Efficacy of first-line immune checkpoint inhibitors in pulmonary sarcomatoid carcinoma.

Background: Pulmonary sarcomatoid carcinomas (PSC) are notorious for their poor prognosis and resistance to chemotherapy. The literature suggests that immunotherapy might be effective against this aggressive tumor. This study aims to evaluate the efficacy of immunotherapy, either alone or combined with chemotherapy, as first-line treatment for PSC patients. Methods: In a retrospective, multicentric, real-world study conducted between July 2017 and April 2021, patients with stage III (ineligible for surgery or radio-chemotherapy) or stage IV PSC were enrolled. These patients received their first-line treatment with immunotherapy and were categorized into two groups based on their treatment modality: the immuno-chemotherapy (IO CT) group or the immunotherapy-alone (IO) group. Results: This study analyzed a population of 34 patients from eight different hospital centers. In this cohort, the objective response rate (ORR) was 56%, median duration of response was 20.5 months, median progression-free survival (PFS) was 5.11 months, and median overall survival (OS) 13.9 months. Demographic characteristics remained consistent among the treatment groups except for the age (54.0- and 71.0-year-old in the IO CT and IO group, respectively, P=0.02). The IO CT group demonstrated an ORR of 64.0%, a median PFS at 8.72 months, and a median OS of 16.08 months, while the IO group displayed respective values of 52.0%, 3.45 months, and 13.11 months. Conclusions: This study showed the potential efficacy of immunotherapy as a first-line treatment for PSC. While acknowledging the retrospective nature of the study, our findings suggest a trend favoring the combination of IO CT over IO alone in these patients.

Adaptive radiotherapy (up to 74 Gy) or standard radiotherapy (66 Gy) for patients with stage III non-small-cell lung cancer, according to [18F]FDG-PET tumour residual uptake at 42 Gy (RTEP7-IFCT-1402): a multicentre, randomised, controlled phase 2 trial.

BACKGROUND: Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [18F]fluorodeoxyglucose ([18F]FDG)-PET results. METHODS: In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0-1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative-intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 0·8]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [18F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 6·5 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 6·5 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m2 intravenously once every 3 weeks and vinorelbine 30 mg/m2 intravenously on day 1 and 60 mg/m2 orally [or 30 mg/m2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m2 intravenously and vinorelbine 20 mg/m2 intravenously on day 1 and 40 mg/m2 orally (or 20 mg/m2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7-IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing. FINDINGS: From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [18F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 45·1 months (95% CI 39·3-48·3). The 15-month local control rate was 77·6% (95% CI 67·6-87·6%) in group A and 71·2% (95% CI 60·8-81·6%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3-4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3-4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment). INTERPRETATION: A thoracic radiotherapy boost, based on interim [18F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [18F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC. FUNDING: Programme Hospitalier de Recherche Clinique National 2014.

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

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

Successive next-generation sequencing strategy for optimal fusion gene detection in non-small-cell lung cancer in clinical practice.

Metastatic non-small-cell lung cancer (NSCLC) displays various molecular alterations in the RAS-MAPK pathway. In particular, NSCLCs show high rates of targetable gene fusion in ALK, RET, ROS1, NRG1 and NTRK, or MET exon 14 skipping. Rapid and accurate detection of gene fusion in EGFR/KRAS/BRAF mutations is important for treatment selection especially for first-line indications. RNA-based next-generation sequencing (NGS) panels appear to be the most appropriate as all targets are multiplexed in a single run. While comprehensive NGS panels remain costly for daily practice, optimal sequencing strategies using targeted DNA/RNA panel approaches need to be validated. Here, we describe our lung cancer screening strategy using DNA and RNA targeted approaches in a real-life cohort of 589 NSCLC patients assessed for molecular testing. Gene fusions were analysed in 174 patients negative for oncogene driver mutations or ALK immunohistochemistry in a two-step strategy. Targetable alterations were identified in 28% of contributive samples. Non-smokers had a 63.7% probability to have a targetable alteration as compared to 21.5% for smokers. Overall survival was significantly higher (p=0.03) for patients who received a molecularly matched therapy. Our study shows the feasibility in routine testing of NSCLC DNA/RNA molecular screening for all samples in a cost- and time-controlled manner. The significant high fusion detection rate in patients with wild-type RAS-MAPK tumours highlights the importance of amending testing strategies in NSCLC.

Incidental diagnosis of lung cancer on chest CT scan performed for suspected or documented COVID-19 infection.

CONTEXT: Recent studies have shown a benefit of chest computed tomography (CT scan) in lung cancer screening. The COVID-19 pandemic has led to many chest CT scan performed on a large population. The objective of this study was to describe the incidence and characteristics of lung cancer detected on chest CT scan, outside the framework of a clinical trial, for a suspected or documented COVID-19 infection. METHODS: We conducted a multicenter study, carried out from the analysis of data from the prospective COVID-19 database of the Clinical Data Warehouse of the Greater Paris University Hospitals (AP-HP). We identified the patients who had been diagnosed with a lung cancer, due to a chest CT scan done for a suspected or confirmed COVID-19 infection. The study period was limited to the first two epidemic lockdowns: (03/01/20 - 05/31/20) and (10/10/20 - 11/30/20). RESULTS: Over the study period, 24 390 patients had at least one chest CT scan. Among them, 72 lung cancer diagnoses were made (incidence 0.30 %; median age 67.4 years old, 50.0 % current smokers, 55.6 % adenocarcinoma). Half of the lung cancer patients (n = 36) did not meet the National Lung Screening Trial inclusion criteria. Twenty-six patients (36.1 %) were diagnosed at an early stage, 25 (34.7 %) of whom received radical curative treatment. Twenty-six patients died during the follow-up (36.1 %) but none in early stages. The median overall survival in lung cancer patients was 693 days [532 - NA]. CONCLUSIONS: A large-scale chest CT scan strategy for suspected or documented COVID-19 infection has allowed a significant proportion of early-stage lung cancer diagnosis, all of which have benefited from curative treatment.

Colony stimulating factor-1 (CSF-1) signalling is predictive of response to immune checkpoint inhibitors in advanced non-small cell lung cancer.

The identification of biomarkers related to treatment in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) represents a significant challenge. The aim of this study was to determine the predictive value of macrophage-related markers assessed in plasma and tissue samples of patients with NSCLC undergoing ICI treatment. This bicentric study included a prospective cohort of 88 patients with advanced NSCLC who received first-line therapy with ICI (either as monotherapy or in combination with chemotherapy) or chemotherapy alone (CT). Samples were collected from the patients at baseline and during follow-up. Plasma levels of CSF-1 and IL-34 were measured using ELISA, while expression levels of the macrophage receptors CD163 and CSF-1-R were evaluated using immunohistochemistry on lung biopsies. At baseline, the median plasma CSF-1 expression was higher in patients who did not respond to immunotherapy compared to those who responded (8898 pg/mL vs. 14031 pg/mL, p = 0.0005). Importantly, high CSF-1 levels at the initial assessment were associated with disease progression regardless of the treatment received. Furthermore, high CSF-1 levels were associated with shorter progression-free survival (PFS) and overall survival (OS) in patients receiving ICI therapy, but not in those treated with chemotherapy. There was no correlation between IL-34, CSF-1R, CD163 and therapeutic response. We observed in vitro that the activation of lymphocytes mediated by pembrolizumab was hindered by the treatment of PBMC with recombinant CSF-1, suggesting that CSF-1 creates a systemic immunosuppressive state that interferes with ICI treatment. In conclusion, baseline CSF-1 levels represent a potential predictive marker to ICI treatment in NSCLC.

Impact of Waiting Response Evaluation to First-Line Systemic Therapy before Considering Local Ablative Therapy in Metastatic Non-Small-Cell Lung Cancer.

Stereotactic radiotherapy (SRT) is gaining increasing importance in metastatic non-small-cell lung cancer (mNSCLC) management. The optimal sequence of tumor irradiation relative to systemic treatment remains unclear. If waiting response evaluation to first-line systemic therapy (FLST) before considering local treatment may allow for the exclusion of poorer prognosis progressive tumors that may not benefit from SRT, performing irradiation near immune check point inhibitor (ICI) first administration seems to improve their synergic effect. Herein, we aimed to determine whether delaying SRT after response evaluation to FLST would result in better prognosis. We compared overall survival (OS), progression-free survival (PFS), and time to first subsequent therapy (TFST) for 50 patients locally treated before or within 90 days of initiating FLST (early SRT), with 49 patients treated at least 90 days after initiating FLST (late SRT). Patients treated with conventional chemotherapy alone exhibited significantly poorer median OS, PFS, and TFST in the early SRT arm: (in months) 16.5 [8.33-NR] vs. 58.3 [35.05-NR] (p = 0.0015); 4.69 [3.57-8.98] vs. 8.20 [6.66-12.00] (p = 0.017); and 6.26 [4.82-11.8] vs. 10.0 [7.44-21.8] (p = 0.0074), respectively. Patient receiving ICI showed no difference in OS (NR [25.2-NR] vs. 36.6 [35.1-NR], p = 0.79), PFS (7.54 [6.23-NR] vs. 4.07 [2.52-NR], p = 0.19), and TFST (13.7 [9.48-NR] vs. 10.3 [3.54-NR], p = 0.49). These results suggest that delaying SRT treatment in order to filter a rapidly growing tumor may be less necessary when ICI is administered in mNSCLC.

Evaluation of Real-Life Chemoimmunotherapy Combination in Patients with Metastatic Small Cell Lung Carcinoma (SCLC): A Multicentric Case-Control Study.

The current first-line standard treatment for advanced small cell lung cancer (SCLC) is a combination of chemotherapy and immunotherapy. However, few efficacy data are available in a real-life settings, including frail patients. The aim of this study is to describe the real-life efficacy of chemoimmunotherapy in an unselected SCLC population. We conducted a retrospective multicenter study, which compared two cohorts of patients with treatment-naive metastatic SCLC treated in six academic centers in the Greater Paris area. Cohort 1 included patients treated with chemotherapy between January 2017 and December 2018, and cohort 2 included patients treated with chemoimmunotherapy between January 2019 and December 2020. A total of 153 consecutive patients were included (cohort 1: n = 96; cohort 2: n = 57). Clinical characteristics were similar between the two cohorts. Overall survival (OS) was statistically higher in cohort 2 (median survival 15.47 months) than in cohort 1 (median survival 9.5 months) (p = 0.0001). OS for patients with a performance status ≥2 and for patients ≥70 years old was not statistically different between the two cohorts. Chemoimmunotherapy efficacy was better compared to chemotherapy alone in case of brain or liver metastases. In conclusion, the combination of chemoimmunotherapy in metastatic SCLC appears to provide a real-life OS benefit. Dedicated clinical trials are needed to test this strategy in patients with impaired performance status or advanced age.

Brief Report: Severe Sotorasib-Related Hepatotoxicity and Non-Liver Adverse Events Associated With Sequential Anti-Programmed Cell Death (Ligand)1 and Sotorasib Therapy in KRASG12C-Mutant Lung Cancer.

INTRODUCTION: Sequential anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) followed by small targeted therapy use is associated with increased prevalence of adverse events (AEs) in NSCLC. KRASG12C inhibitor sotorasib may trigger severe immune-mediated hepatotoxicity when used in sequence or in combination with anti-PD-(L)1. This study was designed to address whether sequential anti-PD-(L)1 and sotorasib therapy increases the risk of hepatotoxicity and other AEs. METHODS: This is a multicenter, retrospective study of consecutive advanced KRASG12C-mutant NSCLC treated with sotorasib outside clinical trials in 16 French medical centers. Patient records were reviewed to identify sotorasib-related AEs (National Cancer Institute Common Classification Criteria for Adverse Events-Version 5.0). Grade 3 and higher AE was considered as severe. Sequence group was defined as patients who received an anti-PD-(L)1 as last line of treatment before sotorasib initiation and control group as patients who did not receive an anti-PD-(L)1 as last line of treatment before sotorasib initiation. RESULTS: We identified 102 patients who received sotorasib, including 48 (47%) in the sequence group and 54 (53%) in the control group. Patients in the control group received an anti-PD-(L)1 followed by at least one treatment regimen before sotorasib in 87% of the cases or did not receive an anti-PD-(L)1 at any time before sotorasib in 13% of the cases. Severe sotorasib-related AEs were significantly more frequent in the sequence group compared with those in the control group (50% versus 13%, p < 0.001). Severe sotorasib-related AEs occurred in 24 patients (24 of 48, 50%) in the sequence group, and among them 16 (67%) experienced a severe sotorasib-related hepatotoxicity. Severe sotorasib-related hepatotoxicity was threefold more frequent in the sequence group compared with that in the control group (33% versus 11%, p = 0.006). No fatal sotorasib-related hepatotoxicity was reported. Non-liver severe sotorasib-related AEs were significantly more frequent in the sequence group (27% versus 4%, p < 0.001). Severe sotorasib-related AEs typically occurred in patients who received last anti-PD-(L)1 infusion within 30 days before sotorasib initiation. CONCLUSIONS: Sequential anti-PD-(L)1 and sotorasib therapy are associated with a significantly increased risk of severe sotorasib-related hepatotoxicity and severe non-liver AEs. We suggest avoiding starting sotorasib within 30 days from the last anti-PD-(L)1 infusion.

Respiratory recovery trajectories after severe-to-critical COVID-19: a 1-year prospective multicentre study.

BACKGROUND: Survivors of severe-to-critical coronavirus disease 2019 (COVID-19) may have functional impairment, radiological sequelae and persistent symptoms requiring prolonged follow-up. This pragmatic study aimed to describe their clinical follow-up and determine their respiratory recovery trajectories, and the factors that could influence them and their health-related quality of life. METHODS: Adults hospitalised for severe-to-critical COVID-19 were evaluated at 3 months and up to 12 months post-hospital discharge in this prospective, multicentre, cohort study. RESULTS: Among 485 enrolled participants, 293 (60%) were reassessed at 6 months and 163 (35%) at 12 months; 89 (51%) and 47 (27%) of the 173 participants initially managed with standard oxygen were reassessed at 6 and 12 months, respectively. At 3 months, 34%, 70% and 56% of the participants had a restrictive lung defect, impaired diffusing capacity of the lung for carbon monoxide (D LCO) and significant radiological sequelae, respectively. During extended follow-up, both D LCO and forced vital capacity percentage predicted increased by means of +4 points at 6 months and +6 points at 12 months. Sex, body mass index, chronic respiratory disease, immunosuppression, pneumonia extent or corticosteroid use during acute COVID-19 and prolonged invasive mechanical ventilation (IMV) were associated with D LCO at 3 months, but not its trajectory thereafter. Among 475 (98%) patients with at least one chest computed tomography scan during follow-up, 196 (41%) had significant sequelae on their last images. CONCLUSIONS: Although pulmonary function and radiological abnormalities improved up to 1 year post-acute COVID-19, high percentages of severe-to-critical disease survivors, including a notable proportion of those managed with standard oxygen, had significant lung sequelae and residual symptoms justifying prolonged follow-up.

Validation of Liquid Chromatography Coupled with Tandem Mass Spectrometry for the Determination of 12 Tyrosine Kinase Inhibitors (TKIs) and Their Application to Therapeutic Drug Monitoring in Adult and Pediatric Populations.

Tyrosine kinase inhibitors (TKIs) are used as targeted cancer therapies in adults and have an off-label pediatric application for the treatment of Langerhans cell histiocytosis. A multitarget LC-MS/MS method was developed and validated for the determination of alectinib, alectinib-M4, binimetinib, cobimetinib, crizotinib, dabrafenib, encorafenib, imatinib, lorlatinib, osimertinib, AZ5104, and trametinib. A total of 150 µL of internal standard methanolic solution was added to 50 µL of plasma sample to precipitate proteins. After centrifugation, 10 µL of the supernatant was injected into the chromatographic system. The chromatographic separation was conducted on a Kinetex C18 Polar column with a gradient of 2 mM ammonium formate in 0.1% formic acid and acetonitrile over 5 min. Limits of detection and quantification, linearity, accuracy, precision, selectivity, carryover, matrix effect, recovery, and stability were evaluated and satisfied EMA guidelines on bioanalytical methods. This method has been successfully applied to the therapeutic drug monitoring (TDM) of adults with melanoma and lung cancer, as well as children with histiocytosis, to improve the pharmacokinetic data for these drugs, with the aim of enhancing the therapeutic management and follow-up of patients. Blood concentrations of trametinib and binimetinib were different in the two groups, highlighting the age-related inter-individual variability of these molecules and the need for TDM.

Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multicentric Retrospective French Study.

BACKGROUND: Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in first line for the treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC). OBJECTIVE: The identification of related histomolecular resistance mechanisms to first-line osimertinib is a critical step to define the optimal treatment strategy beyond progression. PATIENTS AND METHODS: All consecutive patients treated in the first line with osimertinib for advanced EGFR-mutated NSCLC at 10 hospitals in the Greater Paris area between April 2015 and January 2021 were included. Histomolecular data from plasma and tissue samples taken at progression under osimertinib were collected, and all samples were analyzed using DNA next-generation sequencing. Data on objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to treatment discontinuation (TTD) were also collected. RESULTS: Overall, 104 patients were included. Most patients had adenocarcinoma (n = 102, 98%) with an exon 19 EGFR deletion (n = 54, 52%). Forty-two patients (50%) had central nervous system (CNS) metastasis at the time of osimertinib initiation. ORR was 76%, median PFS and OS were 12.6 months and 52 months, respectively, and TTD was 33 months. At the time of analysis, 44 patients (42%) had tumor progression, and among these patients, 27 (61%) contributive samples were available. The most frequent molecular alterations at progression were mesenchymal epithelial transition factor (MET) amplification (15%; n = 4) and EGFR C797S mutation (11%; n = 3). Histological transformation was found in one patient (4%). RNA next-generation sequencing was performed in eight patients and showed a CCDC6-RET fusion in one patient (12%). CONCLUSIONS: We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation-positive NSCLC. At progression, the most frequent histomolecular alterations were MET amplification and EGFR C797S mutation.

Comprehensive Genome Profiling in Patients With Metastatic Non-Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung/IFCT 1301 Trial.

PURPOSE: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown. PATIENTS AND METHODS: SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS). RESULTS: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6-2.9] with TT versus 2.7 months (1.6-4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7-1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3-4.4) with durvalumab versus 3.0 months (2.0-5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62-1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11-0.75) as compared with PD-L1 <1% (n = 31; HR, 0.71; 95% CI, 0.31-1.60; Pinteraction = 0.036). CONCLUSIONS: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Acute generalized exanthematous pustulosis caused by gemcitabine after nivolumab in metastatic lung adenocarcinoma followed by a dramatic tumor response: A case report.

Herein, we report a case of a 73-year-old female patient diagnosed with cT4N0M1a lung adenocarcinoma with KRAS G12C mutation, PDL1 < 1% and treated in fourth-line setting with gemcitabine after progression under nivolumab. After one infusion of gemcitabine, the patient presented with an acute worsening of general condition (performance status 4) with extensive skin lesions and fever, leading to hospitalization and diagnosis of acute generalized exanthematous pustulosis. Initial blood work revealed multiple organ failures with an important inflammatory syndrome. Patient state improved after intravenous hydration and local and systemic corticosteroids. The decision was made to stop systemic cancer treatment. Two months follow-up showed a remarkable response on all cancer localizations. Although immunotherapy is transforming cancer care, predicting response to immunotherapy remains challenging and resistant mechanisms remain mostly unknown. This case underlines that important immune-stimulation can lead to tumor response in a patient previously refractory to all antitumor treatments.

Gene expression profile of high PD-L1 non-small cell lung cancers refractory to pembrolizumab.

BACKGROUND: Despite high expression of PD-L1, around half of advanced non-small cell lung cancer (NSCLC) will not experience tumor response with pembrolizumab. There is an need for a better understanding of the resistance mechanisms in this setting. METHODS: This bi-centric retrospective study included all consecutive patients with PDL1 ≥ 50% advanced NSCLC treated with pembrolizumab in first-line treatment between 2016 and 2020. We compared the clinical characteristics of patients with early progression (refractory) vs others. We performed a comprehensive gene expression profile screening by RNAseq capture on tumor samples. RESULTS: We included 46 patients. Twenty-two patients were refractory to pembrolizumab, mainly women, with poor performance status and lower albumin concentration. RNAseq analysis was performed on 19 samples. Hierarchical clustering allowed the identification of 3 clusters with various proportion of refractory tumors: intermediate (C1: 57%), high (C2: 71%) and low proportion (C3: 40%). Comparative analysis between C2 and C3 allowed the identification of overexpressed (n = 137) and underexpressed (n = 40) genes. Among the genes of interest, C2 exhibits higher activation of pathways associated with stemness phenotype (Hedgehog, Notch and Hippo pathways) and pathways associated with loss of PTEN and JAK2. In C2, genes associated with PD-1, toll-like receptor-9 (TLR-9), major histocompatibility complex (MHC) and interferon-γ pathways were underexpressed. CONCLUSION: This study gives an overview of activated and downregulated pathways in high PD-L1 NSCLC refractory to pembrolizumab. These tumors showed activation of pathways associated with cancer stem cells, loss of PTEN and JAK2, and inhibition of both priming and effector phases of the immune response.

Corrigendum: High Circulating Sonic Hedgehog Protein Is Associated With Poor Outcome in EGFR-Mutated Advanced NSCLC Treated With Tyrosine Kinase Inhibitors.

[This corrects the article DOI: 10.3389/fonc.2021.747692.].

Discontinuation of immune checkpoint inhibitor (ICI) above 18 months of treatment in real-life patients with advanced non-small cell lung cancer (NSCLC): INTEPI, a multicentric retrospective study.

BACKGROUND: The optimal treatment duration of ICIs for patients with advanced NSCLC remains uncertain. In phase 3 clinical trials, treatment continued for 2 years or until disease progression with similar long-term survival rates. Real-life data are missing. PATIENTS AND METHODS: This academic multicentric retrospective study aims at analyzing the characteristics of patients who discontinued treatment after at least 18 months of ICI monotherapy, in the setting of controlled disease. RESULTS: Of the 1127 patients treated with immunotherapy in the given period in six centers, 107 patients had their tumor controlled after at least 18 months of treatment and 54 (50%) of them had discontinued ICI. The median duration of treatment was 26 months. Treatment was stopped due to prescriber choice or toxicity in 46% and 22% of cases, respectively. After a median follow-up of 21 months from ICI discontinuation (95% CI 15.0-26.1 months), 18 (33%) patients experienced tumor progression after a median time of 10.0 months (range 2-33). From discontinuation, 12-month overall survival (OS) and progression-free survival (PFS) were 90% (95% CI 77.7-95.7) and 71% (95% CI 56.8-81.5), respectively; 24-month OS and PFS were 84% (95% CI 68.7-92.2) and 63% (95% CI 46.1-76.2), respectively. Duration of disease control after ICI discontinuation was correlated with tumor response at treatment discontinuation: PFS rate at 12 months was 76% after complete response (CR n = 11) or partial response (PR n = 37) and 22% after only stable disease (SD n = 6) as best response, p-value = 0.0002. PFS rate at 12 months was 80% for CR and/or complete metabolic response with 18F-FDG PET/CT (CMR) and 65% for others. Fourteen patients out of the 18 relapse patients received a subsequent treatment: seven with ICI rechallenge (best response 14% PR and 86% SD) and five with localized therapy with 60% CR. CONCLUSIONS: This real-life study provides new insight into long-term outcomes of patients with advanced NSCLC treated with ICI for at least 18 months before treatment discontinuation in the absence of PD. Tumor response and CMR with FDG PET just before therapy discontinuation may be a predictive factor of prolonged disease control upon discontinuation. These results call for caution in discontinuing treatment in patients with stable disease as the best response.

EGFR Exon 20 Insertion in Metastatic Non-Small-Cell Lung Cancer: Survival and Clinical Efficacy of EGFR Tyrosine-Kinase Inhibitor and Chemotherapy.

EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs). In this paper, we describe the clinical characteristics, efficacy of EFGR TKIs and chemotherapy, and resulting survival in this population. We retrospectively collected patients with EGFR exon 20 insertions (Exon20ins) from 11 French genetic platforms and paired them (1:2 ratio) with classic Exon 19/21 EGFR mutation patients (controls). Between 2012 and 2017, 35 Exon20ins patients were included. These patients were younger at diagnosis than the controls. All Exon20ins patients who were treated with first-line EGFR TKIs (n = 6) showed progressive disease as the best tumor response. There was no significant difference in the tumor response or the disease control rate with first-line platinum-based chemotherapy between the two groups. A trend towards shorter overall survival was observed in Exon20ins vs. controls (17 months (14-not reach(NR) 95% confidence interval(CI) vs. 29 months (17-NR 95%CI), p = 0.09), respectively. A significant heterogeneity in amino acid insertion in EGFR exon 20 was observed. EGFR exon 20 insertions are heterogeneous molecular alterations in NSCLC that are resistant to classic EGFR TKIs, which contraindicates their use as a first-line treatment.

Prognostic value of inflammatory response biomarkers using peripheral blood and [18F]-FDG PET/CT in advanced NSCLC patients treated with first-line chemo- or immunotherapy.

OBJECTIVES: We aimed to compare the prognostic value of inflammatory biomarkers extracted from pretreatment peripheral blood and [18F]-FDG PET for estimating outcomes in non-small cell lung cancer (NSCLC) patients treated with first-line immunotherapy (IT) or chemotherapy (CT). MATERIALS AND METHODS: In this retrospective multicenter study, we evaluated 111 patients with advanced NSCLC who underwent baseline [18F]-FDG PET/CT before IT or CT between 2016 and 2019. Several blood inflammatory indices were evaluated: derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP) and systemic immune-inflammation index (SII). FDG-PET inflammatory parameters were extracted from lymphoid tissues (BLR and SLR: bone marrow or spleen-to-Liver SUVmax ratios). Association with survival and relationships between parameters were evaluated using Cox prediction models and Spearman's correlation respectively. RESULTS: Overall, 90 patients were included (IT:CT) (51:39pts). Median PFS was 8.6:6.6 months and median OS was not reached:21.2 months. In the IT cohort, high dNLR (>3), high SII (≥1,270) and high SLR (0.77) were independent statistically significant prognostic factors for one-year progression-free survival (1y-PFS) and two-year overall survival (2y-OS) on multivariable analysis. In the CT cohort, high BLR (≥0.80) and high dNLR (>3) were associated with shorter 1y-PFS (HR 2.2, 95% CI 1.0-4.9) and 2y-OS (HR 3.4, 95CI 1.1-10.3) respectively, on multivariable analysis. Finally, BLR significantly but moderately correlated with most blood-based inflammatory indices (CRP, PLR and SII) while SLR was only associated with CRP (p < 0.01 for all). CONCLUSION: In advanced NSCLC patients undergoing first-line IT or CT, pretreatment blood and inflammatory factors evaluating the spleen or bone marrow on [18F]-FDG PET/CT provided prognostic information for 1y-PFS and 2y-OS. These biomarkers should be further evaluated for potential clinical application.

First-Line Afatinib plus Cetuximab for EGFR-Mutant Non-Small Cell Lung Cancer: Results from the Randomized Phase II IFCT-1503 ACE-Lung Study.

PURPOSE: Double inhibition of epidermal growth factor receptor (EGFR) using a tyrosine kinase inhibitor plus a monoclonal antibody may be a novel treatment strategy for non-small cell lung cancer (NSCLC). We assessed the efficacy and toxicity of afatinib + cetuximab versus afatinib alone in the first-line treatment of advanced EGFR-mutant NSCLC. PATIENTS AND METHODS: In this phase II, randomized, open-label study, patients with stage III/IV EGFR-positive NSCLC were randomly assigned (1:1) to receive afatinib (group A) or afatinib + cetuximab (group A + C). Oral afatinib 40 mg was given once daily; cetuximab 250 mg/m² was administered intravenously on day 15 of cycle 1, then every 2 weeks at 500 mg/m² for 6 months. The primary endpoint was time to treatment failure (TTF) rate at 9 months. Exploratory analysis of EGFR circulating tumor DNA in plasma was performed. RESULTS: Between June 2016 and November 2018, 59 patients were included in group A and 58 in group A + C. The study was ended early after a futility analysis was performed. The percentage of patients without treatment failure at 9 months was similar for both groups (59.3% for group A vs. 64.9% for group A + C), and median TTF was 11.1 (95% CI, 8.5-14.1) and 12.9 (9.2-14.5) months, respectively. Other endpoints, including progression-free survival and overall survival, also showed no improvement with the combination versus afatinib alone. There was a slight numerical increase in grade ≥3 adverse events in group A + C. Allele frequency of the EGFR gene mutation in circulating tumor DNA at baseline was associated with shorter PFS, regardless of the treatment received. CONCLUSIONS: These results suggest that addition of cetuximab to afatinib does not warrant further investigation in treatment-naïve advanced EGFR-mutant NSCLC.