Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers.

Treatment Beyond Progression After Anti-PD-1 Blockade in Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICI) can induce atypical tumor responses including pseudoprogression in a subset of patients who may benefit from treatment beyond progression. While ICIs have emerged as frontline treatments for hepatocellular carcinoma (HCC) and are associated with clinical benefit in a minority of patients, it is unclear whether treatment beyond progression has utility in this disease type. In a multicenter cohort analysis, treatment beyond progression was associated with no new safety signals, objective responses in 5.8% of patients, and disease control in 44% of patients. Progression-free survival and overall survival were comparable between patients treated beyond progression and patients treated with subsequent therapies, demonstrating that treatment beyond progression was not detrimental to survival outcomes. Rather, treatment beyond progression may benefit select patients with HCC and could represent a viable strategy for maximizing treatment benefit in these patients. SIGNIFICANCE: Treatment beyond progression with ICIs in patients with HCC is safe and may benefit a subset of patients due to later-onset tumor responses or disease stability. These findings may guide the design of trials testing ICIs in HCC and the use of treatment beyond progression in routine practice.

Surrogate and modified endpoints for immunotherapy in advanced hepatocellular carcinoma.

BACKGROUND AND AIMS: Immunotherapies have altered the treatment paradigm in HCC. Surrogate and modified endpoints are used to assess early success in clinical studies and guide clinical practice. We sought to determine whether surrogate endpoints and modifications to the conventional criteria for tumor response (RECIST), including modified RECIST (mRECIST) and immune-modified RECIST (imRECIST), are valid measures to predict overall survival (OS) in HCC treated with immunotherapies. APPROACH AND RESULTS: We performed an individual-level post hoc analysis of patients treated with atezolizumab and bevacizumab in the IMbrave150 trial (N = 279) and a cross-sectional analysis of a multicenter real-world patient cohort treated with immunotherapy (N = 328). Landmark analyses showed that objective response rates by RECIST were associated with greater OS including among Child-Pugh A and B patients and among patients treated with immunotherapies in the first- or second-line setting (IMbrave150: HR 0.24, 95% CI, 0.17-0.33; RW: HR 0.25, 95% CI, 0.15-0.43). Objective response rates by mRECIST or imRECIST were not associated with the greater predictive power of OS benefit (mRECIST: HR 0.30, 95% CI, 0.22-0.42; imRECIST: HR 0.36, 95% CI, 0.30-0.51). Progression-free survival determined by RECIST was only moderately correlated with OS, and this association was not improved using mRECIST or imRECIST. CONCLUSIONS: Our results clarify the utility of surrogate and modified endpoints in HCC treated with immunotherapies and support the use of RECIST objective response rates as an appropriate signal-finding measure for the evaluation of emerging treatments. Contrary to their intended purpose, mRECIST and imRECIST did not provide meaningful improvements in predicting OS benefits.

Association between immune-related adverse event timing and treatment outcomes.

The timing of immune-related adverse events (irAE) associated with immune checkpoint inhibitors (ICI) is highly variable. Although the development of irAE has been associated with ICI clinical benefit, how irAE timing influences this association is unknown. We analyzed two independent cohorts including 154 patients with non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors at a single institution (UTSW cohort) and a multi-center cohort of 433 patients with NSCLC who received second-line anti-PD-1/PD-L1 therapy (Global cohort) to assess the association between ICI outcomes and irAE timing. In both cohorts, late-onset irAE occurring more than 3 months after ICI initiation compared to irAE occurring earlier were associated with greater rates of radiographic response (UTSW cohort, 41% versus 28%, P = .26; Global cohort, 60% versus 35%, P = .02), longer progression-free (UTSW cohort, 13.7 versus 5.6 months, P < .01; Global cohort, not reached versus 6.0 months, P < .01) and overall survival (UTSW cohort, 30.9 versus 14.6 months, P < .01; Global cohort, not reached versus 10.6 months, P < .01). Modified landmark analysis at 6 months confirmed an overall survival difference between early- and late-onset irAE. Late-onset irAE was similarly associated with greater response rates and prolonged survival in a cohort of 130 patients with non-NSCLC malignancies, suggesting a conserved association across tumor types. The favorable association between irAE and ICI clinical outcomes may be attributed to later-onset events, which is not wholly explained by survivor bias. These results allude to a distinct biology between early- and late-onset irAE and may guide clinician expectations and thresholds for continuing or modifying immunotherapy.

Impact of tumor mutational burden on checkpoint inhibitor drug eligibility and outcomes across racial groups.

The FDA approval of immune checkpoint inhibitors for cancers with tumor mutation burden (TMB) of at least 10 mut/Mb is postulated to reduce healthcare disparities by broadly expanding treatment eligibility. In a cohort of 39,400 patients with available genomic and race data, black and Asian patients were less likely to have TMB-high cancers in multiple types of malignancies based on the currently approved cut-off. Decreasing TMB thresholds preferentially increased the eligibility of minority patients for immune checkpoint inhibitors while retaining predictive value of treatment benefit in a cohort of immune checkpoint inhibitor treated patients. This study highlights differing distributions of TMB-high cancers between racial groups and provides guidance in developing more rational eligibility criteria for immune checkpoint inhibitors.

Clinical and biological determinants of circulating tumor DNA detection and prognostication using a next-generation sequencing panel assay.

Circulating tumor DNA (ctDNA) is utilized for molecular profiling of cancers, and is under investigation for a growing number of applications based on the assumption that ctDNA levels faithfully reflect disease burden. Our objective was to investigate whether patient and tumor characteristics may impact ctDNA detection or levels and the prognostic significance of ctDNA levels or mutations. We performed a retrospective cohort analysis of a comprehensively annotated cohort of 561 patients at a National Cancer Institute-designated comprehensive cancer center with advanced solid cancers who underwent ctDNA testing using a commercial targeted next-generation sequencing assay. ctDNA detection in advanced cancers was associated with older age, non-obese body mass index, and diabetes, but not with tumor diameter, volume, lesion number, or other pathological features. Regression models indicate that no more than 14.3% of the variance in ctDNA levels between patients was explained by known clinical factors and disease burden. Even after adjusting for established prognostic factors and tumor burden, ctDNA levels were associated with worse survival among patients without prior systemic therapy, while ctDNA mutations were associated with survival among patients who previously received systemic treatment. These findings uncover clinical factors that affect ctDNA detection in patients with advanced cancers and challenge the convention that ctDNA is a surrogate for tumor burden. Our study also indicates that the prognostic value of ctDNA levels and mutations are independent of tumor burden and dependent on treatment context.

Clinical Efficiency and Safety Outcomes of Virtual Care for Oncology Patients During the COVID-19 Pandemic.

PURPOSE: Telehealth has been an integral response to the COVID-19 pandemic. However, no studies to date have examined the utility and safety of telehealth for oncology patients undergoing systemic treatments. Concerns of the adequacy of virtual patient assessments for oncology patients include the risk and high acuity of illness and complications while on treatment. METHODS: We assessed metrics related to clinical efficiency and treatment safety after propensity matching of newly referred patients starting systemic therapy where care was in large part replaced by telehealth between March and May 2020, and 206 newly referred patients from a similar time period in 2019 where all encounters were in-person visits. RESULTS: Patient-initiated telephone encounters that capture care or effort outside of visits, time to staging imaging, and time to therapy initiation were not significantly different between cohorts. Similarly, 3 month all-cause or cancer-specific emergency department presentations and hospitalizations, and treatment delays were not significantly different between cohorts. There were substantial savings in travel time with virtual care, with an average of 211.4 minutes saved per patient over a 3-month interval. CONCLUSION: Our results indicate that replacement of in-person care with virtual care in oncology does not lead to worse efficiency or outcomes. Given the increased barriers to patients seeking oncology care during the pandemic, our study indicates that telehealth efforts may be safely intensified. These findings also have implications for the continual use of virtual care in oncology beyond the pandemic.

Prevalence of Female Authors in Case Reports Published in the Medical Literature.

Importance: Underrepresentation of female authors in research publications is prevalent, but it is unclear whether this is attributable to sex disparities in research conduct or authorship practices. Case reports are a poorly understood component of the biomedical corpus, and the production of anecdotal observations is not confounded by factors associated with disparities in female representation in research publications. Whether female authorship disparities exist in nonresearch publications of clinical information is unknown. Objectives: To examine the authorship of case reports and elucidate factors associated with sex disparity. Design and Setting: Cross-sectional study of all case reports published by US authors in 2014 and 2015 indexed in PubMed performed from July 2015 to July 2018. Main Outcomes and Measures: The primary outcome measure was the proportion of female first authors. The secondary outcome measures were the proportion of female last authors and female authorship representation among different clinical specialties. Results: Bibliometric data was abstracted from 20 427 case reports published across 2538 journals. A total of 7252 (36%) and 4825 (25%) case reports had a female first and last author, respectively. In comparison, 44% and 34% of US trainees and physicians, respectively, were female in 2015. Among adult case reports, female authorship was more prevalent in academic environments compared with community settings (34.0% vs 28.2% for female first authors and 23.4% vs 19.7% for female last authors). Across states, the proportions of female first authors and last authors were universally less than the proportions of female trainees and active female physicians, respectively. Female first authorship was associated with larger author teams (odds ratio [OR], 1.02; 95% CI, 1.01-1.03), an academic affiliation (OR, 1.16; 95% CI, 1.06-1.27), and a female last author (OR, 1.58; 95% CI, 1.47-1.70). Relative to general internal medicine, specialties dominated by male clinicians were less frequently associated with female first authors. Several exceptions displaying a relatively equivalent tendency for male and female first authorship included oncology (OR, 0.97; 95% CI, 0.81-1.16), ophthalmology (OR, 0.87; 95% CI, 0.72-1.05), and radiation oncology (OR, 0.94 95% CI, 0.56-1.56). Conclusions and Relevance: The underrepresentation of women among first and last authors in publications of case reports underscores the pervasiveness of sex disparities in medicine. Collaboration and female mentors may be critical instruments in upsetting longstanding practices associated with sex bias. Not all clinical specialties were associated with lower-than-expected female authorship, and further exploration of specialty-specific norms in publication and mentorship may elucidate specific barriers to female authorship.

Systematic characterization of gastrointestinal clinical trials.

BACKGROUND: Clinical guidelines are commonly based on inadequate evidence, suggesting deficiencies in the present portfolio of clinical research. AIMS: To investigate characteristics of clinical trials examining gastrointestinal (GI) diseases registered in ClinicalTrials.gov. METHODS: A cross-sectional analysis of 13,647 GI trials and 111,535 non-GI trials initiated between January 1997 and September 2013 was performed. Entries were sorted by operational status, purpose, interventions, trial design, and epochs to identify trends and interactions in trial properties. RESULTS: The global production of GI trials has remained static in recent years and a majority of research efforts are focused on a few diseases. While GI trials are generally produced by highly populated US states and countries, they are also seldom larger than 500 patients. The likelihood of using data monitoring committees, randomization, and double blinding in GI trials has increased over time, though a substantial fraction of GI trials still do not employ rigorous trial designs. While levels of GI trials correlate with disease burden, the explained variance of GI trials by disease burden worldwide is poor. CONCLUSION: GI trials are chiefly concentrated in few diseases and highly populated regions, exhibit heterogeneous trends and methodologies, and are sensitive to disease burdens, though more so within North America than worldwide.

Multinational teams and diseconomies of scale in collaborative research.

Collaborative research has become the mainstay in knowledge production across many domains of science and is widely promoted as a means of cultivating research quality, enhanced resource utilization, and high impact. An accurate appraisal of the value of collaborative research efforts is necessary to inform current funding and research policies. We reveal contemporary trends in collaborative research spanning multiple subject fields, with a particular focus on interactions between nations. We also examined citation outcomes of research teams and confirmed the accumulative benefits of having additional authors and unique countries involved. However, when per capita citation rates were analyzed to disambiguate the effects of authors and countries, decreasing returns in citations were noted with increasing authors among large research teams. In contrast, an increasing number of unique countries had a persistent additive citation effect. We also assessed the placement of foreign authors relative to the first author in paper bylines of biomedical research articles, which demonstrated a significant citation advantage of having an international presence in the second-to-last author position, possibly occupied by foreign primary co-investigators. Our analyses highlight the evolution and functional impact of team dynamics in research and suggest empirical strategies to evaluate team science.

The Cooperative Landscape of Multinational Clinical Trials.

The scale and nature of cooperative efforts spanning geopolitical borders in clinical research have not been elucidated to date. In a cross-sectional study of 110,428 interventional trials registered in Clinicaltrials.gov, we characterized the evolution, trial demographics, and network properties of multinational clinical research. We reveal that the relative growth of international collaboratives has remained stagnant in the last two decades, although clinical trials have evolved to become much larger in scale. Multinational clinical trials are also characterized by higher patient enrollments, industry funding, and specific clinical disciplines including oncology and infectious disease. Network analyses demonstrate temporal shifts in collaboration patterns between countries and world regions, with developing nations now collaborating more within themselves, although Europe remains the dominant contributor to multinational clinical trials worldwide. Performances in network centrality measures also highlight the differential contribution of nations in the global research network. A city-level clinical trial network analysis further demonstrates how collaborative ties decline with physical distance. This study clarifies evolving themes and highlights potential growth mechanisms and barriers in multinational clinical trials, which may be useful in evaluating the role of national and local policies in organizing transborder efforts in clinical endeavors.