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Aim: This study aims to evaluate the prognostic role of the KRAS G12C mutation in patients with advanced non-small cell lung cancer and PD-L1 expression ≥50% who are treated with immune checkpoint inhibitor monotherapy., Methods: We conducted a systematic review of clinical studies fulfilling the following criteria: (1) enrolling patients with advanced/metastatic non-small cell lung cancer with high PD-L1 tumour expression receiving first-line therapy with anti-PD-(L)1 immune checkpoint inhibitors; (2) comparing the outcomes of patients with the KRAS G12C mutation to those without this mutation, and (3) reporting overall survival and progression-free survival (PFS). The electronic databases Medline, EMBASE, Cochrane and Google Scholar, along with reference lists, were systematically searched., Results: We identified four publications that fulfilled the inclusion criteria, comprising a total of 469 patients. Of these, two studies reported hazard ratios (HR) for PFS, resulting in a final pooled patient sample of 163 for the meta-analysis. In patients with non-small cell lung cancer who received anti-PD-(L)1 monotherapy, the presence of a KRAS G12C mutation was associated with improved PFS compared to patients with KRAS wild-type tumours, with a pooled hazard ratio of 0.39 and a 95% Confidence Interval (CI) of 0.25-0.63. Among all patients with KRAS mutations, those harbouring a KRAS G12C mutation had improved PFS compared to patients with any other KRAS mutation (pooled HR 0.33, 95% CI 0.19-0.57)., Conclusions: Patients with non-small cell lung cancer who have the KRAS G12C mutation and high PD-L1 expression demonstrate favourable PFS with first-line PD-(L)1 immune checkpoint inhibitor monotherapy compared to patients with KRASwt or other KRAS mutations and high PD-L1 expression.

Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in patients with melanoma, although long-term responses seem restricted in patients who have complete remissions. Many patients develop secondary resistance to TIL-ACT but the involved mechanisms are unclear. In this study, we describe a case of secondary resistance to TIL-ACT possibly due to intratumoral heterogeneity and selection of a resistant tumor cell clone by the transferred T cells. To the best our knowledge, this is the first case of clonal selection of a pre-existing nondominant tumor cell clone; this report demonstrates the mechanism involved in secondary resistance to TIL-ACT that can potentially change current clinical practice because it advocates for T-cell collection from multiple tumor sites and analysis of tumor heterogeneity before treatment with TIL-ACT., (©2024 American Association for Cancer Research.)

Purpose: Many studies on cancer patients investigate the impact of treatment on health-related quality of life (QoL). Typically, QoL is measured longitudinally, at baseline and at predefined timepoints thereafter. The question is whether, at a given timepoint, patients who return their questionnaire (available cases, AC) have a different QoL than those who do not return their questionnaire (non-AC)., Methods: We employed augmented inverse probability weighting (AIPW) to estimate the average QoL of non-AC in two studies on advanced-stage cancer patients. The AIPW estimator assumed data to be missing at random (MAR) and used machine learning (ML)-based methods to estimate answering probabilities of individuals at given timepoints as well as their reported QoL, as a function of auxiliary variables. These auxiliary variables were selected by medical oncologists based on domain expertise. We aggregated results both by timepoint and by time until death and compared AIPW estimates to the AC averages. Additionally, we used a pattern mixture model (PMM) to check sensitivity of our AIPW estimates against violation of the MAR assumption., Results: Our study included 1927 patients with advanced pancreatic and 797 patients with advanced breast cancer. The AIPW estimate for average QoL of non-AC was below the average QoL of AC when aggregated by timepoint. The difference vanished when aggregated by time until death. PMM estimates were below AIPW estimates., Conclusions: Our results indicate that non-AC have a lower average QoL than AC. However, estimates for QoL of non-AC are subject to unverifiable assumptions about the missingness mechanism., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Available treatments for older patients with primary diffuse large B-cell CNS lymphoma (PCNSL) offer progression-free survival of up to 16 months. We aimed to investigate an intensified treatment of high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT) in older patients with PCNSL., Methods: MARTA was a prospective, single-arm, phase 2 study done at 15 research hospitals in Germany. Patients aged 65 years or older with newly diagnosed, untreated PCNSL were enrolled if they had an Eastern Cooperative Oncology Group performance status of 0-2 and were fit for high-dose chemotherapy and autologous HSCT. Induction treatment consisted of two 21-day cycles of high-dose intravenous methotrexate 3·5 g/m 2 (day 1), intravenous cytarabine 2 g/m 2 twice daily (days 2 and 3), and intravenous rituximab 375 mg/m 2 (days 0 and 4) followed by high-dose chemotherapy with intravenous rituximab 375 mg/m 2 (day -8), intravenous busulfan 3·2 mg/kg (days -7 and -6), and intravenous thiotepa 5 mg/kg (days -5 and -4) plus autologous HSCT. The primary endpoint was progression-free survival at 12 months in all patients who met eligibility criteria and started treatment. The study was registered with the German clinical trial registry, DRKS00011932, and recruitment is complete., Findings: Between Nov 28, 2017, and Sept 16, 2020, 54 patients started induction treatment and 51 were included in the full analysis set. Median age was 71 years (IQR 68-75); 27 (53%) patients were female and 24 (47%) were male. At a median follow-up of 23·0 months (IQR 16·8-37·4), 23 (45%) of 51 patients progressed, relapsed, or died. 12-month progression-free survival was 58·8% (80% CI 48·9-68·2; 95% CI 44·1-70·9). During induction treatment, the most common grade 3-5 toxicities were thrombocytopenia and leukopenia (each in 52 [96%] of 54 patients). During high-dose chemotherapy and autologous HSCT, the most common grade 3-5 toxicity was leukopenia (37 [100%] of 37 patients). Treatment-related deaths were reported in three (6%) of 54 patients, all due to infectious complications., Interpretation: Although the primary efficacy threshold was not met, short induction followed by high-dose chemotherapy and autologous HSCT is active in selected older patients with PCNSL and could serve as a benchmark for comparative trials., Funding: Else Kröner-Fresenius Foundation, Riemser Pharma, and Medical Center-University of Freiburg., Competing Interests: Declaration of interests ES received research funding to her institution from the Else Kröner-Fresenius Foundation, Riemser Pharma, Roche Pharma, and Bundesministerium für Bildung und Forschung Germany; received honoraria for lectures from Riemser Pharma and SERB SAS Pharmaceuticals; is on the advisory board for SERB SAS Pharmaceuticals; and is an unpaid member of the steering committee of the German Lymphoma Alliance. AK received honoraria from Roche, Celgene, Sobi, AbbVie, Takeda, and Bristol Myers Squibb; and support for attending meetings or travel from AbbVie, BeiGene, ENSA Pharma, Sobi, and Takeda. ARö received honoraria from Alexion, Amgen, Apellis, Novartis, Roche, Sanofi, and Sobi, and support for attending meetings or travel from Sobi; and is on a data safety monitoring board or advisory board from Alexion, Amgen, Apellis, Novartis, Roche, Bioverativ, Sanofi, Sobi, and Samsung. BK received consulting fees from Dayton Therapeutics and Incyte and honoraria from Dayton Therapeutics, Incyte, and Roche. LP received travel support from Medac and Gilead. JW is an unpaid member of the steering committee of the German Lymphoma Alliance. FS received research funding from Roche Sequencing Solutions, Gilead, and Takeda, and honoraria from AstraZeneca. GIh is part of the data safety monitoring board for Novartis trials. EB-M and HF received institutional research funding from the Else Kröner-Fresenius Foundation and Riemser Pharma. AO received honoraria for presentation from SERB SAS Pharmaceuticals. JF received honoraria from Medac, Neovii, and Riemser; payment for expert testimony from Sanofi; and support for attending meetings or travel from Medac and Neovii. GIl received research funding from Bundesministerium für Bildung und Forschung Germany; honoraria from Roche, Gilead, and Incyte; support for attending meetings or travel from Roche, Janssen, and Lilly; and is on an advisory board for Miltenyi Biotec. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I 2  = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Precision oncology, defined as treatment of patients with targeted therapies matched to specific molecular alterations, has entered routine clinical practice. Particularly in patients with advanced cancer or hematologic malignancies, for whom no further standard therapies are available, this approach is increasingly applied as last resort option outside of the approved indication. However, data on patient outcomes are not systematically collected, analyzed, reported, and shared. We have initiated the INFINITY registry to provide evidence from routine clinical practice to fill this knowledge gap., Methods: INFINITY is a retrospective, non-interventional cohort study conducted at approximately 100 sites in Germany (office-based oncologists/hematologists and hospitals). We aim to include 500 patients with advanced solid tumors or hematologic malignancies who received a non-standard targeted therapy based on potentially actionable molecular alterations or biomarkers. INFINITY aims to provide insights into the use of precision oncology in routine clinical practice within Germany. We systematically collect details on patient and disease characteristics, molecular testing, clinical decision-making, treatment, and outcome., Discussion: INFINITY will provide evidence on the current biomarker landscape driving treatment decisions in routine clinical care. It will also provide insights on effectiveness of precision oncology approaches in general, and of specific drug class/alteration matches used outside their approved indications., Trial Registration: The study is registered at ClinicalTrials.gov, NCT04389541., (© 2023. The Author(s).)

Background: Premature trial discontinuation and non-publication of trial results are still major issues negatively affecting reliable evidence generation., Objectives: To investigate trial completion and publication rate of cancer trials conducted within the Swiss Group for Clinical Cancer Research (SAKK)., Design: Cohort study of clinical trials., Setting: Cohort of interventional cancer trials conducted in Switzerland with accrual closure between 1986 and 2021 identified from the SAKK trial management system., Outcomes: Premature trial discontinuation and publication in peer-reviewed journal., Results: We included 261 trials; median number of recruited patients was 150.5 (range 1-8028). Most trials (67.0%) were randomised. Overall, 76 of 261 (29.1%) trials were prematurely closed for accrual. The three main reasons for premature closure were insufficient accrual in 28 trials, followed by stopping for futility in 17 or efficacy in 8 trials. We included 240 trials for the publication status (21 excluded, because 8 still in follow-up, for 10 the primary completion date was less than a year ago and for 3 the manuscript was submitted, but to accepted yet). 216 of 240 (90.0%) were published as a full article, 14 were published in other formats, leading to an overall publication rate of 95.8%. The rate of premature discontinuation declined over time, with 34.2%, 27.8% and 23.5% in trials activated before 2000, between 2000 and 2009, and since 2010, respectively. We observed an increasing publication rate in peer-reviewed journals over time: 79.2% (closed before 2000), 95.7% (closed between 2000 and 2009) and 93.2% (closed after 2010)., Conclusion: Insufficient patient recruitment is still the major reason for premature trial discontinuation. SAKK has continuously improved its quality management of trial conduct over time leading to increased successful trial completion and publication. However, there is still room for improvement to increase the number of trials reaching their target sample size., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The management of primary central nervous system (PCNSL) is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the limited number of controlled studies available. In 2021, given recent advances and the publication of practice-changing randomized trials, the European Association of Neuro-Oncology (EANO) created a multidisciplinary task force to update the previously published evidence-based guidelines for immunocompetent adult patients with PCNSL and added a section on immunosuppressed patients. The guideline provides consensus considerations and recommendations for the treatment of PCNSL, including intraocular manifestations and specific management of the elderly. The main changes from the previous guideline include strengthened evidence for the consolidation with ASCT in first-line treatment, prospectively assessed chemotherapy combinations for both young and elderly patients, clarification of the role of rituximab even though the data remain inconclusive, of the role of new agents, and the incorporation of immunosuppressed patients and primary ocular lymphoma. The guideline should aid the clinicians in everyday practice and decision making and serve as a basis for future research in the field., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immune checkpoint blockade (ICB) has substantially improved the prognosis of patients with cancer, but the majority experiences limited benefit, supporting the need for new therapeutic approaches. Up-regulation of sialic acid-containing glycans, termed hypersialylation, is a common feature of cancer-associated glycosylation, driving disease progression and immune escape through the engagement of Siglec receptors on tumor-infiltrating immune cells. Here, we show that tumor sialylation correlates with distinct immune states and reduced survival in human cancers. The targeted removal of Siglec ligands in the tumor microenvironment, using an antibody-sialidase conjugate, enhanced antitumor immunity and halted tumor progression in several murine models. Using single-cell RNA sequencing, we revealed that desialylation repolarized tumor-associated macrophages (TAMs). We also identified Siglec-E as the main receptor for hypersialylation on TAMs. Last, we found that genetic and therapeutic desialylation, as well as loss of Siglec-E, enhanced the efficacy of ICB. Thus, therapeutic desialylation represents an immunotherapeutic approach to reshape macrophage phenotypes and augment the adaptive antitumor immune response.

Objective: To describe the characteristics and the survival of patients with cancer with intended off-label use (OLU) cancer treatment and reimbursement request., Design: Cohort study using medical record data., Setting: Three major cancer centres in Switzerland., Participants: 519 patients with cancer and a reimbursement request for OLU between January 2015 and July 2018., Main Outcomes: Characteristics of patients with cancer with and without access to intended OLU. Characteristics included the Glasgow prognostic score (GPS) which includes C reactive protein and albumin and discriminates prognostic groups., Results: OLU was intended for 519 (17%) of 3046 patients with cancer, as first-line treatment in 51% (n=264) and second-line in 31% (n=162). Of the 519 patients, 63% (n=328) were male, 63% (n=329) had solid cancer and 21% (n=111) had a haematological malignancy. Their median overall survival was 23.6 months (95% CI: 19.0 to 32.5). Access to OLU had 389 (75%) patients who were compared with patients without access on average 4.9 years younger (mean; 95% CI: 1.9 to 7.9 years), had a better overall prognosis according to the GPS (51% with GPS of 0 vs 39%; OR: 1.62 (95% CI: 1.01 to 2.59)), had less frequently solid cancer (62% vs 71%; OR: 0.66 (95% CI: 0.41 to 1.05)) and advanced stage cancer (53% vs 70%; OR: 0.48 (95% CI: 0.30 to 0.75)), were more frequently treatment-naive (53% vs 43%; OR: 1.55 (95% CI 1.01 to 2.39)) and were more frequently in an adjuvant/neoadjuvant treatment setting (14% vs 5%; OR: 3.39 (95% CI: 1.45 to 9.93)). Patients with access to OLU had a median OS of 31.1 months versus 8.7 months for patients without access (unadjusted HR: 0.54; (95% CI: 0.41 to 0.70))., Conclusion: Contrary to the common assumption, OLU in oncology is typically not primarily intended for patients with exhausted treatment options. Patient characteristics largely differ between patients with and without access to intended OLU. More systematic evaluations of the benefits and harms of OLU in cancer care and the regulation of its access is warranted., Competing Interests: Competing interests: Andreas M Schmitt received an educational grant (SAKK/ Dr Paul Janssen Fellowship) from Janssen-Cilag AG and support for congress attendance from Novartis. Benjamin Kasenda was employed by iOMEDICO AG, Freiburg, Germany during the conduct of this study. His employer had no role in the design and conduct of the project and preparation, review, approval of the manuscript; and decision to submit the manuscript for publication. He has received support for traveling and consultancy fees from Roche, Abbvie and Riemser that were not related to this project in the 36 months before the resubmission of this manuscript. Markus Joerger’s Institute has received consultant/advisory fees from Novartis, Astra Zeneca, Basilea Pharmaceutica, Bayer, BMS, Debiopharm, MSD, Roche, Sanofi. He is principal/subinvestigator of clinical trials for AstraZeneca, Basilea Pharmaceutica, Bayer, BMS, Daiichi Sankyo, Immunophotonics, Innomedica, Janssen, Lilly, MSD, Novartis, Intensity Therapeutics, Pfizer, Pharmamar, Roche, Sanofi, Takeda. He has received travel grants from BMS, Roche, MSD. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Comprehensive protocols are key for the planning and conduct of randomised clinical trials (RCTs). Evidence of low reporting quality of RCT protocols led to the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist in 2013. We aimed to examine the quality of reporting of RCT protocols from three countries before and after the publication of the SPIRIT checklist., Design: Repeated cross sectional study., Setting: Swiss, German and Canadian research ethics committees (RECs)., Participants: RCT protocols approved by RECs in 2012 (n=257) and 2016 (n=292)., Primary and Secondary Outcome Measures: The primary outcomes were the proportion of reported SPIRIT items per protocol and the proportion of trial protocols reporting individual SPIRIT items. We compared these outcomes in protocols approved in 2012 and 2016, and built regression models to explore factors associated with adherence to SPIRIT. For each protocol, we also extracted information on general trial characteristics and assessed whether individual SPIRIT items were reported RESULTS: The median proportion of reported SPIRIT items among RCT protocols showed a non-significant increase from 72% (IQR, 63%-79%) in 2012 to 77% (IQR, 68%-82%) in 2016. However, in a preplanned subgroup analysis, we detected a significant improvement in investigator-sponsored protocols: the median proportion increased from 64% (IQR, 55%-72%) in 2012 to 76% (IQR, 64%-83%) in 2016, while for industry-sponsored protocols median adherence was 77% (IQR 72%-80%) for both years. The following trial characteristics were independently associated with lower adherence to SPIRIT: single-centre trial, no support from a clinical trials unit or contract research organisation, and investigator-sponsorship., Conclusions: In 2012, industry-sponsored RCT protocols were reported more comprehensively than investigator-sponsored protocols. After publication of the SPIRIT checklist, investigator-sponsored protocols improved to the level of industry-sponsored protocols, which did not improve., Competing Interests: Competing interests: BvN is currently employed by Roche Pharma AG, Grenzach-Wyhlen, Germany. BK is currently employed by iOMEDICO AG, Freiburg, Germany. All other authors declare no financial relationships with any organisation that might have an interest in the submitted work and no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs., Methods and Findings: We included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment. Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%). The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations., Conclusions: We have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DG contributed to the ASPIRE project as part of his PhD thesis before his current employment with Idorsia Pharmaceuticals Ltd. (his current employer had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript). BvN contributed to the ASPIRE project as part of her PhD thesis before her current employment with Roche (her current employer had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript). All authors have declared that no competing interests exist.

Objectives: To investigate the adherence of randomised controlled trial (RCT) protocols evaluating non-regulated interventions (including dietary interventions, surgical procedures, behavioural and lifestyle interventions, and exercise programmes) in comparison with regulated interventions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement., Methods: We conducted a repeated cross-sectional investigation in a random sample of RCT protocols approved in 2012 (n = 257) or 2016 (n = 292) by research ethics committees in Switzerland, Germany, or Canada. We investigated the proportion of accurately reported SPIRIT checklist items in protocols of trials with non-regulated as compared to regulated interventions., Results: Overall, 131 (24%) of trial protocols tested non-regulated interventions. In 2012, the median proportion of SPIRIT items reported in these protocols (59%, interquartile range [IQR], 53%-69%) was lower than in protocols with regulated interventions (median, 74%, IQR, 66%-80%). In 2016, the reporting quality of protocols with non-regulated interventions (median, 75%, IQR, 62%-83%) improved to the level of regulated intervention protocols, which had not changed on average., Conclusions: Reporting of RCT protocols evaluating non-regulated interventions improved between 2012 and 2016, although remained suboptimal. SPIRIT recommendations need to be further endorsed by researchers, ethics committees, funding agencies, and journals to optimize reporting of RCT protocols., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: In many health systems, access to off-label drug use is controlled through reimbursement restrictions by health insurers, especially for expensive cancer drugs., Objective: To determine whether evidence from randomized clinical trials is associated with reimbursement decisions for requested off-label use of anticancer drugs in the Swiss health system., Design, Setting, and Participants: This cross-sectional study used reimbursement requests from routinely collected health records of 5809 patients with drug treatment for cancer between January 2015 and July 2018 in 3 major cancer centers, covering cancer care of approximately 5% of the Swiss population, to identify off-label drug use. For each off-label use indication with 3 or more requests, randomized clinical trial evidence on treatment benefits was systematically identified for overall survival (OS) or progression-free survival (PFS). Data were analyzed from August 2018 to December 2020., Exposures: Available randomized clinical trial evidence on benefits for OS or PFS for requested off-label use indications., Main Outcomes and Measures: The main outcome was the association between evidence for treatment benefit (expressed as improved OS or PFS) and reimbursement in multivariable regression models., Results: Among 3046 patients with cancer, 695 off-label use reimbursement requests in 303 different indications were made for 598 patients (median [interquartile range] age, 64 [53-73] years; 420 [60%] men). Off-label use was intended as first-line treatment in 311 requests (45%). Reimbursement was accepted in 446 requests (64%). For 71 indications, including 431 requests for 376 patients, there were 3 or more requests. Of these, 246 requests (57%) had no supporting evidence for OS or PFS benefit. Reimbursement was granted in 162 of 246 requests without supporting evidence (66%). Of 117 requests supported by OS benefit, 79 (67%) were reimbursed, and of 68 requests supported by PFS benefit alone, 54 (79%) were reimbursed. Evidence of OS benefit from randomized clinical trials was not associated with a higher chance of reimbursement (odds ratio, 0.76, 95% CI, 0.45-1.27)., Conclusions and Relevance: These findings suggest that in a health care system enabling access to off-label use, it was frequently intended as a first-line treatment in cancer care. Availability of randomized clinical trial evidence showing survival benefit was not associated with reimbursement decisions for off-label anticancer drug treatment in Switzerland. A transparent process with criteria considering clinical evidence is needed for evidence-based reimbursement decisions to ensure fair access to cancer treatments.

Importance: Clinical trial evidence used to support drug approval is typically the only information on benefits and harms that patients and clinicians can use for decision-making when novel cancer therapies become available. Various evaluations have raised concern about the uncertainty surrounding these data, and a systematic investigation of the available information on treatment outcomes for cancer drugs approved by the US Food and Drug Administration (FDA) is warranted., Objective: To describe the clinical trial data available on treatment outcomes at the time of FDA approval of all novel cancer drugs approved for the first time between 2000 and 2016., Design, Setting, and Participants: This comparative effectiveness study analyzed randomized clinical trials and single-arm clinical trials of novel drugs approved for the first time to treat any type of cancer. Approval packages were obtained from drugs@FDA, a publicly available database containing information on drug and biologic products approved for human use in the US. Data from January 2000 to December 2016 were included in this study., Main Outcomes and Measures: Regulatory and clinical trial characteristics were described. For randomized clinical trials, summary treatment outcomes for overall survival, progression-free survival, and tumor response across all therapies were calculated, and median absolute survival increases were estimated. Tumor types and regulatory characteristics were assessed separately., Results: Between 2000 and 2016, 92 novel cancer drugs were approved by the FDA for 100 indications based on data from 127 clinical trials. The 127 clinical trials included a median of 191 participants (interquartile range [IQR], 106-448 participants). Overall, 65 clinical trials (51.2%) were randomized, and 95 clinical trials (74.8%) were open label. Of 100 indications, 44 indications underwent accelerated approval, 42 indications were for hematological cancers, and 58 indications were for solid tumors. Novel drugs had mean hazard ratios of 0.77 (95% CI, 0.73-0.81; I2 = 46%) for overall survival and 0.52 (95% CI, 0.47-0.57; I2 = 88%) for progression-free survival. The median tumor response, expressed as relative risk, was 2.37 (95% CI, 2.00-2.80; I2 = 91%). The median absolute survival benefit was 2.40 months (IQR, 1.25-3.89 months)., Conclusions and Relevance: In this study, data available at the time of FDA drug approval indicated that novel cancer therapies were associated with substantial tumor responses but with prolonging median overall survival by only 2.40 months. Approval data from 17 years of clinical trials suggested that patients and clinicians typically had limited information available regarding the benefits of novel cancer treatments at market entry.

Background: Clearly structured and comprehensive protocols are an essential component to ensure safety of participants, data validity, successful conduct, and credibility of results of randomized clinical trials (RCTs). Funding agencies, research ethics committees (RECs), regulatory agencies, medical journals, systematic reviewers, and other stakeholders rely on protocols to appraise the conduct and reporting of RCTs. In response to evidence of poor protocol quality, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline was published in 2013 to improve the accuracy and completeness of clinical trial protocols. The impact of these recommendations on protocol completeness and associations between protocol completeness and successful RCT conduct and publication remain uncertain., Objectives and Methods: Aims of the Adherence to SPIrit REcommendations (ASPIRE) study are to investigate adherence to SPIRIT checklist items of RCT protocols approved by RECs in the UK, Switzerland, Germany, and Canada before (2012) and after (2016) the publication of the SPIRIT guidelines; determine protocol features associated with non-adherence to SPIRIT checklist items; and assess potential differences in adherence across countries. We assembled an international cohort of RCTs based on 450 protocols approved in 2012 and 402 protocols approved in 2016 by RECs in Switzerland, the UK, Germany, and Canada. We will extract data on RCT characteristics and adherence to SPIRIT for all included protocols. We will use multivariable regression models to investigate temporal changes in SPIRIT adherence, differences across countries, and associations between SPIRIT adherence of protocols with RCT registration, completion, and publication of results. We plan substudies to examine the registration, premature discontinuation, and non-publication of RCTs; the use of patient-reported outcomes in RCT protocols; SPIRIT adherence of RCT protocols with non-regulated interventions; the planning of RCT subgroup analyses; and the use of routinely collected data for RCTs., Discussion: The ASPIRE study and associated substudies will provide important information on the impact of measures to improve the reporting of RCT protocols and on multiple aspects of RCT design, trial registration, premature discontinuation, and non-publication of RCTs observing potential changes over time.