivable to potentiate the synergistic effects of this combination with the need for prospective studies to confirm the encouraging data.

Immune-Checkpoint Inhibitors for Malignant Pleural Mesothelioma: A French, Multicenter, Retrospective Real-World Study.

Backgrounds: Malignant pleural mesothelioma (MPM) is a cancer with poor prognosis. Second-line and onward therapy has many options, including immune-checkpoint inhibitors with demonstrated efficacy: 10−25% objective response rate (ORR) and 40−70% disease-control rate (DCR) in clinical trials on selected patients. This study evaluated real-life 2L+ nivolumab efficacy in MPM patients and looked for factors predictive of response. Methods: This retrospective study included (September 2017−July 2021) all MPM patients managed in 11 French centers. Results: The 109 enrolled patients' characteristics were: median age: 69 years; 67.9% men; 82.6% epithelioid subtype. Strictly, second-line nivolumab was given to 51.4%. Median PFS and OS were 3.8 (3.2−5.9) and 12.8 (9.2−16.4) months. ORR was 17/109 (15.6%); 34/109 patients had a stabilized disease (DCR 46.8%). Univariable analysis identified several parameters as significantly (p < 0.05) prognostic of OS [HR (95% CI)]: biphasic subtype: 3.3 (1.52−7.0), intermediate Lung Immune Prognostic Index score: 0.46 (0.22−0.99), progression on the line preceding nivolumab: 2.1 (1.11−3.9) and age > 70 years: 2.5 (1.5−4.0). Multivariable analyses retained only biphasic subtype: 3.57 (1.08−11.8) and albumin < 25 g/L: 10.28 (1.5−70.7) as significant and independent predictors. Conclusions: Second-line and onward nivolumab is effective against MPM in real life but with less effectiveness in >70 years. Ancillary studies are needed to identify the predictive factors.

Brigatinib for Pretreated, ALK-Positive, Advanced Non-Small-Cell Lung Cancers: Long-Term Follow-Up and Focus on Post-Brigatinib Lorlatinib Efficacy in the Multicenter, Real-World BrigALK2 Study.

Brigatinib is a next-generation ALK inhibitor (ALKi) that shows efficacy in ALK inhibitor naïve and post-crizotinib ALK+ advanced NSCLCs (aNSCLCs). The efficacy of brigatinib was retrospectively assessed in patients with aNSCLCs included in the brigatinib French Early-Access Program (1 August 2016−21 January 2019). The primary endpoint was investigator-assessed progression-free survival (invPFS) and the primary analysis was updated in 2021 with a longer follow-up, focused on post-brigatinib lorlatinib efficacy. Sixty-six centers included 183 patients: median age 60 ± 12.7 years; 78.3% never/former smokers; median of 3 ± 1 previous lines and 2 ± 0.5 ALKis; 37.1% ECOG PS 2 and 55.6% >3 metastatic sites. The median follow-up from brigatinib initiation was 40.4 months (95% CI 38.4−42.4). InvPFS was 7.4 months (95% CI 5.9−9.6), median duration of treatment (mDOT) was 7.3 months (95% CI 5.8−9.4) and median overall survival (mOS) was 20.3 months (95% CI 15.6−27.6). The median DOT and OS from brigatinib initiation tend to decrease with the number of ALK inhibitors used in previous lines of therapy. Based on the data collected, 92 (50.3%) patients received ≥1 agent(s) post-brigatinib and 68 (73.9%) of them received lorlatinib, with 51 (75%) immediately receiving it post-brigatinib, 12 (17.6%) receiving it after one and 5 (7.4%) after ≥2 subsequent treatments. The median follow-up was 29.9 (95% CI 25.7−33.1) months. Lorlatinib mDOT was 5.3 (95% CI 3.6−7.6) months with a median OS from lorlatinib initiation of 14.1 (95% CI 10.3−19.2) months. The results of the brigALK2 study confirm the efficacy of brigatinib in a population of heavily pretreated ALK+ aNSCLC patients and provide new data on the activity of lorlatinib after brigatinib.

Durvalumab-induced lesions of bronchiolitis and fully reversible bronchiectasis in a patient with non-small cell lung cancer: A case report.

Durvalumab is a humanized monoclonal antibody targeting programmed cell death ligand-1 (PD-L1), leading to an antitumor activity, used as consolidation therapy in patients with locally advanced unresectable non-small cell lung cancer (NSCLC). Several immune-related adverse events (irAEs) have previously been described in patients following treatment with immune checkpoint inhibitors (ICIs). To the best of our knowledge, we report the first case of immunotherapy-induced fully reversible bronchiolitis and bronchiectasis, despite the fact that its pathophysiological mechanism has been previously considered to be irreversible.

Vascular Acrosyndromes Associated With Prolonged Tumor Response in Advanced Lung Cancer Patients During Treatment With Antimetabolites: A Report of Two Cases.

BACKGROUND: Pemetrexed and gemcitabine are both antimetabolites drugs approved in advanced non-small cell lung cancer (NSCLC). Their toxicity profile is well known. However, rare vascular side effects can occur such as vascular acrosyndromes and especially digital ischemia. The cause of this disfiguring and painful event is still controversial. Amputation is frequently required and has been described as a predictor of poor survival outcomes. CASE PRESENTATION: This report presents two cases of vascular acrosyndrome in NSCLC patients during treatment with antimetabolites (pemetrexed and gemcitabine). Patients presented severe digital ischemia having required prostacyclin analog and chemotherapy discontinuation. In one case, symptoms improved while in the other case symptoms persisted. Both patients experienced prolonged tumor response. These findings suggest a multifactorial mechanism behind digital necrosis including an autoimmune process, which could lead to prolonged tumor control as described with immune checkpoint inhibitors. CONCLUSION: Severe vascular acrosyndrome such as digital ischemia can occur in lung cancer patients treated with antimetabolites. Awareness needs to be raised when using these drugs in patients with predisposing factors. Whether occurrence of chemotherapy-induced immune vascular side effects might explain prolonged tumor response deserves further investigations.