Improving olaparib exposure to optimize adverse effects management.

Background: Olaparib is an inhibitor of the human poly-(ADP-ribose)-polymerase enzymes (PARP1/2) needed to repair single-strand DNA breaks. It is used in breast, ovarian, prostate and pancreatic cancer. Objectives: This work aimed to describe the pharmacokinetics/pharmacodynamics (PK/PD) relationship between olaparib plasma concentrations and common adverse effects (i.e. anaemia and hypercreatininaemia), in a real-life setting, to propose a target concentration for therapeutic drug monitoring. Methods: Two PK/PD models describing the evolution of haemoglobinaemia and creatininaemia as a function of time were developed, based on data from, respectively, 38 and 37 patients receiving olaparib. The final model estimates were used to calculate the incidence of anaemia and creatinine increase according to plasma trough concentrations for 1000 virtual subjects to define target exposure. Results: The final models correctly described the temporal evolution of haemoglobinaemia and creatininaemia for all patients. The haemoglobinaemia PK/PD model is inspired by Friberg's model, and the creatininaemia PK/PD model is an indirect response model. Model parameters were in agreement with physiological values and close to literature values for similar models. The mean (population) plasma haemoglobin concentration at treatment initiation, as estimated by the model, was 11.62 g/dL, while creatinine concentration was 71.91 µmol/L. Using simulations, we have identified a target trough concentration of 3500-4000 ng/mL, above which more than 20% of patients would report grade ≥3 anaemia. Conclusion: Based on real-world data, we were able to properly describe the time course of haemoglobinaemia and plasma creatininaemia during olaparib treatment.

Advancing precision oncology through systematic germline and tumor genetic analysis: The oncogenetic point of view on findings from a prospective multicenter clinical trial of 666 patients.

INTRODUCTION: With the emergence of targeted therapies, there is a need to accurately identify more tumor biomarkers. The EXOMA trial was designed to offer tumor and germline exome sequencing (ES) to patients with solid malignant tumors and facing therapeutic failure. As hereditary cancer predispositions could be identified, with genetic counseling and health management implications, a genetic consultation was systematically established. This design needs to be discussed as genetic human resources are limited and indication of theranostic tests will increase. METHODS: Genetic counseling was conducted within 15 days following inclusion in the study for patients recruited between December 2015 and July 2019. In silico analyses from theranostic ES were limited to 317 genes involved in oncogenesis, from both tumor and blood DNA. RESULTS: Six hundred and sixty six patients had a genetic consultation before ES. In 65/666 patients, 66 germline pathogenic or likely pathogenic (P/LP) variants were identified in 16 actionable genes and seven non-actionable genes according to French guidelines. 24/65 patients had previously received genetic analysis for diagnostic purposes, and for 17 of them, a P/LP variant had already been identified. Among the 48/65 remaining cases for which the EXOMA protocol revealed a previously unknown P/LP variant, only 19 met the criteria for genetic testing for inherited cancer risk after familial survey. These criteria had not been identified by the oncologist in 10 cases. In 21/65 cases, the variant was considered incidental. DISCUSSION: In 7.4% of patients, an undiagnosed hereditary genetic predisposition was identified, whether or not related to the clinical presentation, and germline analysis impacted oncological management for only 6.3% of the cohort. This low percentage should be weighed against the burden of systematic genetic consultation and urgent circuits. Information or training tools to form oncologists to the prescription of germline genetic analyses should be explored, as well as information supports and patient preferences.

Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes.

BACKGROUND: Non-small cell lung cancer is a very poor prognosis disease. Molecular analyses have highlighted several genetic alterations which may be targeted by specific therapies. In clinical practice, progression-free survival on EGFR TKI treatment is between 12 and 14 months. However, some patients progress rapidly in less than 6 months, while others remain free of progression for 16 months or even longer during EGFR TKI treatment. METHODS: We sequenced tumor exomes from 135 lung cancer patients (79 with EGFR-wildtype (WT), 56 with EGFR-mutant tumors) enrolled in the ALCAPONE trial (genomic analysis of lung cancers by next generation sequencing for personalized treatment). RESULTS: Some germline polymorphisms were enriched in the EGFR-mutant subset compared to EGFR-WT tumors or to a reference population. However, the most interesting observation was the negative impact of some germline SNPs in immunity-related genes on survival on EGFR TKI treatment. Indeed, the presence of one of three particular SNPs in the HLA-DRB5 gene was associated with a decreased PFS on EGFR TKI. Moreover, some SNPs in the KIR3DL1 and KIR3DL2 genes were linked to a decrease in both progression-free and overall survival of patients with EGFR-mutant tumors. CONCLUSION: Our data suggest that SNPs in genes expressed by immune cells may influence the response to targeted treatments, such as EGFR TKIs. This indicates that the impact of these cells may not be limited to modulating the response to immunotherapies. Further studies are needed to determine the exact mechanisms underlying this influence and to identify the associated predictive and prognostic markers that would allow to refine treatments and so improve lung cancer patient outcomes. TRIAL REGISTRATION: NCT02281214: NGS Genome Analysis in Personalization of Lung Cancer Treatment (ALCAPONE).

Clinical, pathological, and comprehensive molecular analysis of the uterine clear cell carcinoma: a retrospective national study from TMRG and GINECO network.

BACKGROUND: Uterine clear cell carcinomas (CCC) represent less than 5% of uterine cancers. Their biological characteristics and clinical management remain uncertain. A multicenter study to explore both clinical and molecular features of these rare tumors was conducted. METHODS: This multicenter retrospective national study was performed within the French TMRG (Rare Gynecologic Malignant Tumors) network. Clinical data and, when available, FFPE blocks were collected. Clinical features, treatments, and outcome (progression-free survival (PFS) and overall survival (OS)) were analyzed and correlated to the protein (tissue micro-array), RNA (Nanostring nCounter® technology), and DNA (array-Comparative Genomic hybridization and target-next generation sequencing) levels using the tumor samples available. RESULTS: Sixty-eight patients with uterine CCC were enrolled, 61 from endometrial localization and 5 with cervix localization. Median age at diagnosis was 68.9 years old (range 19-89.7). Most tumors were diagnosed at an early stage (78% FIGO stage I-II). Hysterectomy (performed in 90%) and lymph node dissection (80%) were the most frequent surgical treatment. More than 70% of patients received external beam radiotherapy and 57% received brachytherapy. Nearly half (46%) of the patients received chemotherapy. After a median follow-up of 24.7 months, median PFS was 64.8 months (95 CI [5.3-124.4]) and median OS was 79.7 (IC95 [31.0-128.4]). Low hormone receptor expression (13% estrogen-receptor positive), frequent PI3K pathway alterations (58% PTEN loss, 50% PIK3CA mutations), and P53 abnormalities (41%) were observed. Mismatch repair deficiency was identified in 20%. P16 expression was associated with shorter PFS (HR = 5.88, 95 CI [1.56-25], p = 0.009). Transcriptomic analyzes revealed a specific transcriptomic profile notably with a high expression of immune response-associated genes in uterine CCC displaying a very good overall prognosis. CONCLUSIONS: Uterine CCC reported to be potentially MSI high, hormone receptors negative, and sometimes TP53 mutated. However, some patients with immune response-associated features and better prognosis may be candidate to treatment de-escalation and immunotherapy.

Exome-Based Genomic Markers Could Improve Prediction of Checkpoint Inhibitor Efficacy Independently of Tumor Type.

Immune checkpoint inhibitors (ICIs) have improved the care of patients in multiple cancer types. However, PD-L1 status, high Tumor Mutational Burden (TMB), and mismatch repair deficiency are the only validated biomarkers of efficacy for ICIs. These markers remain imperfect, and new predictive markers represent an unmet medical need. Whole-exome sequencing was carried out on 154 metastatic or locally advanced cancers from different tumor types treated by immunotherapy. Clinical and genomic features were investigated using Cox regression models to explore their capacity to predict progression-free survival (PFS). The cohort was split into training and validation sets to assess validity of observations. Two predictive models were estimated using clinical and exome-derived variables, respectively. Stage at diagnosis, surgery before immunotherapy, number of lines before immunotherapy, pleuroperitoneal, bone or lung metastasis, and immune-related toxicity were selected to generate a clinical score. KRAS mutations, TMB, TCR clonality, and Shannon entropy were retained to generate an exome-derived score. The addition of the exome-derived score improved the prediction of prognosis compared with the clinical score alone. Exome-derived variables could be used to predict responses to ICI independently of tumor type and might be of value in improving patient selection for ICI therapy.

PARP inhibitors (PARPi) prolongation after local therapy for oligo-metastatic progression in relapsed ovarian cancer patients.

BACKGROUND: PARP inhibitors (PARPi) have revolutionized the management of high-grade epithelial ovarian cancer (HGOC) treatment. However, a significant number of patients relapse or progress under PARPi, leading to the introduction of a new line of systemic therapy such as chemotherapy. In patients with a limited number of metastatic sites at progression, -referred to as an oligometastatic progression- a potential indication for local therapy followed by re-introduction or continuation of PARPi treatment rather than initiating a new line of chemotherapy could be proposed. However, the impact of such strategies on progression free survival (PFS) in these patients remains unknown. METHODS: This international multicenter retrospective study evaluated the efficacy of PARPi continuation or re-introduction in patients with HGOC after local treatment for oligometastatic progression. The main objective was to assess PFS under PARPi after local therapy (PFS post-LT). Secondary objectives included safety and overall survival (OS). RESULTS: 74 patients were identified in 20 centers between April 2020 and November 2021. 65% of patients were BRCA mutated and 92% had received ≥2 lines of prior systemic chemotherapy before the initial introduction of PARPi. Main progression sites were lymph nodes (42%), peritoneum (27%), liver (16%), other visceral (16%) and abdominal wall (4%). Local therapies included radiotherapy (45%), surgery (43%), both (7%), percutaneous thermal ablation (4%) or chemoembolization (1%). Median PFS post-LT was 11.5 months [95% CI 7.4; 17.2]. After a median follow up of 14.8 months, 6 patients (8.1%) discontinued PARPi due to toxicity. The 1-year overall survival rate was 90.7% [95% CI 79.1; 96.0]. CONCLUSIONS: With close to one year without progression or introduction of a new line of systemic therapy, this study reports the feasibility and potential benefit of this original strategy in patients with oligometastatic progression under PARPi.

Impact of complete surgical staging on survival of patients with early-stage (FIGO I or II) ovarian cancer: Data from the Cote d'Or Registry of Gynecological Cancers from 1998 to 2015.

INTRODUCTION: Early-stage ovarian cancer represents 20 to 33% of all ovarian cancers and is thus quite rare in France, with around 1200 new cases per year. No study to date has convincingly demonstrated the utility of lymphadenectomy in early-stage ovarian cancer. We sought to evaluate the impact on overall survival of complete surgical staging in patients management for FIGO stage I and II ovarian cancer. METHODS: We performed a retrospective observational study using data from the Cote d'Or Registry of Gynecological Cancers. We included patients with invasive early stage epithelial ovarian cancer (FIGO stages I and II), diagnosed between 1 January 1998 and 31 December 2015. RESULTS: A total of 179 patients were included in the study. Patients who had lymphadenectomy were younger on average (P<0.001) and had fewer comorbidities (P=0.03). Lymphadenectomy was performed during the first surgery in 59.2% of cases (58 patients) and during a second, re-staging surgery in 40.8% (n=40). When complete surgical staging was performed, the rate of up-staging (to at least FIGO stage III) was 11.2% (11/98). The median follow-up was 8.4 years. At the study, 31.6% patients with complete surgical staging had died and 48.4% patients also died in the group without lymphadenectomy, HR 0.59 CI [0.36-0.97] P<0.04. CONCLUSION: In patients with early-stage ovarian cancer, complete surgical staging appears to yield a benefit in terms of overall survival. In 10 to 15% of cases, it leads to upstaging, with the resultant indication for maintenance therapy, which has also shown a survival benefit.

Efficacy and safety of maintenance olaparib and bevacizumab in ovarian cancer patients aged ≥65 years from the PAOLA-1/ENGOT-ov25 trial.

BACKGROUND: The phase III PAOLA-1/ENGOT-ov25 study (NCT02477644) showed that addition of olaparib to bevacizumab maintenance improved progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer. We evaluated maintenance olaparib plus bevacizumab in older patients in PAOLA-1. METHODS: Baseline clinical and molecular data, and PFS, were compared between older (aged ≥65 years) and younger patients (<65 years). Factors associated with olaparib efficacy, and safety in age subgroups, were also assessed. RESULTS: Of 806 randomised patients, 292 (36.2%) were ≥65 years. A lower proportion of older versus younger patients had an Eastern Cooperative Oncology Group performance status of 0 (61.0% versus 76.2%) and upfront surgery (42.0% versus 55.7%). Older patients were less likely to have a BRCA1/2 mutation (17.1% versus 36.7%) or homologous recombination deficiency-positive status (34.1% versus 55.7%). After median follow-up of 22.1 months, median PFS was 21.6 months with olaparib versus 16.6 months with placebo in the older population (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.41-0.75), comparable with the younger population (median 22.9 versus 16.9 months; HR 0.61, 95% CI 0.49-0.77). PFS benefits were observed in patients with a BRCA mutation or homologous recombination deficiency-positive tumours. Incidence of olaparib-related grade ≥3 adverse events in older patients was comparable with that of younger patients (36.8% versus 31.7%) although hypertension and anaemia were more common in older patients. No treatment-related deaths occurred in older patients receiving olaparib. CONCLUSION: Older patients enrolled in PAOLA-1 achieved similar PFS benefits compared with younger patients, with a similar safety profile.

Neoadjuvant chemotherapy with or without nintedanib for advanced epithelial ovarian cancer: Lessons from the GINECO double-blind randomized phase II CHIVA trial.

AIM: The oral anti-angiogenic therapy nintedanib prolongs progression-free survival (PFS) when combined with chemotherapy after primary surgery for advanced epithelial ovarian cancer. The randomized phase II CHIVA trial evaluated the impact of combining nintedanib with neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer. METHODS: Patients with newly diagnosed unresectable FIGO stage IIIC-IV epithelial ovarian cancer received 3-4 cycles of carboplatin plus paclitaxel every 3 weeks as NACT before interval debulking surgery (IDS), followed by 2-3 post-operative cycles. Patients were randomized 2:1 to receive either nintedanib 200 mg twice daily or placebo on days 2-21 every 3 weeks during NACT (omitting peri-operative cycles), and then as maintenance therapy for up to 2 years. The primary endpoint was PFS. RESULTS: Between January 2013 and May 2015, 188 patients were randomized (124 to nintedanib, 64 to placebo). PFS was significantly inferior with nintedanib (median 14.4 versus 16.8 months with placebo; hazard ratio 1.50, p = 0.02). Overall survival (OS) was also inferior (median 37.7 versus 44.1 months, respectively; hazard ratio 1.54, p = 0.054). Nintedanib was associated with increased toxicity (grade 3/4 adverse events: 92% versus 69%, predominantly hematologic and gastrointestinal), lower response rate by RECIST (35% versus 56% before IDS), and lower IDS feasibility (58% versus 77%) versus placebo. CONCLUSIONS: Adding nintedanib to chemotherapy and in maintenance as part of NACT for advanced epithelial ovarian cancer cannot be recommended as it increases toxicity and compromises chemotherapy efficacy (IDS, PFS, OS). CLINICALTRIALS: govregistration: NCT01583322.

Safety, Immunogenicity, and 1-Year Efficacy of Universal Cancer Peptide-Based Vaccine in Patients With Refractory Advanced Non-Small-Cell Lung Cancer: A Phase Ib/Phase IIa De-Escalation Study.

PURPOSE: Universal cancer peptide-based vaccine (UCPVax) is a therapeutic vaccine composed of two highly selected helper peptides to induce CD4+ T helper-1 response directed against telomerase. This phase Ib/IIa trial was designed to test the safety, immunogenicity, and efficacy of a three-dose schedule in patients with metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with refractory NSCLC were assigned to receive three vaccination doses of UCPVax (0.25 mg, 0.5 mg, and 1 mg) using a Bayesian-based phase Ib followed by phase IIa de-escalating design. The primary end points were dose-limiting toxicity and immune response after three first doses of vaccine. Secondary end points were overall survival (OS) and progression-free survival at 1 year. RESULTS: A total of 59 patients received UCPVax; 95% had three prior lines of systemic therapy. No dose-limiting toxicity was observed in 15 patients treated in phase Ib. The maximum tolerated dose was 1 mg. Fifty-one patients were eligible for phase IIa. The third and sixth dose of UCPVax induced specific CD4+ T helper 1 response in 56% and 87.2% of patients, respectively, with no difference between three dose levels. Twenty-one (39%) patients achieved disease control (stable disease, n = 20; complete response, n = 1). The 1-year OS was 34.1% (95% CI, 23.1 to 50.4), and the median OS was 9.7 months, with no significant difference between dose levels. The 1-year progression-free survival and the median OS were 17.2% (95% CI, 7.8 to 38.3) and 11.6 months (95% CI, 9.7 to 16.7) in immune responders (P = .015) and 4.5% (95% CI, 0.7 to 30.8) and 5.6 months (95% CI, 2.5 to 10) in nonresponders (P = .005), respectively. CONCLUSION: UCPVax was highly immunogenic and safe and provide interesting 1-year OS rate in heavily pretreated advanced NSCLC.

Uncommon EGFR mutations in lung carcinoma: features and treatment outcomes in a retrospective French cohort.

Background: The best management for rare epidermal growth factor receptor (EGFR) mutations in advanced non-small cell lung carcinoma (NSCLC) remains uncertain. The literature indicates that response to usual treatment could differ in certain subgroups such as exon 20 insertion/duplication (E20ID), other single uncommon mutation (OSUM), and EGFR complex mutation (ECM). Methods: In this observational, regional, multi-center, retrospective study, we gathered data on uncommon EGFR mutations in NSCLC from 2007 to 2021. We analyzed patient characteristics, prognostic factors and treatment outcomes [objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS)]. Results: Among 119 patients with an uncommon EGFR mutant, 34 harbored E20ID, 23 ECM, and 62 OSUM. There were significantly more non-smokers in E20ID. Female gender and performance status <2 were associated with a better prognosis. Among the 97 metastatic patients with available data for 1st line treatment, median estimated OS was 21 months (95% CI: 18-31 months), with better non-significant OS for ECM. Median estimated PFS was 7 months (95% CI: 4-9 months). We found significant differences in ORR, DCR and PFS favoring 1st line chemotherapy for E20ID, whereas the outcomes for OSUM and ECM were more favorable for tyrosine kinase inhibitor (TKI) (mainly 2nd and 3rd generation). Conclusions: There were variations in treatment outcomes among subgroups in our cohort. Exon 20 insertions showed better ORR and PFS with 1st line chemotherapy compared to TKI. Conversely, other rare EGFR mutations including ECM had better ORR and PFS with TKI than chemotherapy. There was no significant difference in OS among treatment groups overall or within rare mutation subgroups.

Association of Anti-EGFR Antibody and MEK Inhibitor in Gynecological Cancer Harboring RAS Mutation: A Case Series.

Low-grade serous carcinoma represents a minority of serous carcinoma. Although they have better prognosis than high-grade serous carcinoma, they respond poorly to chemotherapy. Thus, it appears necessary to find other treatments such as targeted therapies. Since RAS or RAF mutations occur frequently in low-grade serous carcinoma and lead to constitutively activated MAPK cascade, MEK inhibition should be effective in the treatment of low-grade serous carcinoma. So, we wanted to evaluate the clinical benefit of MEK inhibitors in the management of advanced-stage low-grade serous carcinoma harboring KRAS or NRAS mutation. We report a case series of three women with advanced-stage low-grade serous carcinoma harboring RAS mutation who had stabilization of their disease during several months under targeted therapy combining anti-EGFR antibody and MEK inhibitor. We performed in vitro experiments, confirming the effectiveness of MEK inhibitor on the KRAS-mutated OVCAR-5 cell line, and the constitutively activation of MAPK cascade in RAS-mutated carcinoma. However, it seems that the anti-EGFR antibody does not provide any additional benefit. After whole exome analysis is carried out on the patient with the shortest response, we observed the appearance of RB1 loss-of-function mutation that could be a mechanism of resistance to MEK inhibitors in RAS- of RAF-mutated cancers. The MEK inhibitor is effective in the advanced stages of low-grade serous carcinoma harboring RAS mutation with acceptable tolerance. RB1 loss could be a mechanism of resistance to MEK inhibitors in RAS-mutated low-grade serous carcinoma.

MER4 endogenous retrovirus correlated with better efficacy of anti-PD1/PD-L1 therapy in non-small cell lung cancer.

BACKGROUND: Endogenous retroviruses (ERVs) are highly expressed in various cancer types and are associated with increased innate immune response and better efficacy of antiprogrammed death-1/ligand-1 (anti-PD1/PD-L1)-directed immune checkpoint inhibitors (ICI) in preclinical models. However, their role in human non-small cell lung cancer (NSCLC) remains unknown. METHODS: We conducted a retrospective study of patients receiving ICI for advanced NSCLC in two independent cohorts. ERV expression was determined by RNA sequencing. The primary endpoint was progression-free survival (PFS) under ICI. The secondary endpoint was overall survival (OS) from ICI initiation. We studied expression of 6205 ERVs. Multivariate Cox regression model with lasso penalty was estimated on the training set to select ERVs significantly associated with survival. The predictive power of these ERVs was compared with that of previously described transcriptomic signatures. RESULTS: We studied two independent cohorts of 89 and 70 patients, used as training and validation sets. Clinicopathological characteristics included 75% of patients with non-squamous NSCLC. We selected four ERVs significantly associated with PFS. Only high MER4 ERV was associated with better PFS and OS in both cohorts. From a biological point of view, high MER4 expression is associated with higher infiltration of eosinophils and inflammatory gene signatures, while low MER4 expression is associated with enrichment in metabolism and proliferation signatures. Adding MER4 to previously described transcriptomic signatures of response to ICI improved their predictive power. CONCLUSIONS: MER4 ERV expression is useful to stratify risk and predict PFS and OS in patients treated with ICI for NSCLC. It also improves the predictive power of other known transcriptomic signatures.

Parallel evolution and differences in seroprevalence of SARS-CoV-2 antibody between patients with cancer and health care workers in a tertiary cancer centre during the first and second wave of COVID-19 pandemic: canSEROcov-II cross-sectional study.

BACKGROUND: Patients with cancer are a population at high risk of severe infection from SARS-CoV-2. Patients with cancer regularly attend specialised healthcare centres for management and treatment, where they are in contact with healthcare workers (HCWs). Numerous recommendations target both patients with cancer and HCWs to minimise the spread of SARS-CoV-2 during these interactions. OBJECTIVE: To investigate the parallel evolution of the COVID-19 epidemic in these 2 populations over time, we studied the seroprevalence of anti-SARS-CoV-2 antibodies after both the first and second waves of the pandemic, and in both cancer patients and HCWs from a single specialised anti-cancer centre. Factors associated with seropositivity were identified in both populations. METHODS: We conducted a cross-sectional study after the second wave of the COVID pandemic in France. All participants were invited to undergo serological testing for SARS-CoV-2 and complete a questionnaire collecting data about their working conditions (for HCWs) or medical management (for patients) during this period. Results after the second wave were compared to those of a previous study among 1011 patients with cancer and 663 HCWs performed in the same centre after the first wave, using the same evaluations. FINDINGS: We included 502 HCWs and 507 patients with cancer. Seroprevalence of anti-SARS-CoV-2 antibodies was higher after the second wave than after the first wave in both HCWs (15.1% versus 1.8%; p < 0.001), and patients (4.1% versus 1.7%; p = 0.038). By multivariate analysis, the factors found to be associated with seropositivity after the second wave for HCWs were: working in direct patient care (p = 0.050); having worked in a dedicated COVID-19 unit (p = 0.0036); contact with a person with COVID-19-positive in the workplace (p = 0.0118) or outside of the workplace (p = 0.0297). Among patients with cancer, only a contact with someone who tested positive for COVID-19 was found to be significantly associated with positive serology. The proportion of reported contacts with individuals with COVID-19-positive was significantly lower among patients with cancer than among HCWs (7.6% versus 40.7%, respectively; p < 0.0001) INTERPRETATION: Between the first and second waves of the epidemic in France, the seroprevalence of anti-SARS-CoV-2 antibodies increased to a lesser extent among patients with cancer than among their HCWs, possibly due to better self-protection, notably social distancing. The risk factors for infection identified among HCWs plead in favour of numerous intra-hospital contaminations, especially for HCWs in contact with high-risk patients. This underlines the compelling need to pursue efforts to implement strict hygiene and personal protection measures (including vaccination) to protect HCWs and patients with cancer.

MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells.

Chemotherapy with anti PD-1/PD-L1 antibodies has become the standard of care for patients with metastatic non-small cell lung cancer (mNSCLC). Using lung tumor models, where pemetrexed and cisplatin (PEM/CDDP) chemotherapy remains unable to synergize with immune checkpoint inhibitors (ICIs), we linked the failure of this treatment with its inability to induce CXCL10 expression and CD8+ T cell recruitment. Using drug screening, we showed that combining a MEK inhibitor (MEKi) with PEM/CDDP triggers CXCL10 secretion by cancer cells and CD8+ T cell recruitment, sensitizing it to ICIs. PEM/CDDP plus a MEKi promotes optineurin (OPTN)-dependent mitophagy, resulting in CXCL10 production in a mitochondrial DNA- and TLR9-dependent manner. TLR9 or autophagy/mitophagy inhibition abolishes the anti-tumor efficacy of PEM/CDDP plus MEKi/anti-PD-L1 therapy. In human NSCLCs, high OPTN, TLR9, and CXCL10 expression is associated with a better response to ICIs. Our results underline the role of TLR9- and OPTN-dependent mitophagy in enhancing chemoimmunotherapy efficacy.

Therapeutic Challenges in Patients with Gynecologic Carcinosarcomas: Analysis of a Multicenter National Cohort Study from the French Prospective TMRG Network.

BACKGROUND: Gynecological carcinosarcomas are rare and aggressive diseases, with a poor prognosis. The rarity of these tumors explains the lack of robust and specific data available in the literature. The objective of this study was to investigate the impact of initial adjuvant treatment and recurrent therapeutic strategies. PATIENTS AND METHODS: A multicentric cohort study within the French national prospective Rare Malignant Gynecological Tumors (TMRG) network was conducted. Data from all included carcinosarcomas diagnosed between 2011 and 2018 were retrospectively collected. RESULTS: 425 cases of uterine and ovarian carcinosarcomas (n = 313 and n = 112, respectively) were collected and analyzed from 12 participating centers. At diagnosis, 140 patients (48%) had a FIGO stage III-IV uterine carcinosarcoma (UCS) and 88 patients (83%) had an advanced ovarian carcinosarcoma (OCS) (FIGO stage ≥ III). Two hundred sixty-seven patients (63%) received adjuvant chemotherapy, most preferably carboplatin-paclitaxel regimen (n = 227, 86%). After a median follow-up of 47.4 months, the median progression-free survival (mPFS) was 15.1 months (95% CI 12.3-20.6) and 14.8 months (95% CI 13.1-17.1) for OCS and UCS, respectively. The median overall survival for OCS and UCS was 37.1 months (95% CI 22.2-49.2) and 30.6 months (95% CI 24.1-40.9), respectively. With adjuvant chemotherapy followed by radiotherapy, mPFS was 41.0 months (95% CI 17.0-NR) and 18.9 months (95% CI 14.0-45.6) for UCS stages I-II and stages III-IV, respectively. In the early stage UCS subgroup (i.e., stage IA, n = 86, 30%), mPFS for patients treated with adjuvant chemotherapy (n = 24) was not reached (95% CI 22.2-NR), while mPFS for untreated patients (n = 62) was 19.9 months (95% IC 13.9-72.9) (HR 0.44 (0.20-0.95) p = 0.03). At the first relapse, median PFS for all patients was 4.2 months (95% CI 3.5-5.3). In the first relapse, mPFS was 6.7 months (95% CI 5.1-8.5) and 2.2 months (95% CI 1.9-2.9) with a combination of chemotherapy or monotherapy, respectively (p < 0.001). CONCLUSIONS: Interestingly, this vast prospective cohort of gynecological carcinosarcoma patients from the French national Rare Malignant Gynecological Tumors network (i) highlights the positive impact of adjuvant CT on survival in all localized stages (including FIGO IA uterine carcinosarcomas), (ii) confirms the importance of platinum-based combination as an option for relapse setting, and (iii) reports median PFS for various therapeutic strategies in the relapse setting.

Does large NGS panel analysed using exome tumour sequencing improve the management of advanced non-small-cell lung cancers?

INTRODUCTION: Non-small-cell lung cancer (NSCLC) is one of the most common and deadly cancers. Several molecular drivers of oncogene addiction are now known to be strong predictive biomarkers for target therapies. Advances in large Next Generation Sequencing (LNGS) have improved the ability to detect potentially targetable mutations. However, the integration of LNGS into clinical management in an individualized manner remains challenging. METHODS: In this single-center observational study we included all patients with advanced NSCLC who underwent LNGS. Somatic and germline exome analysis was performed with a restriction on 323 cancer related genes. Variants were classified and Molecular Tumour Board (MTB) made therapeutic propositions. RESULTS: We performed LNGS analysis in 281 patients with advanced NSCLC between March 2015 and January 2018. Technical failure occurred in only 3% of cases. Three hundred and fifty-six targetable mutations were detected. At least one targetable mutation was found in 209 patients. For all these patients, the MTB was able to recommend treatment with a targeted agent based on the evaluation of the tumour's genetic profile and treatment history. Twenty-nine patients (13.9%) were subsequently treated with an MTB-recommended targeted therapy. We did not observe any improvement in terms of clinical benefit for these patients. CONCLUSIONS: In this case series, we show that including LNGS into routine clinical management was feasible but does not appear to provide clinical benefit in the management of patients with advanced NSCLC.

Splenic Volume as a Surrogate Marker of Immune Checkpoint Inhibitor Efficacy in Metastatic Non Small Cell Lung Cancer.

Monoclonal antibodies targeting PD1/PD-L1 are game changers in advanced non-small cell lung cancer (NSCLC), but biomarkers are lacking. We previously reported the prognostic role of splenic volume in digestive cancer and its correlation with the presence of immunosuppressive cells. The aim of this study was to evaluate the prognostic role of splenic volume in NSCLC patients treated with immune checkpoint inhibitors (ICIs). We conducted a retrospective study of 276 patients receiving ICIs for advanced NSCLC in the Georges François Leclerc Cancer Center. The association between splenic volume at baseline and at two months of therapy and progression-free survival (PFS) during ICI treatment or overall survival (OS) from ICI initiation was evaluated using univariate and multivariable Cox analyses. Splenic volume during treatment and the change in splenic volume were associated with poor PFS (respectively p = 0.02 and p = 0.001) and with OS (respectively p < 1.10-3 and p < 1.10-3). Baseline splenic volume at the first evaluation was also associated with poor OS (p = 0.001). LDH rate and dNLR were positively correlated with splenic volume, as well as with its evolution. After the adjustment of clinical variables, splenic volumes remained a predictive marker of immunotherapy efficacy. Splenic volume is a prognostic biomarker in patients with advanced NSCLC treated with ICIs.

Seroprevalence of SARS-CoV-2 among the staff and patients of a French cancer centre after first lockdown: The canSEROcov study.

BACKGROUND: In view of the potential gravity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection for patients with cancer, epidemiological data are vital to assess virus circulation among patients and staff of cancer centres. We performed a prospective study to investigate seroprevalence of SARS-CoV-2 antibodies among staff and patients with cancer at a large cancer centre, at the end of the period of first national lockdown in France and to determine factors associated with the risk of SARS-CoV-2 infection. METHODS: After the first lockdown, all medical and non-medical staff, as well as all patients attending the medical oncology department were invited to undergo serological testing for SARS-CoV-2 between 11 May and 30 June 2020. All participants were also invited to complete a questionnaire collecting data about their living and working conditions, and for patients, medical management during lockdown. FINDINGS: A total of 1,674 subjects (663 staff members, 1011 patients) were included. Seroprevalence was low in both staff (1.8%) and patients (1.7%), despite more features of high risk for severe forms among patients. None of the risk factors tested in our analysis (working or living conditions, comorbidities, management characteristics during lockdown) was found to be statistically associated with seroprevalence in either staff or patients. There was no significant difference in the proportion of symptomatic and asymptomatic subjects between staff and patients. Only fever, loss of smell, and loss of taste were significantly more frequent among seropositive patients, in both staff and patients. INTERPRETATION: We report very low seroprevalence of antibodies against SARS-CoV-2 in the staff (caregiving and non-caregiving) and patients of a large cancer care centre in which strict hygiene, personal protection, and social distancing measures were implemented.

Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial.

BACKGROUND: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. METHODS: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. FINDINGS: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. INTERPRETATION: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. FUNDING: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.