Explore the vast range of titles available.

Randomised controlled trials (RCTs) are the gold standard for evaluating new therapies but have limitations, notably in terms of external validity. Real-world data (RWD) studies could complement RCT evidence. However, a consensus has not yet been reached on situations where RWD could offer rigorous complementary evidence to an RCT when evaluating the effectiveness of therapeutic innovations. This research aims to: (1) propose a categorisation of complex clinical situations; (2) classify the real-world evidence (RWE) approaches to be used in each situation to help reduce uncertainties or provide further evidence in drug benefit assessments; (3) summarise the best methodological considerations to adopt when using these RWE approaches; and (4) propose general recommendations to increase confidence in the use of RWE approaches during the assessment process. The main recommendations within the framework around the RWD-generation plan for complex evaluations are related to four main issues: quality (establishing criteria and standards for quality data), methodology (ensuring the use of the best methodological approaches), transparency (from the industry and from the health technology agencies (HTAs) and sharing/collaborating across countries and HTAs (promoting collaboration between HTAs and involving all parties). Our proposal and recommendations could help the scientific community better consider the therapeutic value of innovations through RWD, so that their potential can be fully realised to benefit the quality of care and the regulation of the healthcare system.

Background Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177 Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. Methods This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177 Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177 Lu-PSMA-1 (phase I) and the efficacy of 177 Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). Discussion Our prospective study may lead to new potential indications for the use of 177 Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177 Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. Trial registration ClinicalTrials.gov: NCT06059014.

The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8–236·6) after the 1-year randomisation, 200·9 months (190·2–208·4) after the 3-year randomisation, and 164·5 months (134·4–176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5–10·1) versus 27·8 months (19·5–37·9; hazard ratio [HR] 0·36 [95% CI 0·20–0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5–11·7) versus 67·0 months (48·8–85·6; 0·15 [0·07–0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0–16·6) versus not reached (NR; NR–NR; 0·13 [0·03–0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1–39·1) versus 90·6 months (25·3–156·1; HR 0·93 [95% CI 0·51–1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0–89·6) versus 127·3 months (15·0–239·7; 0·35 [0·17–0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0–167·4) versus NR (NR–NR; 0·24 [0·05–1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3–82·9) versus 105·0 months (20·6–189·6; HR 0·84 [95% CI 0·46–1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7–118·7) versus 134·0 months (89·7–178·3; 0·40 [0·20–0·82], log-rank p=0·0096), and after 5 years was NR (NR–NR) versus 110·4 months (82·7–154·1; 1·28 [0·41–3·99]; log-rank p=0·67), Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.

CSF1R tyrosine kinase inhibitors (TKI) and antibodies yield response rates and tumor control in patients with diffuse type tenosynovial giant cell tumors (dTGCT). The long term management of patients with dTGCT treated with TKI is however not known. We conducted a retrospective single center study on the 39 patients with advanced and/or inoperable dTGCT referred to the Centre Leon Berard for a medical treatment. The clinical characteristics and treatments of patients who had received at least one line of CSF1R TKI or Ab was collected from the electronic patient records and analyzed, after this study was approved by the Institutional Review Board of the Centre Leon Berard. Statistics were conducted using SPSS 23.0. Thirty-nine patients received at least one line of TKI among the 101 patients with histologically confirmed dTGCT refered to this center. Imatinib, nilotinib, pexidartinib, emactuzumab were the most frequently used agents. First line treatment was given for a median duration of 7 months. With a median follow-up from the initiation of TKI of 30 months, the progression-free rate at 30 months is 56% for the 39 patients. 15 patients had recurrent disease after first line CSF1R inhibitor: 12 (80%) received a 2nd line treatment for a median duration of 6 months and a median time to progression (TTP) of 12 months. Six patients had afterwards a recurrent disease and 5 (83%) received a 3rd line treatment for a median duration of 5 months and a median TTP of 9 months. Progression-free rate at 30 months was observed in 3 of 12 (25%) after line 2 and 1 of 5 (20%) after line 3. None of the patients refered died with a median follow-up of 67 months. CSF1R TKI or Ab provide prolonged tumor control and symptom relief for a majority of patients with inoperable or relapsing dTGCT, in first and subsequent lines. Multiple lines are required for close to 50% of patients with relapsing dTGCT.

The effect is obvious in advanced disease in oncology when an experimental drug or agent from the same class is available after disease progression. 2 Routinely collected data allow medical interventions to be evaluated for all ongoing medical interventions in the same patients throughout a study, whether they were for the underlying disease, supportive care, or for concomitant conditions. The goal of the first advanced analysis was to describe, on an observational basis, survival in patients with HER2 negative metastatic breast cancer treated with paclitaxel as first line chemotherapy, with or without bevacizumab, and to explore whether clinical trial results are confirmed in conventional medical care. 3 Despite limitations such as a potential prescription bias, these initiatives focus on major issues, including the need to publish standards that will improve the accuracy of matching hospital data and administrative databases; to mitigate bias; and to improve understanding of the contributions of real world evidence to causal reasoning. Large randomised controlled trials are critical in addressing clinical questions for major patient outcomes such as mortality and individual evaluation of a single medical intervention, but robust real world routinely collected data are ideal for supplementing trial data, as suggested by the US Food and Drug Administration. 4 This challenge is especially relevant to personalised medicine, when drugs are developed \"to treat subsets of patients who may respond to one treatment but not another because of genetic or other factors.\"

When used as maintenance therapy, the PARP inhibitor olaparib provided a significant progression-free survival benefit in women with ovarian cancer who had a response to primary chemotherapy, particularly in those whose tumors were deficient in homologous recombination (e.g., BRCA -mutated tumors). Hematologic toxic effects were observed.

We read with great interest Richard ten Broek and colleagues' meta-analysis about the use of four different anti-adhesion barriers. Reoperation for adhesive small bowel obstruction was the primary outcome.

Metastatic endocrine-resistant breast cancer (MBC) is a disease with poor prognosis and few treatment options. Low lymphocyte count is associated with limited overall survival. In a prospective cohort of lymphopenic patients with HER-2 negative MBC, we assessed the clinical and biological impact of pembrolizumab combined with metronomic cyclophosphamide. This multicenter Phase II study evaluated the safety and clinical activity of pembrolizumab (intravenous (IV), 200mg, every 3 weeks) combined with metronomic cyclophosphamide (50mg/day, per os) in lymphopenic adult patients with HER2-negative MBC previously treated by at least one line of chemotherapy in this setting according to a Simon's minimax two-stage design. Blood and tumor samples were collected to assess the impact of the combined treatment on circulating immune cells and the tumor immune microenvironment through multiparametric flow cytometry and multiplex immunofluorescence analyses. Primary endpoint was the clinical benefit rate at 6 months of treatment (CBR-6M). Secondary endpoints were objective response rate (ORR), duration of response, progression free survival (PFS), and overall survival (OS). Two out of the twenty treated patients presented clinical benefit (one Tumor Mutational Burden (TMB)-high patient with complete response (CR) and one patient with objective response (OR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) associated with a strong increase of cytokine-producing and proliferating CD4 T cells and higher CD8 T cells to macrophage ratios in the tumor. This impact on CD4 and CD8 T cell polyfunctionality was still observed more than one year for the patient with CR. A decreased in their absolute number of CD4 and CD8 memory T cells was observed in other patients. Pembrolizumab combined with metronomic cyclophosphamide was well tolerated, and displayed limited anti-tumoral activity in lymphopenic MBC. Correlative translational data of our trial advocates for additional studies with other chemotherapy combinations.

Pigmented villonodular synovitis (alternatively known as diffuse-type giant cell tumour) is a rare, locally aggressive tumour driven by a specific translocation resulting in the overexpression of colony-stimulating factor 1 (CSF1). CSF1 receptor (CSF1R) inhibitors (ie, tyrosine kinase inhibitors and antibodies) induce a response in patients with pigmented villonodular synovitis. We investigated the safety and efficacy of a CSF1R tyrosine kinase inhibitor, nilotinib, in patients with locally advanced non-resectable pigmented villonodular synovitis. In this phase 2, open-label, single-arm study, we enrolled patients from 11 cancer centres of hospitals in four countries (France, Netherlands, Italy, and Australia). Eligible patients were aged at least 18 years with a WHO performance status of 2 or less, and histologically confirmed progressive or relapsing pigmented villonodular synovitis that was inoperable, or resectable only with mutilating surgery. Patients received oral nilotinib (400 mg twice per day) until disease progression, unacceptable toxicity, or completion of 1 year of treatment. The primary endpoint was the proportion of patients who were progression free at 12 weeks, which was centrally assessed according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were by modified intention to treat (ie, all patients with no major protocol violations who were treated with nilotinib for at least 3 weeks were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT01261429, and the results presented here are the final analysis of the trial. Between Dec 15, 2010, and Sept 28, 2012, we enrolled 56 patients with pigmented villonodular synovitis and treated them with nilotinib. Five (9%) patients discontinued study treatment before week 12; therefore, 51 patients were evaluable for the primary endpoint at 12 weeks. The estimated proportion of patients who were progression free at 12 weeks was 92·6% (95% credible interval 84·3–97·9). 54 (96%) of 56 patients had a treatment-related adverse event. Six (11%) of 56 patients had at least one grade 3 treatment-related adverse event (headache, dizziness, and hepatic disorders [n=1], pruritus and toxidermia [n=1], diarrhoea [n=1], increased γ-glutamyl transferase concentration [n=1], anorexia [n=1], and increased headache [n=1]). No grade 4 or 5 adverse events were reported. One patient had a treatment-related serious adverse event (toxidermia) and two patients had serious adverse events not considered to be related to the study drug (borderline ovarian tumour [n=1] and pilonidal cyst excision [n=1]). More than 90% of patients with locally advanced unresectable progressive pigmented villonodular synovitis achieved disease control with 12 weeks of nilotinib treatment. These results indicate that CSF1R tyrosine kinase inhibitors have anti-tumour activity with manageable toxicity in patients with inoperable progressive pigmented villonodular synovitis. Randomised trials investigating the efficacy of nilotinib for patients with unresectable pigmented villonodular synovitis are warranted. Novartis, Institut National du Cancer, EuroSARC, French National Cancer Institute, General Directorate of Care Supply, Lyon Research Innovation for Cancer, L'Agence nationale de la recherche, Laboratory of Excellence, Fondation ARC pour la recherche sur le cancer, Ligue contre le Cancer (comité de l'Ain), Info Sarcomes, and Association DAM'S.