Intravesical Bacillus Calmette-Guérin (BCG) is the standard-of-care treatment for high-risk non-muscle invasive bladder cancer (HR-NMIBC). However, patients with BCG-unresponsive disease are unlikely to benefit from further BCG. To overcome BCG unresponsiveness, the addition of immune checkpoint inhibition (ICI) to BCG has been investigated in three recently randomized controlled trials: CREST, POTOMAC, and ALBAN, studying sasanlimab, durvalumab, and atezolizumab, respectively. While CREST and POTOMAC demonstrated improvements in event/disease-free survival (EFS/DFS), ALBAN was negative. Several potential explanations have been proposed for these discrepant findings. We propose an additional explanation: censoring. In the experimental arm, toxicity-related discontinuation may preferentially remove frailer patients, artificially enriching the remaining population for healthier individuals potentially biasing EFS or DFS. We explored censoring patterns across trials and conducted sensitivity analyses based on reconstructed Kaplan-Meier curves, and modifying only a few patients in POTOMAC and CREST eroded the EFS/DFS benefit as reported. The addition of immunotherapy to BCG significantly increases toxicity, and supports that some level of toxicity-related informative censoring might have differentially affected the three trials. Informative censoring may represent an important, underrecognized explanation for the inconsistent efficacy results reported across ICI plus BCG trials. More broadly, given the expanding use of immunotherapy in earlier disease settings and the reliance on time-to-event endpoints in open-label trials with differential toxicity, systematic attention to censoring mechanisms is essential for accurate interpretation.

Background The quality of video content published by oncology media outlets is poorly characterized. We analyzed short form videos discussing oncology trials to determine the methodological rigor of their reporting, whether content invoked shared decision-making principles, and the prevalence of relevant financial conflicts of interest (FCOIs) among speakers. Methods Videos discussing oncology trials published by Oncology Live TV [OncLive TV], Targeted Oncology, and the Video Journal Oncology [VJ Oncology] between January and April 2024 were analyzed. Abstracted data included whether study characteristics, therapy characteristics, treatment recommendations, and shared decision-making principles were discussed. Speakers’ general payment data from 2021 to 2023 were extracted from the U.S. Centers for Medicaid and Medicare Services Open Payments database. Results A majority of the 97 identified videos did not mention inclusion criteria (72%), exclusion criteria (95%), study limitations (81%), study strengths (91%), standard of care (75%), cost (96%), or shared decision-making (91%). Nearly one in five (18%) made specific treatment recommendations, of which only 13% invoked shared decision-making principles. Over half (52%) had speakers who received general payments from an entity with a financial interest in the discussed therapy. Conclusion Digital coverage of oncology trials has gaps in the transparency, methodological rigor, and disclosure of FCOIs, and rarely includes shared decision-making principles—representing a missed opportunity for outlets to disseminate patient-centered, evidence-based information to their audiences. Clear standards for reporting trial and therapy characteristics and FCOI disclosures among oncology media outlets would promote responsible dissemination of emerging evidence and further their mission to promote evidence-based and patient-centered care.

For the first time, an anti-cancer therapy-the combination of nivolumab and ipilimumab-has been recommended for tumour-agnostic reimbursement without biomarker requirements. In a bold step, Australia's Pharmaceutical Benefits Advisory Committee (PBAC) proposes that prescribing should be guided by "clinical judgement" for undefined "immunotherapy-sensitive" advanced or metastatic cancers. This decision raises several concerns. Firstly, tumour-agnostic approvals have typically depended on molecular markers such as MSI-H/dMMR and high tumour mutational burden (TMB), which predict substantially higher response rates. In contrast, activity in biomarker-low populations is overall limited. Second, immune-related toxicities, including their potential for long-lasting impact on quality of life, are rather unique to immunotherapy, and particularly significant with dual checkpoint inhibition. Third, a broad tumour-agnostic listing risks incentivising use in tumour types even where evidence is negative, potentially displacing effective therapies and reducing enrolment in clinical trials. Collectively, such authorisation would increase unwarranted variation in clinical practice, expose many patients to serious adverse events without benefit, and undermine the evidence generation needed for sustainable reimbursement. We recommend managed access programs that define explicit eligibility criteria, use biomarker-based patient selection when supported by evidence, and implement structured prospective registries to systematically track patient outcomes, adverse events, and cost-effectiveness. This approach would ensure that data collected can directly inform future evidence-based reimbursement and coverage decisions.

Smoldering multiple myeloma (SMM) represents a biological continuum between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM), and not all individuals with smoldering disease will progress to symptomatic multiple myeloma. The AQUILA trial compared daratumumab with active monitoring in high-risk SMM and led to regulatory approvals and guideline updates. However, several challenges complicate interpretation of contemporary trials, including QuiRedex (lenalidomide-dexamethasone) and ECOG E3A06 (lenalidomide). Progression definitions differ across studies. Progression-free survival (PFS) in SMM reflects progression to MM using the hypercalcemia, renal dysfunction, anemia, and bone disease (CRAB) criteria, but AQUILA uniquely included the "SLiM" biomarkers. Presymptomatic disease constituted most progression events, and the clinical benefit of delaying progression to SLiM multiple myeloma remains unknown. Imaging frequency and modality also vary, with advanced imaging in AQUILA increasing detection of asymptomatic lesions and limiting comparability with prior trials. AQUILA is further affected by concerns about informative censoring. In open-label trials, patient dropouts may not occur at random, and reconstructed Kaplan-Meier analyses and sensitivity analyses indicate that modest changes in censoring assumptions could eliminate the appearance of an OS advantage. Additionally, OS was a secondary endpoint in AQUILA and in previous trials, and none of which were powered for survival. Overall, before stronger clinical evidence showing otherwise, observation including appropriate surveillance should remain the standard of care for high-risk smoldering multiple myeloma.

Tumor Treating Fields (TTFs) deliver low-intensity electric fields through adhesive skin arrays and have been approved in different oncology indications. However, concerns remain regarding the evidence supporting their benefit. Here, we highlight four limitations. First, TTFields utilization includes 24/7 assistance, home deliveries, and regular home-based interactions for array changes. In the absence of sham-controlled randomized trials, which are the equivalent of placebo-controlled trials for devices, the specific contribution of TTFields cannot be distinguished from the additional supportive care and infrastructure accompanying device use. Second, although a mechanistic rationale exists, the biological plausibility remains limited, particularly because of the lack of validated human in vivo dosimetry data. Third, while reviewing six pivotal randomized trials, we describe the use of suboptimal control arms in half of them, including two trials that reported a survival gain. As a result, it remains unclear whether such a benefit would also be observed in settings with optimal access to contemporary standard-of-care treatments. Fourth, we describe occurrences of protocol changes and unusual censoring patterns, both warranting further examination. The specificities of regulatory pathways for medical devices permit greater evidentiary flexibility than for drugs, while post-market evidence generation remains insufficiently transparent. In contrast to other types of devices, a single company has generated the main evidence base with no substantial replication from competing manufacturers to date. High-quality sham-controlled trials and harmonized post-market obligations are needed to isolate the specific contribution of TTFs and determine the extent to which the observed clinical benefit derives from the device itself as compared with the care surrounding its use. This is particularly relevant in patients with a poor prognosis, as increased clinical attention and supportive care may themselves contribute to improved outcomes.

Viral infections are estimated to contribute to 12% to 20% of all cancers worldwide, with virus-driven malignancies disproportionately affecting low- and middle-income countries, whereas metabolic and nonviral factors predominate in high-income regions. Key oncogenic viruses that cause solid tumors include high-risk human papillomaviruses, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, Kaposi sarcoma-associated herpesvirus, and Merkel cell polyomavirus. Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy by boosting immune responses against tumors. Although viral infection-associated tumors often exhibit "hot" immune profiles, clinical outcomes with ICIs remain inconsistent. Some studies report improved survival in virus-associated cancers, whereas others indicate no clear benefit, which might reflect high variability in tumor microenvironments and immune responses. In this review, we aim to explore the direct and indirect contribution of different viruses to carcinogenesis in solid tumors, with a particular focus on immunotherapy effectiveness based on infection status.

Three different PARP (Poly (ADP-ribose) Polymerase)-inhibitors have been approved in combination with androgen receptor pathway inhibitors (ARPIs) for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Regulatory authorities, however, have divergent opinions. Although the US Food and Drug Administration (FDA) has limited approval of two PARP-inhibitors to patients with BRCA mutations or other alterations in homologous recombination repair (HRR) genes, the European Medicines Agency (EMA) has approved the indication for the overall mCRPC population, irrespective of HRR status. Of all trials, only MAGNITUDE, evaluating niraparib and abiraterone, led to aligned conclusions from both the EMA and FDA, as its design effectively identified the subgroup most likely to benefit. The discrepancies observed in the assessment of the other two trials stem from limitations in their designs. A key issue with PROpel is the lack of patient stratification based on known biomarkers, and the subgroup analysis is underpowered. In TALAPRO-2, although an enriched cohort is included, combining these data with the all-comers cohort results in a potentially misleading conclusion. Currently, there is a need for harmonisation in biomarker-driven trial designs and the definition of homologous recombination repair deficiency (HRD). Access to biomarker and clinical data from all PARP-inhibitor trials would allow researchers to clarify the impact of different HRR mutations on outcomes.

Though vascular endothelial growth factor receptor (VEGFR)-targeting drugs have been approved in the past and are known for their potential off-site action, fruquintinib is a possible new, specific inhibitor of VEGFR-1, 2, and 3. The US Food and Drug Administration (FDA) recently approved fruquintinib based on the FRESCO-2 trial results. However, the FRESCO-2 trial is potentially problematic given the suboptimal choice of placebo in the trial, and the poor cost-effectiveness of fruquintinib. Firstly, we argue that fruquintinib should have been tested against regorafenib, and only offered a moderate benefit despite being tested against a suboptimal placebo. Secondly, fruquintinib is likely cost ineffective (measured in quality-adjusted life years (QALY)), with a crude estimation placing its value over a million USD per QALY. Lastly, we show that the use of a suboptimal placebo is unfortunately not new.

BACKGROUND:Immune checkpoint inhibitors (ICIs) have transformed the landscape of tumor therapy. Yet, little is known about the collective long-term survival from these therapies. We sought to characterize long-term survival. METHODS:In a cross-sectional analysis of US FDA oncology ICI drug approvals (2011-2023), we retrieved data from supporting registration trials. We examined the percentage of study participants surviving at 12-, 24-, 36-, and 60-months follow-up; the American Society of Clinical Oncology (ASCO) Value Framework Tail of the Curve calculation; and the correlation between the longest time with 10 % of patients still at-risk and the difference in the percentage of patients in each treatment group alive. RESULTS:Out of 88 included approvals, 20 (22.7 %) qualified for ASCO's tail of the curve bonus. Twenty-seven studies (30.7 %) did not report OS at 12 months; 44 (50.0 %) did not report OS at 24 months; 60 (68.2 %) did not report OS at 36 months; and 78 (88.6 %) did not report OS at 60 months. We found no correlation between the last time that at least 10 % of patients were still at-risk and the difference in the percentage of patients in each group still alive at that time-point (R2=0.1; p = 0.30). Among 81 studies that reported an OS curve, the longest time with at least 10 % of participants at-risk was a median of 30 months. The median difference in survival was 8 %. CONCLUSIONS:Few registration trials testing ICI oncology therapies report long-term overall survival data. The gathering and reporting of this information should be incentivized so that the value of these drugs for patients can be more readily assessed.

The share of immune checkpoint inhibitors (ICIs) used in cancer treatment has rapidly increased in recent years. Although ICIs have the potential to provide a durable survival benefit in a subset of patients, many patients do not respond to these costly and often toxic therapies.Recent retrospective clinical data indicate that the time of day of ICI infusion may be a powerful modulator of their efficacy. These observational studies suggest an enhanced efficacy of morning over evening infusion. However, randomized trials have not confirmed in other fields findings obtained by observational studies, possibly because of selection bias and residual confounding factors. Thus, while the data are intriguing, the time dependence of the efficacy of immunotherapy needs to be confirmed in pragmatic randomized clinical trials. Here, we provide an overview of the modulation of ICI efficacy by the timing of immunotherapy infusion and critically discuss the biological rationale for chrono-immunotherapy, the circadian regulation of the immune system, and the need for pragmatic randomized clinical trials to confirm an effect of the timing of immunotherapy infusions on patient outcomes.

In 2018, we estimated that eligibility for and response to immune checkpoint inhibitor (ICI) therapies were 44% and 12%, respectively. Since these estimates were published, there have been additional approvals. We sought to provide updated estimates of the percentage of patients with advanced and/or metastatic cancers in the US who are eligible for and respond to immune checkpoint inhibitors (ICIs). Using a cross-sectional analysis (2011-2023) of US Food and Drug Administration approvals (FDA) and deaths reported by the American Cancer Society, we estimated the percentage of patients in the US with advanced or metastatic cancers who are eligible and respond to ICI therapies and the long-term response of ICI drugs. Eleven ICI drugs have been approved for 20 tumor types in the metastatic setting. The estimated eligibility for ICIs increased from 1.54% in 2011 to 56.55% in 2023. The estimated response to ICIs increased from 0.14% in 2011 to 20.13% in 2023. The tumor types with the highest contribution to response and eligibility estimates in 2023 were non-small-cell lung cancer with PD-L1 expression ≤50% and PD-L1 expression >50%. Sixteen drug approvals had long-term progression-free survival (PFS) data available at 3 years follow-up, and 2 had PFS data at 5 years follow-up. Estimated eligibility and response have increased over time, but many people with advanced or metastatic cancers are currently ineligible for ICIs. Only about one-fifth of the patients will respond. Given the wide range of uses, the cost implications of ICIs globally are large.

The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene has revolutionized the management of lung cancer, enabling the development of targeted tyrosine kinase inhibitors (TKIs). These therapies offer improved survival and reduced side effects compared with conventional treatments. Recent advancements have significantly reshaped the treatment paradigm for EGFR-mutant non-small cell lung cancer. TKIs are now incorporated into the management of early stage and locally advanced disease, and phase 3 trials have explored combination strategies in metastatic settings. Although these intensified approaches improve progression-free survival, they come with increased toxicity and higher costs, underscoring the need for precise patient selection to maximize benefit. Emerging data on biomarkers, such as co-mutations and circulating tumor DNA, show promise for refining treatment decisions. In addition, significant progress in understanding resistance mechanisms to EGFR TKIs has broadened therapeutic options. This review provides a comprehensive overview of the current landscape of EGFR-mutant nonsmall cell lung cancer, highlighting recent breakthroughs and discussing strategies to optimize treatment based on the latest evidence.

This cross-sectional study compares US Food and Drug Administration–approved anticancer “me-too,” or next-in-class, drugs with randomized clinical trial comparators of first-in-class drugs.

The LUNAR trial investigated the addition of Tumor Treating Fields (TTFs) to "standard therapy" in patients with metastatic lung cancer after at least one line of platinum-based chemotherapy. The "standard therapy" was either an anti-PD(L)1 therapy (immunotherapy) or docetaxel. The addition of TTFs provided a 3.3 months median survival gain. We raised concerns about LUNAR results internal and external validity. First, patient selection and the control arm do not mirror current practice. Two-thirds of patients did not receive prior immunotherapy, which is standard in first-line treatment. Also, the "choice" of the "standard therapy" was restricted by drug availability, resulting in 41 % of patients not receiving immunotherapy during the trial - those allocated to receive docetaxel - had no prior exposure to immunotherapy. Some patients may have harbored actionable mutations, and did not receive targeted therapy. Second, we raised statistical questions. The sample size was shrunk after an unplanned analysis, with unshared and unclear justifications. The decision may have been influenced by a chance deviation in data favoring the intervention. Also, as significantly more patients were censored after withdrawals in the TTFs group, informative censoring could have amplified the survival gain. Third and last, without a sham-control design (the equivalent of placebo for devices), it's hard to isolate the impact of TTFs from the extra-attention associated with its administration (continuous 24/7 support, frequent home-based interactions). Overall, LUNAR do not apply to clinical settings where immunotherapy and molecular testing is offered, and many factors may have artificially boosted the reported survival gain. A sham-controlled trial is needed to answer whether TTFs are beneficial.

New therapeutic agents in oncology are emerging rapidly, both in terms of the number of approved drugs and the technological and biological innovation of new treatments. Antibody-drug conjugates (ADC) offer a promising cancer therapy by specifically targeting tumor cells. ADC are composed of a monoclonal antibody recognizing the tumor cell via specific antigens, coupled with a potent cytotoxic agent that resembles classical chemotherapy. This mechanism of action aims to deliver the cytotoxic agent directly to the tumor cell and spare healthy cells. However, important toxicities have been reported. On the one hand, these toxicities are related to the cytotoxic agents that, once delivered locally, spread to other parts of the body. On the other hand, there are specific toxicities associated with these ADC, which we address in this article.

In time-to-event analyses of clinical trials, some data will inevitably be missing at the time of data cut-off. The Kaplan-Meier estimator aims to address these "incomplete observations", which has become a cornerstone of statistical methods in oncology trials. However, for the Kaplan-Meier principles to apply, censoring must occur randomly. If patients drop out for reasons related to treatment, this may lead to a remaining patient population with a different underlying risk of experiencing the event, producing biased estimates referred to as informative censoring. Here, we introduce the concept of an "informative censoring area", defined as a time period over which informative censoring more likely occurred. We demonstrate how examining the evolution of censoring patterns over time can help distinguish between informative and non-informative censoring. Using two clinical trials as examples, we show that comparing data from different follow-up periods reveals distinct patterns: NADINA trial showed early censored patients progressively disappearing with longer follow-up, indicating non-informative censoring, while NATALEE trial demonstrated stable early censoring patterns over time, reinforcing concerns of informative censoring. This approach helps identify when early censoring remains significant even with longer follow-up. We conclude that studying the evolution of censoring patterns over time may help differentiate between informative and non-informative censoring, reinforcing the need for systematic data sharing including reasons for censoring in trials seeking regulatory approval.