CONFIRM: a double-blind, placebo controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial

Background: Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Early promising signals of activity relating to both PD-L1- and PD-1-targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint. There is a need to evaluate checkpoint inhibitors in patients with relapsed mesothelioma where treatment options are limited. Methods: The addition of 12 months of nivolumab (anti-PD1 antibody) to standard practice will be conducted in the UK using a randomised, placebo-controlled phase III trial (the Cancer Research UK CONFIRM trial). A total of 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy will be recruited from UK secondary care sites. Patients will be randomised 2:1 (nivolumab:placebo), stratified according to epithelioid/non-epithelioid, to receive either 240 mg nivolumab monotherapy or saline placebo as a 30-min intravenous infusion. Treatment will be for up to 12 months. We will determine whether the use of nivolumab increases overall survival (the primary efficacy endpoint). Secondary endpoints will include progression-free survival, objective response rate, toxicity, quality of life and cost-effectiveness. Analysis will be performed according to the intention-to-treat principle using a Cox regression analysis for the primary endpoint (and for other time-to-event endpoints). Discussion: The outcome of this trial will provide evidence of the potential benefit of the use of nivolumab in the treatment of relapsed mesothelioma. If found to be clinically effective, safe and cost-effective it is likely to become the new standard of care in the UK

Influence of the SARS-CoV-2 outbreak on management and prognosis of new lung cancer cases, a retrospective multicenter real-life cohort study

International audienceIntroductionThe SARS-CoV-2 pandemic has impacted the care of cancer patients. This study sought to assess the pandemic’s impact on the clinical presentations and outcomes of newly referred patients with lung cancer from the Greater Paris area.MethodsWe retrospectively retrieved the electronic health records and administrative data of 11.4 million patients pertaining to Greater Paris University Hospital (AP-HP). We compared indicators for the 2018-2019 period to those of 2020 in regard to newly referred lung cancer cases. We assessed initial tumor stage, delay between first multidisciplinary tumor board (MTB) and anticancer treatment initiation, and 6-month overall survival (OS) rates depending on the anticancer treatment including surgery, palliative systemic treatment, and best supportive care (BSC).ResultAmong 6,240 patients with lung cancer, 2,179 (35%) underwent tumor resection, 2,069 (33%) systemic anticancer therapy, 775 (12%) BSC, whereas 1,217 (20%) did not receive any treatment. During the first lockdown, the rate of new diagnoses decreased by 32% compared with that recorded in 2018-2019. Initial tumor stage, repartition of patients among treatment categories, and MTB-related delays remained unchanged. The 6-month OS rates of patients diagnosed in 2018-2019 who underwent tumor resection were 98% vs. 97% (HR=1.2; 95% CI: 0.7-2.0) for those diagnosed in 2020; the respective rates for patients who underwent systemic anticancer therapy were 78% vs. 79% (HR=1.0; 95% CI: 0.8-1.2); these rates were 20% vs. 13% (HR=1.3; 95% CI: 1.1-1.6) for those who received BSC. COVID-19 was associated with poorer OS rates (HR=2.1; 95% CI: 1.6-3.0) for patients who received systemic anticancer therapy.ConclusionsThe SARS-CoV-2 pandemic has not exerted any deleterious impact on 6-month OS of new lung cancer patients that underwent active anticancer therapy in Greater Paris University hospitals

Osteoblastic Reaction in Non-small Cell Lung Carcinoma and its Association to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Response and Prolonged Survival

IntroductionThe aim of this study was to describe the characteristics and epidermal growth factor receptor (EGFR) mutational status of patients with non-small cell lung cancer (NSCLC) with osteoblastic reactions diagnosed before or during treatment with EGFR tyrosine kinase inhibitors (TKIs).MethodsRetrospective study including patients with 36 NSCLC with at least one site of osteoblastic reaction at the time of diagnosis or during treatment with EGFR-TKI.ResultsThe rate of patients with mutated EGFR tumors with osteoblastic reactions before or after EGFR-TKI treatment was similar. Median progression-free survival (PFS) for the entire group was more than 9 months and median survival was more than 12 months. There was no statistically significant difference in survival between patients with osteoblastic reactions before initiation of TKI and those diagnosed during TKI treatment. Patients with extraosseous metastases when treated with TKI had the lowest survival (P < 0.0001).ConclusionsIn patients with NSCLC treated with TKI, initial or development of an osteoblastic reaction seems to be related to a more favorable outcome. In patients with osteoblastic reactions, tumors present with clinical and biologic characteristics of better survival and response to TKI. The occurrence of osteoblastic reactions during treatment with TKI, while primary tumor and metastases are stable or in response, should not be considered as disease progression

Extended antigen sparing potential of AS03-adjuvanted pandemic H1N1 vaccines in children, and immunological equivalence of two formulations of AS03-adjuvanted H1N1 vaccines: results from two randomised trials.

International audienceBACKGROUND: Pandemicinfluenza vaccinemanufacturing capacity and distribution agility is enhanced through the availabilityof equivalent antigen-sparing vaccines. We evaluated equivalence in terms of immunogenicity between GlaxoSmithKline Vaccines' A/California/7/2009(H1N1)v-like-AS03 vaccines manufactured in Dresden (D-Pan), and Quebec (Q-Pan). METHODS: In two studies,334 adults 18-60 years of age received 2 doses of D-Pan or Q-Pan containing 3.75 mug haemagglutinin antigen (HA) adjuvanted with AS03Aadministered21 days apart, and 209 children 3-9 years of age received 1reduced dose of D-Panor Q-Pan (0.9 mug HA) or Q-Pan (1.9 mug HA) with AS03B. Haemagglutination inhibition (HI)titres were assessed before and 21 days post-vaccination. HI persistence was assessed after 12 months in adults and 6 months in children. RESULTS: Pre-defined criteria for immunological equivalence of Q-Pan versus D-Pan were achieved in both populations. After one vaccine dose, >=97.6% of adults and children had HI titres >=1:40, with increases in titre>=25.7-fold. CHMP and CBER regulatory acceptance criteria for influenza vaccines were exceeded by all groups in both studies at Day 21. In adults,the percentage with HI titres >=1:40 at Month 12 was 82.9% (Q-Pan) and 84.0% (D-Pan). In children, the percentages at Month 6 were 75.3.3% (Q-Pan0.9), 85.1% (D-Pan0.9) and 79.3% (Q-Pan1.9). Safety profile of the study vaccines was consistent with previously published data. CONCLUSION: Two studies indicate that A/California/7/2009 (H1N1)v-like HA manufactured at two sitesand combined with AS03 are equivalent in terms of immunogenicity in adults and children and highly immunogenic. Different HA doses elicited an adequate immune response through 180 days post-vaccination in children 3-9 years of age.Trial registrationClinicalTrials.gov: NCT00979407 and NCT01161160

Phase Ib/II study of the pan-cyclin-dependent kinase inhibitor roniciclib in combination with chemotherapy in patients with extensive-disease small-cell lung cancer

Objectives: This phase Ib/II study evaluated safety, pharmacokinetics, maximum tolerated dose (MTD), and efficacy of the pan-cyclin-dependent kinase inhibitor roniciclib with cisplatin-etoposide (CIS-ETOP) or carboplatin-etoposide (CARBO-ETOP) in patients with extensive-disease small-cell lung cancer (ED-SCLC). Patients and methods: In this open-label, non-randomized study, patients with previously untreated ED-SCLC received roniciclib twice daily (BID) in a 3 days on/4 days off schedule. Cisplatin 75 mg/m(2) or carboplatin (AUC5) dose was administered on day 1, and etoposide 100 mg/m(2) on days 1-3, of 21-day cycles. Phase Ib used a dose-escalation design to define the MTD for phase II. Pharmacokinetics were assessed. Results: Forty-three patients received treatment (roniciclib 2.5 mg BID [+ CARBO-ETOP, n = 4; + CIS-ETOP, n = 3] and roniciclib 5 mg BID [+ CARBO-ETOP, n = 24; + CIS-ETOP, n = 12]). The MTD of roniciclib was 5 mg BID with CARBO-ETOP or CIS-ETOP. Common adverse events were nausea (90.7%) and vomiting (69.8%). Roniciclib was readily absorbed following oral administration at the MTD (median t,,, 0.5-1 h), with a 30-40% reduction in exposure when co-administered with CARBO-ETOP or CIS-ETOP; administration of roniciclib had no effect on etoposide or platinum pharmacokinetics. The response rate was 81.4% (35/43) overall and 86.1% (31/36) in the pooled roniciclib 5 mg BID population (all partial responses). Conclusion: Roniciclib co-administered with chemotherapy in patients with ED-SCLC demonstrated tolerability, acceptable pharmacokinetics, and promising efficacy. An observed safety signal in a related phase II study resulted in discontinuation of the present study and termination of further roniciclib development.